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Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma:a multicenter cohort study in China

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Cancer Biology & Medicine 2024年第4期21卷 347-362页

作者： Jian Chen Zhe Yang Fengqiang Gao Zhisheng Zhou Junli Chen Di Lu Kai Wang Meihua Sui Zhengxin Wang Wenzhi Guo Guoyue Lyu Haizhi Qi Jinzhen Cai Jiayin Yang Shusen Zheng Xiao Xu Zhejiang University School of Medicine Hangzhou 310030China Institute of Organ transplantation Zhejiang UniversityHangzhou 310030China department of hepatobiliary and pancreatic surgery Shulan Hospital of HangzhouHangzhou 310006China National Center for Healthcare Quality Management in liver Transplant Hangzhou 310003China department of General surgery Huashan HospitalFudan UniversityShanghai 200040China department of hepatobiliary and pancreatic surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China department of hepatobiliary and pancreatic surgery The First Hospital of Jilin UniversityChangchun 130021China department of liver transplantation Second Xiangya HospitalCentral South UniversityChangsha 410008China department of Organ transplantation Center The Affiliated Hospital of Qingdao UniversityQingdao 266003China department of liver surgery and liver transplantation Center West China HospitalSichuan UniversityChengdu 610044China NHC Key Laboratory of Combined Multi-organ transplantation Hangzhou 310003China department of hepatobiliary and pancreatic surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Objective:Sex-specific differences are observed in various liver diseases,but the influence of sex on the outcomes of hepatocellular carcinoma(HCC)after liver transplantation(LT)remains to be *** study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with ***:Data for recipients with HCC registered in the China liver Transplant Registry between January 2015 and December 2020 were *** associations between donor,recipient,or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching(PSM).The survival associated with different sex-based donor-recipient transplant patterns was further ***:Among 3,769 patients enrolled in this study,the 1-,3-,and 5-year overall survival(OS)rates of patients with HCC after LT were 96.1%,86.4%,and 78.5%,respectively,in female recipients,and 95.8%,79.0%,and 70.7%,respectively,in male recipients after PSM(P=0.009).However,the OS was comparable between recipients with female donors and male *** analysis indicated that male recipient sex was a risk factor for post-LT survival(HR=1.381,P=0.046).Among the donor-recipient transplant patterns,the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival(P<0.05).Conclusions:Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients,and the male-male donor-recipient transplant pattern was associated with the poorest post-LT *** from male donors may provide the most benefit to female *** results indicate that sex should be considered as a critical factor in organ allocation.

关键词： Sex liver transplantation hepatocellular carcinoma outcome recipient donor

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Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges

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hepatobiliary & pancreatic Diseases International 2024年第2期23卷 117-122页

作者： Xin Yang Lu Lu Wen-Wei Zhu Yi-Feng Tao Cong-Huan Shen Jin-Hong Chen Zheng-Xin Wang Lun-Xiu Qin hepatobiliary surgery and liver transplantation Centers Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan UniversityShanghai 200040China

Hepatectomy is still the major curative treatment for patients with liver ***,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic *** vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver *** to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver *** efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar ***,the application of ELRA for liver malignances has gained more ***,standardization of clinical practice norms and international consensus are still *** prognostic impact in these oncologic patients also needs further *** this review,we summarized the principles and recent progresses on ELRA.

关键词： Ex vivo liver resection liver auto-transplantation Oncology liver malignancies

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Deep learning-based radiomics allows for a more accurate assessment of sarcopenia as a prognostic factor in hepatocellular carcinoma

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 83-90页

作者： Zhikun LIU Yichao WU Abid Ali KHAN Lun LU Jianguo WANG Jun CHEN Ningyang JIA Shusen ZHENG Xiao XU Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou310006China Zhejiang University School of Medicine Hangzhou310058China department of Radiology Easter Hepatobiliary Surgery HospitalNaval Medical UniversityShanghai200438China department of hepatobiliary and pancreatic surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China NHC Key Laboratory of Combined Multi-organ transplantation Hangzhou310003China department of hepatobiliary and pancreatic surgery Shulan(Hangzhou)HospitalHangzhou310022China

Hepatocellular carcinoma(HCC)is one of the most common malignancies and is a major cause of cancer-related mortalities worldwide(Forner et al.,2018;He et al.,2023).Sarcopenia is a syndrome characterized by an accelerated loss of skeletal muscle(SM)mass that may be age-related or the result of malnutrition in cancer patients(Cruz-Jentoft and Sayer,2019).Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival(Voron et al.,2015;van Vugt et al.,2016).

