劈离式供肝儿童肝移植门静脉并发症的诊断与治疗

目的探讨劈离式供肝儿童肝移植门静脉并发症的诊断及治疗策略。方法回顾性分析接受劈离式肝移植的88例儿童受者的临床资料。术中根据受者门静脉内径、发育情况,利用门静脉左右分支处进行吻合或间置供者髂静脉搭桥吻合,围手术期采用规范化的门静脉血流监测,术后按肝素钠桥接华法林的方案进行抗凝治疗。经增强CT或门静脉造影确诊门静脉狭窄或血栓形成后,予切开取栓、全身抗凝、介入下取栓、球囊扩张和(或)支架置入等处理。结果88例受者中共10例患儿确诊门静脉并发症,其中4例门静脉狭窄,确诊时间分别为术后1 d、2个月、8个月、11个月,6例门静脉血栓形成,确诊时间分别为术中、术后2 d、术后3 d(2例)、术后6 d、术后11个月。1例门静脉狭窄者和1例门静脉血栓形成者于围手术期死亡,门静脉并发症相关病死率为2%(2/88)。其余8例患者中,1例行全身抗凝治疗、2例行门静脉切开取栓术、1例行介入下球囊扩张、4例行介入下球囊扩张及支架置入,术后均长期随访,未再出现门静脉相关症状,复查门静脉血流参数正常。结论规范化的术中及术后门静脉血流监测有助于早期发现门静脉并发症,及时采取术中门静脉切开取栓,术后介入下球囊扩张、支架置入等手段可有效治疗门静脉并发症,减少门静脉并发症导致的移植物丢失和受者死亡。

Clinical analysis of Wernicke encephalopathy after liver transplantation

Background:Wernicke encephalopathy(WE)is an acute neurological disease resulting from vitamin B1 deficiency,and there are only very few case reports of WE after liver transplantation.The present study aimed to investigate the clinical characteristics,etiology,magnetic resonance imaging(MRI)features,treatment and prognosis of patients with WE after liver transplantation.Methods:Twenty-three patients with WE after liver transplantation from the First Affiliated Hospital,Zhejiang University School of Medicine and Jiangxi Provincial People’s Hospital between January 2011 and December 2021 were retrospectively analyzed.Results:Among the 23 patients diagnosed with WE after liver transplantation,6(26%)had a classic triad of impaired consciousness,oculomotor palsy and ataxia,and 17(74%)had two features.The misdiagno-sis rate was 65%.After treatment with high-dose vitamin B1,19(83%)patients showed improvement,whereas 4(17%)showed no improvement,including 3 with residual short-term memory impairments and 1 with residual spatial and temporal disorientation and ataxia.Conclusions:The misdiagnosis rate is high in the early stage of WE,and the prognosis is closely asso-ciated with whether WE is diagnosed early and treated timely.High-dose glucose or glucocorticoids can trigger WE and cannot be administered before vitamin B1 treatment.Vitamin B1 is suggested to be used as a prophylactic treatment for patients with WE after liver transplantation.

Different techniques for harvesting grafts for living donor liver transplantation: A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis on minimally vs conventional invasive techniques for harvesting grafts for living donor liver transplantation. METHODS PubMed, Web of Science, EMBASE, and the Cochrane Library were searched comprehensively for studies comparing MILDH with conventional living donor hepatectomy (CLDH). Intraoperative and postoperative outcomes (operative time, estimated blood loss, postoperative liver function, length of hospital stay, analgesia use, complications, and survival rate) were analyzed in donors and recipients. Articles were included if they: (1) compared the outcomes of MILDH and CLDH; and (2) reported at least some of the above outcomes. RESULTS Of 937 articles identified, 13, containing 1592 patients, met our inclusion criteria and were included in the meta-analysis. For donors, operative time [weighted mean difference (WMD) = 20.68, 95% CI: -6.25-47.60, p = 0.13] and blood loss (WMD = -32.61, 95% CI: -80.44-5.21, p = 0.18) were comparable in the two groups. In contrast, analgesia use (WMD = -7.79, 95% CI: -14.06-1.87, p = 0.01), postoperative complications [odds ratio (OR) = 0.62, 95% CI: 0.44-0.89, p = 0.009], and length of hospital stay (WMD): -1.25, 95% CI: -2.35-0.14, p = 0.03) significantly favored MILDH. No differences were observed in recipient outcomes, including postoperative complications (OR = 0.93, 95% CI: 0.66-1.31, p = 0.68) and survival rate (hr = 0.96, 95% CI: 0.27-3.47, p = 0.95). Funnel plot and statistical methods showed a low probability of publication bias. CONCLUSION MILDH is safe, effective, and feasible for living donor liver resection with fewer donor postoperative complications, reduced length of hospital stay and analgesia requirement than CLDH.

