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Targeting angiogenesis for liver cancer: Past, present, and future

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Genes & Diseases 2020年第3期7卷 328-335页

作者： Xiao-Dong Zhu Zhao-You Tang hui-chuan sun Department of Liver Surgery and Transplantation Liver Cancer Institute and Zhongshan HospitalFudan UniversityShanghai200032China

Liver cancer,mostly hepatocellular carcinoma(HCC),is the second leading cause of cancer mortality *** patients were diagnosed at an advanced stage,and systemic therapy is the standard of *** the approved systemic therapies for HCC are molecular targeted therapies with anti-angiogenic effects targeting the vascular endothelial growth factor signaling *** and lenvatinib are the first-line treatment,and regorafenib,ramucirumab,and cabozantinib are second-line treatment *** anti-PD-1 antibodies,including nivolumab and pembrolizumab,demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials,both failed in phase III ***-angiogenic treatment remains the backbone of systemic therapy for *** this review,we summarized the approved anti-angiogenic medicines and discussed the potential strategies to improve the efficacy of anti-angiogenic therapy,including combination therapy with other treatments,and discussed the approaches to overcome the drawbacks of anti-angiogenic therapies.

关键词： Anti-angiogenic therapy Combinational therapy Hepatocellular carcinoma Molecular targeted therapy Systemic therapy

Effect of octreotide on angiogenesis induced by hepatocellular carcinoma in vivo

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Hepatobiliary & Pancreatic Diseases International 2003年第3期2卷 404-409页

作者： Wei-Dong Jia Ge-Liang Xu hui-chuan sun Lu Wang Rong-Nang Xu Qiong Xue Department of General Surgery Anhui Provincial Hospital Hefei 230001 China. jwd@***

OBJECTIVE: To investigate the effect of somatostatin analogue octreotide on angiogenesis induced byhepatocellular carcinoma (HCC) in ***: LCI-D20 corneal micropocket model in nude mouse was used to dynamically observeangiogenesis under a stereoscopic zoom microscope and a digital camera system and to evaluate the effectof octreotide on angiogenesis. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissuesfor tumor xenograft studies. Microvessel density in CD34-stained tumor sections was analyzed byimmunohistochemical SP ***: Tumor tissues from LCI-D20 implanted into the corneal micropocket induced *** animals received systemic octreotide treatment, angiogenesis response in the cornea of mice wasmoderate, the appearance of vascular buds was delayed, and the new capillaries were sparse and grewslowly. Compared with the control group, the neovascularization induced by HCC in the cornea of micewas markedly inhibited on day 7, 9, 12, 15, 18 and 21 after implantation in the octreotide-treated group(P<0.05). Systemic administration of octreotide produced a significant suppression of the growth ofLCI-D20. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in theoctreotide-treated animals as compared with the controls (21.7±4.27 versus 31.8±3.87, P<0. 01).CONCLUSION: Somatostatin analogue octreotide is able to inhibit angiogenesis induced by HCC invivo and may provide a new approach to the treatment of HCC.

关键词： liver neoplasms neovascularization angiogenesis octreotide

Development and Validation of a Nomogram Based on Perioperative Factors to Predict Post-hepatectomy Liver Failure

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Journal of Clinical and Translational Hepatology 2021年第3期9卷 291-300页

作者： Bin Xu Xiao-Long Li Feng Ye Xiao-Dong Zhu Ying-Hao Shen Cheng Huang Jian Zhou Jia Fan Yong-Jun Chen hui-chuan sun Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education ShanghaiChina Department of Hepatobiliary Surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

(PHLF)is a severe complication and main cause of death in patients undergoing *** aim of this study was to build a predictive model of PHLF in patients undergoing ***:We retrospectively analyzed patients undergoing hepatectomy at Zhongshan Hospital,Fudan University from July 2015 to June 2018,and randomly divided them into development and internal validation *** validation was performed in an independent *** absolute shrinkage and selection operator(commonly referred to as LASSO)logistic regression was applied to identify predictors of PHLF,and multivariate binary logistic regression analysis was performed to establish the predictive model,which was visualized with a ***:A total of 492 eligible patients were *** and multivariate analysis identified three preoperative variables,total bilirubin(p=0.001),international normalized ratio(p<0.001)and platelet count(p=0.004),and two intraoperative variables,extent of resection(p=0.002)and blood loss(p=0.004),as independent predictors of *** area under receiver operating characteristic curve(referred to as AUROC)of the predictive model was 0.838 and outperformed the model for end-stage liver disease score,albumin-bilirubin score and platelet-albumin-bilirubin score(AUROCs:0.723,0.695 and 0.663,respectively;p<0.001 for all).The optimal cut-off value of the predictive model was *** validation showed the model could predict PHLF accurately and distinguish high-risk ***:PHLF can be accurately predicted by this model in patients undergoing hepatectomy,which may significantly contribute to the postoperative care of these patients.