关键词： cancer patients

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Incidence,Risk Factors,and Prognosis of Patients with Hepatocellular Carcinoma and Brain Metastases

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Current Medical Science 2024年第1期44卷 180-186页

作者： Jin-cheng FENG Ying HE Georgios Polychronidis Jian XIN Shen YOU Jun XIONG department of liver transplantation Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Key Laboratory of Transplant Engineering and Immunology Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China department of General Visceral and Transplant SurgeryUniversity of HeidelbergIm Neuenheimer Feld 110Heidelberg 69120Germany department of hepatobiliary and pancreatic surgery Fujian Provincial HospitalFuzhou 350001China

Objective Brain metastases significantly impact the clinical course of patients with hepatocellular carcinoma(HCC).This study aimed to examine the age-related incidence,demographics,and survival of patients with HCC and brain *** Data of HCC patients from 2010 to 2015 in the Surveillance,Epidemiology,and End Results(SEER)Registry were screened for the presence of brain *** were stratified by age and *** logistic and Cox regression analyses were used to identify factors associated with brain metastases and those with overall survival(OS)and liver cancer-specific survival(CSS),*** A total of 141 HCC patients presenting with brain metastases were identified,accounting for 0.35% of all HCC patients and 2.37% of patients with metastatic *** all HCC patients,the incidence rate was the highest among patients aged 30-49 years old(0.47%).Ethnicity was not associated with the presence of brain metastases at the time of HCC ***,African-American patients presented with a significantly lower disease-specific survival[median time:1 month;interquartile range(IQR):0-3.0 months].Initial lung or bone metastasis was independently associated with an increased risk of the presence of brain metastases[odds ratio(OR):12.62,95% confidence interval(CI):8.40-18.97]but was not associated with a worse OS or CSS among those with brain *** This study identified the age-related incidence and risk factors of brain metastases in HCC *** results may contribute to the consideration of brain screening among patients with initial metastatic HCC with lung or bone metastases,and influence the counseling of this patient population regarding their prognosis.

关键词： brain metastases hepatocellular carcinoma age-related incidence cancer-specific survival overall survival

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M2-type macrophage membrane-mediated delivery of Carvedilol nanocomplex for acute liver failure treatment and remodeling inflammatory microenvironment

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Nano Research 2024年第7期17卷 6362-6375页

作者： Mingge Shang Yaohui Zhang Junjie Qian Wenchao Wang Xizhi Yu Jiacheng Huang Lin Zhou Shusen Zheng Division of hepatobiliary and pancreatic surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China NHC Key Laboratory of Combined Multi-organ transplantation Key Laboratory of Organ TransplantationHangzhou 310003China Key Laboratory of the diagnosis and treatment of organ transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical Sciences(2019RU019)Hangzhou 310003China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesHangzhou 310003China department of Thyroid surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College Hangzhou 310000China

Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure(ALF).Hence,reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting *** group found Carvedilol possessed potential anti-inflammatory property previously,which had been scarcely reported in *** present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4(IL-4)and IL-10 at *** Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform(termed as M2M@CNP)to evade reticuloendothelial system(RES)and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species(ROS),further prolonging its circulation and *** released Carvedilol produced anti-inflammatory,antioxidant and anti-apoptosis effects,combining local M2-type cell membranes(M2-CM)inhibited pro-inflammatory cytokines and ROS levels,which in turn promoted and amplified M1 to M2 phenotype polarization *** study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.