Cutting balloon treatment of anastomotic biliary stenosis after liver transplantation: Report of two cases

Biliary stenosis is a common complication after liver transplantation,and has an incidence rate ranging from4.7%to 12.5%based on our previous study.Three types of biliary stenosis(anastomotic stenosis,nonanastomotic peripheral stenosis and non-anastomotic central hilar stenosis)have been identified.We report the outcome of two patients with anastomotic stricture after liver transplantation who underwent successfulcutting balloon treatment.Case 1 was a 40-year-old male transplanted due to subacute fulminant hepatitis C.Case 2 was a 57-year-old male transplanted due to hepatitis B virus-related end-stage cirrhosis associated with hepatocellular carcinoma.Both patients had similar clinical scenarios:refractory anastomotic stenosis after orthotopic liver transplantation and failure of balloon dilation of the common bile duct to alleviate biliary stricture.

Surgical resection versus liver transplantation for hepatocellular carcinoma within the Hangzhou criteria: a preoperative nomogram-guided treatment strategy

BACKGROUND: With the expansion of surgical criteria, the comparative efficacy between surgical resection (SR) and liver transplantation (LT) for hepatocellular carcinoma is inconclusive. This study aimed to develop a prognostic nomogram for predicting recurrence-free survival of hepatocellular carcinoma patients after resection and explored the possibility of using nomogram as treatment algorithm reference. METHODS: From 2003 to 2012, 310 hepatocellular carcinoma patients within Hangzhou criteria undergoing resection or liver transplantation were included. Total tumor volume, albumin level, HBV DNA copies and portal hypertension were included for constructing the nomogram. The resection patients were stratified into low- and high-risk groups by the median nomogram score of 116. Independent risk factors were identified and a visually orientated nomogram was constructed using a Cox proportional hazards model to predict the recurrence risk for SR patients. RESULTS: The low-risk SR group had better outcomes compared with the high-risk SR group (3-year recurrence-free survival rate, 71.1% vs 35.9%; 3-year overall survival rate, 89.8% vs 78.9%, both P<0.001). The high-risk SR group was associated with a worse recurrence-free survival rate but similar overall survival rate compared with the transplantation group (3-year recurrence-free survival rate, 35.9% vs 74.1%, P<0.001; 3-year overall survival rate, 78.9% vs 79.6%, P>0.05). CONCLUSIONS: This nomogram offers individualized recurrence risk evaluation for hepatocellular carcinoma patients within Hangzhou criteria receiving resection. Transplantation should be considered the first-line treatment for high risk patients.

Development and validation of a nomogram based on perioperative risk factors for the prediction of early thrombotic complications following pediatric liver transplantation

To the Editor:Despite dramatic improvements in the prognosis of pediatric liver transplantation(LT),postoperative complications are still a leading cause of death in grafts and patients.Child recipients were shown to have a higher risk of thrombotic complications than in adult recipients,due to differences in etiology,narrowed hepatic vessels due to hypoplasia,more meticulous surgical techniques,and other factors.[1]Thrombotic complications include hepatic artery thrombosis(HAT).

标准化护理操作规程管理在提升肾移植术后护理质量及患者满意度中的作用

目的探讨标准化护理操作规程管理在提升肾移植术后护理质量及患者满意度的作用。方法通过实施标准化护理操作规程,对实施前后肾移植科发生的护理工作缺陷率、护理质量以及患者满意度进行统计分析。结果实施标准化护理操作规程后,护理工作缺陷率为4.88%,远低于实施前(24.39%);护理质量的5个方面评分均高于实施前,P<0.05;患者满意度在4个方面的得分均高于实施前,差异具有统计学意义。结论实施标准化护理操作规程,可以提高肾移植科的护理质量,提升患者的满意度,减少甚至避免护理不良事件的发生。