关键词： Hepatectomy Post-hepatectomy liver failure LASSO Nomogram

Modulation of gene expression in MHCC97 cells by interferon alpha

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World Journal of Gastroenterology 2005年第42期11卷 6613-6619页

作者： Wei-Zhong Wu hui-chuan sun Lu Wang Jie Chen Kang-Da Liu Zhao-YouTang Liver Cancer Institute and ZhongshanHospital Fudan University 136 Yi Xue Yuan Road Shanghai200032 China

AIM： To elucidate the molecular mechanisms of the inhibitory effects of IFN-α on tumor growth and metastasis in MHCC97 xenografts. METHODS： Three thousand milliliter of IFN-α-treated and international units per -untreated MHCC97 cells were enrolled for gene expression analysis using cDNA microarray. The mRNA levels of several differentially expressed genes in cDNA microarray were further identified by Northern blot and RT-PCR. RESULTS- A total of 190 differentially expressed genes including 151 IFN-α-repressed and 39 -stimulated genes or expressed sequence tags from 8 464 known human genes were found to be regulated by IFN-α in MHCC97. With a few exceptions, mRNA levels of the selected genes in RT-PCR and Northern blot were in good agreement with those in cDNA microarray. CONCLUSION： IFN-α might exert its complicated anti- tumor effects on MHCC97 xenografts by regulating the expression of functional genes involved in cell metabolism, proliferation, morphogenesis, angiogenesis, and signaling.

关键词： Interferon α cDNA microarray Geneexpression profile HCC

Peripheral naïve CD8^(+)T cells as a predictive biomarker of response to lenvatinib plus an anti-PD-1 antibody in advanced hepatocellular carcinoma:a biomarker study

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Cancer Communications 2022年第11期42卷 1226-1230页

作者： Cheng Huang Bin Xu Xiao-Dong Zhu Ying-Hao Shen Mei-Ling Li Jin-Jin Zhu Jian Zhou Jia Fan hui-chuan sun Department of Liver Surgery and Transplantation Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationLiver Cancer Institute and Zhongshan HospitalFudan UniversityShanghai 200032P.R.China

Dear Editor,Most patients with hepatocellular carcinoma(HCC)are diagnosed at an advanced stage and are ineligible for rad-ical surgery[1].As anti-programmed cell death protein 1(PD-1)monotherapy has not shown promising anti-tumor effects in advanced HCC in first-line settings,combination therapy with targeted therapy plus immunotherapy,such as atezolizumab plus bevacizumab,has become the new first-line treatment for advanced ***,lenva-tinib combined with an anti–PD-1 antibody has shown an objective response rate(ORR)of around 40%in a phase I trial in advanced HCC[2].

关键词： hepatocellular therapy surgery

Preventive treatments for recurrence after curative resection of hepatocellular carcinoma-A literature review of randomized control trials

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World Journal of Gastroenterology 2003年第4期9卷 635-640页

作者： hui-chuan sun Zhao-You Tang Liver Cancer Institute and Zhong Shan Hospital,Fudan University,Shanghai 200032,China Associate Professor of Surgery Liver Cancer Institute and Zhong Shan Hospital Fudan University 136 Yi Xue Yuan Road Shanghai 200032 China. sunhc@***

To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications. reporting randomized control trial indexed in PubMed. The treatment approaches presented above included preoperative transcatheter arterial chemoembolization (TACE),post-operative TACE, systemic or locoregional chemotherapy,immunotherapy, Interferons and acyclic retinoic acid Although no standard treatment has been established,several approaches presented promising results, which were both effective and tolerable in post-operative patients. Preoperative TACE was not effective on prolonging survivals,while post-operative TACE was shown with both diseasefree survival and overall survival benefits in some papers,however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant *** immunotherapy using LAK cells was proved to be beneficial to patients' survival in a recent paper. Interferon and Interferon β can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multi-centric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities;in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation.

关键词：预防性治疗肝细胞癌肿瘤切除术复发随机对照研究肝动脉化疗栓塞术

Do the existing staging systems for primary liver cancer apply to combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma?