关键词： acute liver failure hepatic drug delivery M2 macrophage-camouflaged nanoplatform inflammatory microenvironment macrophage polarization

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Efficacy and safety of low-dose cyclophosphamide combined with lenvatinib, pembrolizumab and TACE for unresectable hepatocellular carcinoma:A single-center, prospective,single-arm clinical trial

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Chinese Journal of Cancer Research 2024年第2期36卷 114-123页

作者： Yupeng Ren Yuxuan Li Mingbo Cao Yongchang Tang Feng Yuan Gaoyuan Yang Zhiwei He Zheng Shi Xiaorui Su Zhicheng Yao Meihai Deng department of hepatobiliary surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China department of General surgery Qilu HospitalShandong UniversityJinan 250012China department of hepatobiliary surgery the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China department of hepatobiliary and pancreatic surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China

Objective: Unresectable hepatocellular carcinoma(uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization(TACE) for the treatment of ***: From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival(PFS), objective response rate(ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST), while survival analysis was conducted through KaplanMeier curve analysis for overall survival(OS) and PFS. Adverse events(AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events(version 5.0).Results: A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval(95% CI), 5.3-14.6] months, and the median PFS(mPFS) was 15.5(95% CI, 5.4-NA) *** OS(mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate(DCR) was 70.6%. AEs were reported in 27(79.4%) patients. The most frequently reported AEs(with an incidence rate >10%) included abnormal liver function(52.9%), abdominal pain(44.1%), abdominal distension and constipation(29.4%), hypertension(20.6%), leukopenia(17.6%), constipation(17.6%), ascites(14.7%), and insomnia(14.7%). Abnormal liver function(14.7%) had the most common grade 3 or higher ***: A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for u HCC, showcasing a promising therapeutic strategy for managing uHCC.

关键词： Hepatocellular carcinoma lenvatinib low-dose cyclophosphamide pembrolizumab transarterial chemoembolization

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Integrative analysis of the transcriptome and metabolome reveals the importance of hepatokine FGF21 in liver aging

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Genes & Diseases 2024年第5期11卷 407-427页

作者： Wenchao Wang Junjie Qian Mingge Shang Yiting Qiao Jiacheng Huang Xinxin Gao Zhou Ye Xinyu Tong Kangdi Xu Xiang Li Zhengtao Liu Lin Zhou Shusen Zheng Division of hepatobiliary and pancreatic surgery Department of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang 310003China NHC Key Laboratory of Combined Multi-organ transplantation HangzhouZhejiang 310003China Key Laboratory of the Diagnosis and Treatment of Organ transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical Sciences(2019RU019)HangzhouZhejiang 310003China Key Laboratory of Organ transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiang 310003China Shulan International Medical College Zhejiang Shuren UniversityHangzhouZhejiang 310015China Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College HangzhouZhejiang 310000China

Aging is a contributor to liver ***,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly *** our study,the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted *** aged rat liver model was established with D-galactose,and two other senescent hepatocyte models were established by treating HepG2 cells with D-galactose and *** then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte *** livers,genes related to peroxisomes,fatty acid elongation,and fatty acid degradation exhibited down-regulated expression with aging,and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these *** senescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also ***,the expressions of cell cycle-related genes were significantly down-regulated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription *** then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging *** successfully validated the results from cellular and animal experiments using human liver and blood *** study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.

关键词： Antioxidant capability FGF21 liver aging liver regeneration Multiomics analysis

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HepG2.2.15-derived exosomes facilitate the activation and fibrosis of hepatic stellate cells

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World Journal of Gastroenterology 2024年第19期30卷 2553-2563页

作者： Yang Gao Li Li Sheng-Ning Zhang Yuan-Yi Mang Xi-Bing Zhang Shi-Ming Feng department of hepatobiliary pancreatic and Vascular surgery The Affiliated Calmette Hospital of Kunming Medical University and The First Hospital of KunmingKunming 650011Yunnan ProvinceChina