人工智能在肝移植中的应用

随着5G和大数据时代的来临,多维度、大样本的复杂医疗数据为新时代临床医学带来众多机遇和挑战。与传统方法相比,人工智能可以更高效地挖掘庞大数据集中的隐藏联系,越来越多的学者将这一先进技术应用于疾病的诊断和治疗。经过半个多世纪的发展和完善,肝移植已成为治疗各种终末期肝病最有效的方法。与其他领域的“单患者”数据分析不同,肝移植通常需要考虑供体和受体“双患者”的特征以及移植过程中的变量,产生较其他疾病更为庞大的医疗数据,这与人工智能的优势尤为契合。有效利用人工智能的手段、结合临床研究开展将为智能精准临床医学时代拉开新的序幕。对于人工智能在肝移植的交叉应用,需要全面讨论人工智能技术在肝移植中的优势和局限性,并提出该领域的未来方向。

Laparoscopic VS open hepatectomy for hepatolithiasis: An updated systematic review and meta-analysis

AIM To perform a meta-analysis on laparoscopic hepatectomy VS conventional liver resection for treating hepatolithiasis.METHODS We conducted a systematic literature search on Pub Med,Embase,Web of Science and Cochrane Library,and undertook a meta-analysis to compare the efficacy and safety of laparoscopic hepatectomy V S conventional open liver resection for local hepatolithiasis in the left or right lobe. Intraoperative and postoperative outcomes(time,estimated blood loss,blood transfusion rate,postoperative intestinal function recovery time,length of hospital stay,postoperative complication rate,initial residual stone,final residual stone and stone recurrence) were analyzed systematically.RESULTS A comprehensive literature search retrieved 16 publications with a total of 1329 cases. Meta-analysis of these studies showed that the laparoscopic approach for hepatolithiasis was associated with significantly less intraoperative estimated blood loss [weighted mean difference(WMD): 61.56,95% confidence interval(CI): 14.91-108.20,P = 0.01],lower blood transfusion rate [odds ratio(OR): 0.41,95%CI: 0.22-0.79,P = 0.008],shorter intestinal function recovery time(WMD: 0.98,95%CI: 0.47-1.48,P = 0.01),lower total postoperative complication rate(OR: 0.52,95%CI: 0.39-0.70,P < 0.0001) and shorter stay in hospital(WMD: 3.32,95%CI: 2.32-4.32,P < 0.00001). In addition,our results showed no significant differences between the two groups in operative time(WMD: 21.49,95%CI: 0.27-43.24,P = 0.05),residual stones(OR: 0.79,95%CI: 0.50-1.25,P = 0.31) and stone recurrence(OR: 0.34,95%CI: 0.11-1.08,P = 0.07). Furthermore,with subgroups analysis,our results proved that the laparoscopic approach for hepatolithiasis in the left lateral lobe and left side could achieve satisfactory therapeutic effects. CONCLUSION The laparoscopic approach is safe and effective,with less intraoperative estimated blood loss,fewer postoperative complications,reduced length of hospital stay and shorter intestinal function recovery time than with conventional approaches.

15-PGDH表达水平与肝癌肝移植临床预后关系研究

目的探讨15-羟基前列腺素脱氢酶(15-PGDH)表达水平与肝细胞癌(肝癌)肝移植临床预后的关系。方法回顾性分析行肝癌肝移植术的94例受者临床资料。用免疫组织化学法检测所有受者病理组织切片中15-PGDH表达情况;分析15-PGDH蛋白表达水平与肝癌患者各项临床参数的关系;计算肝癌肝移植受者术后5年的无瘤生存率和总生存率;分析可能影响肝癌肝移植受者预后的独立危险因素。结果15-PGDH的表达水平与受者的年龄、Child-Pugh分级和术前甲胎蛋白(AFP)水平相关(均为P<0.05)。15-PGDH低表达组受者的无瘤生存率和总生存率均显著低于15-PGDH高表达组受者(均为P<0.05)。15-PGDH表达水平、肿瘤分化程度、美国癌症联合会(AJCC)分期是影响肝癌肝移植受者预后的独立危险因素(均为P<0.05)。结论15-PGDH表达水平是影响肝癌肝移植受者预后的独立危险因素。

Rapamycin combined with allogenic immature dendritic cells selectively expands CD4^+CD25^+Foxp3^+ regulatory T cells in rats