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Hepatobiliary & Pancreatic Diseases International 2021年第1期20卷 13-20页

作者： Qiang Zhou Hao Cai Ming-Hao Xu Yao Ye Xiao-Long Li Guo-Ming Shi a Cheng Huang Xiao-Dong Zhu Jia-Bin Cai Jian Zhou Jia Fan Yuan Ji hui-chuan sun Ying-Hao Shen Department of Liver Surgery Liver Cancer InstituteZhongshan Hospitaland Key Laboratory of Carcinogenesis and Cancer Invasion(Ministry of Education)Fudan UniversityShanghai 200032China Department of Pathology Zhongshan HospitalFudan UniversityShanghai 200032China

Background:The incidence of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma(cHCC-ICC)is relatively low,and the knowledge about the prognosis of cHCC-ICC remains *** the study,we aimed to screen existing primary liver cancer staging systems and shed light on the prognosis and risk factors for ***:We retrospectively reviewed 206 cHCC-ICC patients who received curative surgical resection from April 1999 to March *** correlation of survival measures with the histological types or with tumor staging systems was determined and predictive values of tumor staging systems with cHCC-ICC prognosis were ***:The histological type was not associated with overall survival(OS)(P=0.338)or disease-free survival(DFS)(P=0.843)of patients after curative surgical ***,TNM for HCC,and TNM for ICC stages correlated with both OS and DFS in cHCC-ICC(all P<0.05).The predictive values of TNM for HCC and TNM for ICC stages were similar in terms of predicting postoperative OS(P=0.798)and DFS(P=0.191)in *** for HCC was superior to BCLC for predicting postoperative OS(P=0.022)in ***:The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-ICC prognosis.

关键词： Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Histological type Tumor staging system Prognosis Risk stratification

Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma:a single-center,single-arm,phase 2 study

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1983-1992页

作者： Guo-Ming Shi Xiao-Yong Huang Dong Wu hui-chuan sun Fei Liang Yuan Ji Yi Chen Guo-Huan Yang Jia-Cheng Lu Xian-Long Meng Xin-Ying Wang Lei sun Ning-Ling Ge Xiao-Wu Huang Shuang-Jian Qiu Xin-Rong Yang Qiang Gao Yi-Feng He Yang Xu Jian sun Zheng-Gang Ren Jia Fan Jian Zhou Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina Department of Radiology Zhongshan HospitalFudan UniversityShanghaiChina Department of Statistics Zhongshan HospitalFudan UniversityShanghaiChina Department of Pathology Zhongshan HospitalFudan UniversityShanghaiChina Department of Hepatic Oncology Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina Tianjin Medical Laboratory BGI-TianjinBGI ShenzhenTianjinChina

Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal ***,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced *** patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one *** expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)*** primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete ***(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant *** median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,*** DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825).

关键词： regimen intrahepatic treatment

Risk factors for postoperative complications after liver resection

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Hepatobiliary & Pancreatic Diseases International 2005年第3期4卷 370-374页

作者： hui-chuan sun, Lun-Xiu Qin, Lu Wang, Qin-Hai Ye, Zhi-Quan Wu, Jia Fan and Zhao-You Tang Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China Liver Cancer Institute and Zhongshan Hospital Fudan University Shanghai 200032 China. sunhc@***

Liver resection is still a complicated operation with a high risk of postoperative morbidity. This study was undertaken to analyze the risk factors for postoperative complications after liver resection. METHODS:From 2001 to 2004, a total of 146 patients underwent liver resection for malignant or benign lesions. Postoperative complications after the resection were classified as surgical and medical, their incidences were analyzed *** risk factors for both surgical and medical complications were analyzed. To increase the safety of liver resection, surgical techniques were modified after April 2003, including control of inflow or outflow and intra- operative test with methylene blue. RESULTS:Before April 2003, a series of 58 patients received liver resection. Modified surgical techniques were used in liver resections for 88 patients after April 2003.A total of 36 patients (24.7%) had postoperative complications. Surgical and medical complications occurred in 24 and 13 patients respectively (One patient had both surgical and medical complications). Perioperative blood transfusion was related to a higher risk of surgical complications (P<0.05). Patients with diabetes mellitus were associated with a higher risk of medical complications (P<0.05). Surgical complications and postoperative hospitalization were decreased after the use of modified surgical techniques (P<0.05). CONCLUSION:Postoperative surgical complications can be decreased by modified surgical techniques, and careful selection of patients for liver resection may help to decrease postoperative medical complications also.

关键词： hepatocellular carcinoma resection complications