BACKGROUND The role of exosomes derived from HepG2.2.15 cells,which express hepatitis B virus(HBV)-related proteins,in triggering the activation of LX2 liver stellate cells and promoting liver fibrosis and cell proliferation remains *** focus was on comprehending the relationship and influence of differentially expressed microRNAs(DE-miRNAs)within these *** To elucidate the effect of exosomes derived from HepG2.2.15 cells on the activation of hepatic stellate cell(HSC)LX2 and the progression of liver *** Exosomes from HepG2.2.15 cells,which express HBV-related proteins,were isolated from parental HepG2 and WRL68 *** blotting was used to confirm the presence of the exosomal marker protein *** activation of HSCs was assessed using oil red staining,whereas DiI staining facilitated the observation of exosomal uptake by LX2 ***,we evaluated LX2 cell proliferation and fibrosis marker expression using 5-ethynyl-2′-deoxyuracil staining and western blotting,***-miRNAs were analyzed using *** Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways were used to annotate the target genes of *** Exosomes from HepG2.2.15 cells were found to induced activation and enhanced proliferation and fibrosis in LX2 cells.A total of 27 miRNAs were differentially expressed in exosomes from HepG2.2.15 *** analysis indicated that these DE-miRNA target genes were associated with cell differentiation,intracellular signal transduction,negative regulation of apoptosis,extracellular exosomes,and RNA *** pathway analysis highlighted ubiquitin-mediated proteolysis,the MAPK signaling pathway,viral carcinogenesis,and the toll-like receptor signaling pathway,among others,as enriched in these *** These findings suggest that exosomes from HepG2.2.15 cells play a substantial role in the activation,proliferation,and fibrosis of LX2 cells and that DE-miRNAs within these exos

关键词： Hepatic stellate cells liver fibrosis Exosomes small RNA sequencing HepG2.2.15

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SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation

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Cancer Communications 2024年第3期44卷 384-407页

作者： Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie Shusen Zheng Penghong Song Division of hepatobiliary and pancreatic surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China National Health Commission Key Laboratory of Combined Multi-organ transplantation HangzhouZhejiangP.R.China Key Laboratory of the Diagnosis and Treatment of Organ transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical SciencesHangzhouZhejiangP.R.China Key Laboratory of Organ transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiangP.R.China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China

Background:liver cancer is a malignancy with high morbidity and mortality *** family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many *** this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer ***:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver *** from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of *** methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and *** sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer ***-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using ***:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA ***2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver ***2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and ***/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with ***,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,***,EGFR was activated in liver cancer cells after sorafenib treatment,and SER

关键词： liver cancer metastasis DNA methylation SERPINE2 EGFR c-Cbl ubiquitination

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HSP110 aggravates ischemia-reperfusion injury after liver transplantation by promoting NF-κB pathway

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hepatobiliary & pancreatic Diseases International 2024年第4期23卷 344-352页

作者： Qing-Zhi Hu Zhen-Rui Cao Wei-Xiong Zheng Min-Jie Zhao Jun-Hua Gong Cong Chen Zhong-Jun Wu Rui Tao department of hepatobiliary surgery Bishan Hospital of Chongqing Medical UniversityChongqing 402760China department of Cardiothoracic surgery the First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China c department of hepatobiliary surgery the First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China department of hepatobiliary surgery the Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400010China

Background:Ischemia-reperfusion injury(IRI)poses a significant challenge to liver transplantation(LT).The underlying mechanism primarily involves overactivation of the immune *** shock protein 110(HSP110)functions as a molecular chaperone that helps stabilize protein ***:An IRI model was established by performing LT on Sprague-Dawley rats,and HSP110 was silenced using ***-eosin staining,TUNEL,immunohistochemistry,ELISA and liver enzyme analysis were performed to assess IRI following *** blotting and quantitative reverse transcription-polymerase chain reaction were conducted to investigate the pertinent molecular ***:Our findings revealed a significant increase in the expression of HSP110 at both the mRNA and protein levels in the rat liver following LT(Pliver enzymes and inflammatory chemokines in rat serum were significantly reduced(Pliver and downregulated the NF-κB pathway in the liver(Pliver promotes IRI after LT in rats by activating the NF-κB pathway and inducing M1-type polarization of Kupffer *** HSP110 to prevent IRI after LT may represent a promising new approach for the treatment of LT-associated IRI.

关键词： Ischemia-reperfusion injury liver transplantation Inflammation HSP110 Heat shock proteins NF-κB

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