ReferencesReferencesBackgroundDendritic cells (DCs) can initiate the expansion of regulatory T cells (Tregs), which play an indispensable role in inducing transplantation tolerance. Some studies have investigated the effect of the immunosuppressant rapamycin (Rapa) on Tregs in vitro. However, the in vivo effect of Rapa combined with immature DCs (iDCs) on Tregs is unknown. This study was undertaken to determine whether allogenic iDCs combined with a short course of Rapa have the ability to selectively expand the CD4+CD25+Foxp3+ Tregs in a rat model.MethodsBrown Norway rats were injected intravenously with 2×106 Lewis iDCs followed by 1 mg/kg per day Rapa intraperitoneally for 7 consecutive days. On day 8, the levels of CD4+CD25+Foxp3+ Treg cells in peripheral blood and spleen cells were analyzed by flow cytometry. IL-2, IL-4, TGF-β1, and IFN-γ levels in serum were assessed by ELISA. The experimental animals were divided into four groups: control, Rapa-treated, iDC-treated, and combination-treated.ResultsCD4+CD25+Foxp3+ Tregs comprised 7%-8%of CD4+ T cells in control rats. Rapa combined with iDCs enhanced this percentage in the peripheral blood and spleen. However, the levels of Tregs did not significantly change after treatment with Rapa or iDCs alone. The levels of CD4+CD25?/sup>Foxp3+ T cells and CD4+ CD25+Foxp3?/sup> T cells in CD4+ T cells did not significantly change in the combined group. The TGF-β1 level in serum from the combined group increased significantly compared with the other groups.ConclusionsA significantly higher percentage of CD4+ CD25+ Foxp3+ Tregs was found in rats treated with allogenic iDCs and a short course of Rapa, along with an increase in the TGF-β1 level in serum. This improved protocol may be a promising therapeutic strategy to increase Tregs, which are beneficial to the induction of peritransplant tolerance.

Hepatitis B and C virus-induced hepatitis: Apoptosis, autophagy, and unfolded protein response

AIM: To investigate the co-incidence of apoptosis, autophagy, and unfolded protein response(UPR) in hepatitis B(HBV) and C(HCV) infected hepatocytes.METHODS: We performed immunofluorescence confocal microscopy on 10 liver biopsies from HBV and HCV patients and tissue microarrays of HBV positive liver samples. We used specific antibodies for LC3β, cleaved caspase-3, BIP(GRP78), and XBP1 to detect autophagy, apoptosis and UPR, respectively. AntiHCV NS3 and anti-HBs antibodies were also used to confirm infection. We performed triple blind counting of events to determine the co-incidence of autophagy(LC3β punctuate), apoptosis(cleaved caspase-3), and unfolded protein response(GRP78) with HBV and HCV infection in hepatocytes. All statistical analyses were performed using SPSS software for Windows(Version 16 SPSS Inc, Chicago, IL, United States). P-values < 0.05 were considered statistically significant. Statistical analyses were performed with Mann-Whitney test to compare incidence rates for autophagy, apoptosis, and UPR in HBV- and HCV-infected cells and adjacent noninfected cells.RESULTS: Our results showed that infection of hepatocytes with either HBV and HCV induces significant increase(P < 0.001) in apoptosis(cleavage of caspase-3), autophagy(LC3β punctate), and UPR(increase in GRP78 expression) in the HCV- and HBVinfected cells, as compared to non-infected cells of the same biopsy sections. Our tissue microarray immunohistochemical expression analysis of LC3β in HBV^(Neg) and HBV^(Pos) revealed that majority of HBVinfected hepatocytes display strong positive stainingfor LC3β. Interestingly, although XBP splicing in HBVinfected cells was significantly higher(P < 0.05), our analyses show a slight increase of XBP splicing was in HCV-infected cells(P > 0.05). Furthermore, our evaluation of patients with HBV and HCV infection based on stage and grade of the liver diseases revealed no correlation between these pathological findings and induction of apoptosis, autophagy, and UPR.CONCLUSION: The results of this study indicate that HCV and HBV infection activates apoptosis, autophagy and UPR, but slightly differently by each virus. Further studies are warranted to elucidate the interconnections between these pathways in relation to pathology of HCV and HBV in the liver tissue.

Hepatitis B virus genotypes in southwest Iran: Molecular, serological and clinical outcomes

AIM: To investigate the associations of hepatitis B virus (HBV) genotype with HBeAg and anti-HBe status, alanine aminotransferase (ALT) levels and HBV-DNA detection in different groups of HBV-infected patients in southwest Iran. METHODS: A total of 89 HBsAg-positive serum samples were collected from the same number of patients. All sera were then investigated to determine HBV DNA and serological markers. For all the polymerase chain reaction (PCR)-positive samples, biochemical, histopathological assays and genotyping were also performed. RESULTS: Genotype D was the only type of HBV foundin different clinical forms of acute and chronic infections. There was a high prevalence of HBeAg-negative HBV- infected patients with chronic hepatitis (52.7%). Out of 55 patients with chronic hepatitis, seven (12.7%) were diagnosed with cirrhosis. A significant association between the presence of anti-HBe antibody and an increase in ALT level, among either HBeAg-negative (P = 0.01) or HBeAg-positive (P = 0.026) patients, was demonstrated. No significant differences were observed between the clinical outcomes of HBeAg-positive and -negative individuals (P = 0.24). CONCLUSION: Genotype D has been recognized as the only type of HBV found in different clinical forms of HBV infections, including cirrhosis, among the residents of southwest Iran. Anti-HBe possibly plays a role in disease progression in some patients with chronic hepatitis, at least for a period of disease.

MiR-516a-3p is a Novel Mediator of Hepatocellular Carcinoma Oncogenic Activity and Cellular Metabolism

Hepatocellular carcinoma(HCC)remains one of the most lethal malignancies.We previously demonstrated that the chromosome 19 microRNA cluster(C19MC)was associated with tumor burden and prognosis in patients with HCC.In the current study,we aim to explore the role of miR-516a-3p-an identical mature microRNA(miRNA)co-spliced by four oncogenic pre-miRNAs of C19MC(i.e.,mir-516a-1,mir-516a-2,mir-516b-1,and mir-516b-2)-in HCC.In our cohort of HCC patients,miR-516a-3p was highly expressed in HCC tissues in comparison with adjacent non-tumor tissues.High expression of tumor miR-516a-3p significantly correlated with advanced tumor stages,distinguished high HCC recurrence and mortality,and independently predicted poor prognosis.We further found that miR-516a-3p enhanced the proliferation,migration,and invasiveness of HCC cells in vitro and promoted tumor growth and metastasis in vivo.Among cancer cells,miR-516a-3p could be delivered via exosomes or extracellular vesicles and increased the oncogenic activity of recipient cells.Moreover,we performed comprehensive transcriptomics,proteomics,and metabolomics analysis on the potential mechanism underlying miR-516a-3p-promoted oncogenicity.MixOmic DIABLO analysis showed a close correlation and strong cluster consistency between the proteomics and metabolomics datasets.We further confirmed six proteins(i.e.,LMBR1,CHST9,RBM3,SLC7A6,PTGFRN,and NOL12)as the direct targets of miR-516a-3p and as central players in miR-516a-3p-mediated metabolism regulation.The integrated multi-omics and co-enriched pathway analysis showed that miR-516a-3p regulates the metabolic pathways of HCC cells,particularly purine and pyrimidine metabolism.In conclusion,our findings suggest that miR-516a-3p promotes malignant behaviors in HCC cells by regulating cellular metabolism and affecting neighboring cells via the exosome delivery system.Thus,we suggest miR-516a-3p as a novel molecular target for HCC therapy.

劈离式肝移植203例临床应用

目的:探讨劈离式肝移植(SLT)临床应用的安全性与疗效。方法:本研究为回顾性病例系列研究。回顾性分析2014年7月至2023年7月中山大学附属第三医院肝脏外科暨肝移植中心连续完成的203例SLT、79例活体肝移植(LDLT)及1298例全肝移植(WLT)供者和受者的临床资料。203例SLT供者中,公民去世后捐献109名,离体劈离产生127个移植物,在体劈离产生76个移植物;成人受者90例,儿童受者113例。根据时间先后将SLT患者分为两组:SLT开展早期组40例(2014年7月至2017年12月),SLT技术成熟期组163例(2018年1月至2023年7月)。分析各组生存情况及影响SLT患者生存率的主要原因。生存分析采用Kaplan-Meier法和Log-rank检验。结果:SLT开展早期组受者术后1、3、5年累积生存率分别为74.58%、71.47%、71.47%,SLT技术成熟期组分别为88.03%、87.23%、87.23%,两组差异有统计学意义(χ^(2)=5.560,P=0.018)。LDLT组术后1、3、5年累积生存率分别为93.41%、93.41%、89.95%,WLT组分别为87.38%、81.98%、77.04%,SLT技术成熟期组、LDLT组和WLT组间差异无统计学意义(χ^(2)=4.016,P=0.134)。腹腔出血、感染、原发性移植肝无功能和门静脉血栓形成是SLT患者术后早期死亡主要原因。结论:在技术成熟的肝移植中心可实现与LDLT和WLT相当的疗效,但需要经过一定时间的学习曲线。

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

Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.Methods: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 can-cer.Data 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 patients.DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells.RNA 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 metastasis.Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.Results:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA methylation.SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer.SERPINE2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and angiogenesis.IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with EGFR.Mechanistically,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,c-Cbl.Additionally,EGFR was activated in liver cancer cells after sorafenib treatment,and SER-PINE2 knockdown-induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer.Furthermore,we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.Conclusions:SERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c-Cbl-mediated ubiquitination,suggesting that inhibition of the SERPINE2-EGFR axis may be a potential target for liver cancer treatment.

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

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

Aging is a contributor to liver disease.Hence,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly understood.In our study,the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy.An 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 H2O2.We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models.In 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 genes.In senescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also decreased.Moreover,the expressions of cell cycle-related genes were significantly down-regulated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor.We 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 liver.We successfully validated the results from cellular and animal experiments using human liver and blood samples.Our 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.

Single-center Experience in the Diagnosis and Treatment of Hepatic Perivascular Epithelioid Cell Neoplasm

Background and Aims:Perivascular epithelioid cell neo-plasms(PEComas)are a rare type of mesenchymal neo-plasm and their preoperative diagnosis is challenging.In this study,we summarized the experience from a single medical center to study the examinations,clinical presen-tations,and pathological and histological characteristics of PEComas in the liver in order to optimize overall un-derstanding of the diagnosis and treatment of these neo-plasms.Methods:We conducted a retrospective analysis to investigate the clinical and pathological characteristics as well as imaging presentations of 75 patients diagnosed with hepatic PEComa in The First Affiliated Hospital of Zhe-jiang University between April 2010 and April 2020.Re-sults:Among the 75 patients,52 were women,and the median age was 48 years.Most patients had no specific symptoms,and two were admitted to the hospital for a second time owing to relapse.All patients underwent surgi-cal resection.Histologically,38 patients had classical angio-myolipoma(AML)and 37 had epithelioid AML.The PECo-mas were accompanied by positive immunohistochemical expression of HMB45,Melan-A,and smooth muscle actin.Follow-up data were obtained from 47 of the total 75 pa-tients,through October 2020.Two patients had metastasis after surgery.Conclusions:AML is the most common type of hepatic PEComa.There are no specific symptoms of he-patic PEComa,and serological examinations and imaging modalities for accurate preoperative diagnosis are lacking.Epithelioid AML should be considered a tumor of uncertain malignant potential;however,the prognosis of PEComa af-ter resection is promising.

A scoring model based on plasma fibrinogen concentration for predicting recurrence of hepatocellular carcinoma after liver transplantation

Background:We investigated the prognostic value of preoperative fibrinogen levels in hepatocellular carcinoma patients receiving liver transplantation by building a scoring model for predicting tumor recurrence.Methods:Cox regression analysis was used to identify factors that predicted tumor recurrence,and a scoring model was generated by assigning a value of 0 or 1 to each independent risk factor.The cut-off value for fibrinogen was determined by receiver operating characteristic curve analysis.Results:Preoperative fibrinogen concentration was significantly higher in patients with vs.without tumor recurrence(3.27 g/L vs.2.34 g/L,P<0.001),with vs.without macrovascular invasion(3.54 g/L vs.2.82 g/L,P?0.007),and with>400 vs.400 ng/mL plasma alpha-fetoprotein concentration(3.43 g/L vs.2.76 g/L,P?0.007).The 5-year disease-free survival rate was significantly lower for patients with elevated(2.68 g/L)vs.normal(<2.68 g/L)fibrinogen concentration(37.2%vs.78.4%,P?0.001).Macrovascular invasion,>3 tumor nodules,and elevated fibrinogen concentration were independent risk factors for tumor recurrence.A scoring model based on these risk factors predicted recurrence with a sensitivity of 68.3%and a specificity of 87.5%.Conclusions:Elevated preoperative plasma fibrinogen concentration is associated with tumor recurrence in HCC patients after liver transplantation.A new scoring model predicted recurrence with good sensitivity and specificity.