目的 总结介入术治疗后并发肿瘤溶解综合征(Tumor lysis syndrome,TLS)的肝细胞癌(Hepatocellular carcinoma,HCC)患者的临床特点,并探讨其有效治疗方法.方法 收集9例介入术治疗后并发TLS的HCC患者临床资料,作回顾性分析,总结其临床特点、诊断及治疗方法.结果 9例HCC患者中7例存在门静脉癌栓,均行介入术治疗,其中肝动脉化疗栓塞术7例、经皮射频消融术1例、肝动脉栓塞联合经皮射频消融术1例,对介入术治疗敏感.术后第2天,3例患者出现24 h尿量＜400 mL,9例患者血清尿素氮、肌酐、尿酸、钾、磷水平均升高,钙及甲胎蛋白水平降低,确诊为TLS,进行静脉补液水化、应用利尿剂、纠正电解质紊乱、连续性肾脏替代治疗,术后第7天血清各项指标均明显好转.结论 肿瘤负荷重、肿瘤对治疗敏感的HCC患者容易并发TLS.尿量减少、肾功能及电解质水平紊乱可诊断TLS.TLS的有效治疗方法为补液、利尿、纠正电解质紊乱、降尿酸及CRRT治疗.

肝细胞癌(hepatocellular carcinoma,HCC)是常见的消化系统恶性肿瘤之一,其具有起病隐袭、早期症状不明显、进展迅速等特点,一经发现已发展至中晚期,给患者生命健康带来严重威胁.近年来,随着新型生物标志物的发现和检测技术的构建与应用,HCC的诊断、疗效及预后评估效果有了显著提升,大大提高了HCC患者生存质量.本文就近年来HCC的诊断、疗效及预后标志物的研究进展作一综述,重点分析HCC不同标志物的功能作用,为HCC标志物的临床应用提供重要依据.

目的 分析多个血清标志物联合检测对甲胎蛋白(AFP)阴性原发性肝癌患者经导管肝动脉化疗栓塞术(TACE)治疗后疗效及预后的临床价值.方法 纳入解放军总医院第五医学中心2016年9月至2018年3月接受TACE治疗的120例肝细胞癌(HCC)患者,其中44例AFP水平正常(AFP阴性),76例AFP水平增高(AFP阳性),分别检测患者TACE术前、术后1个月和3个月的血清AFP、癌胚抗原(CEA)、糖类抗原-199(CA199)、CA125、γ-谷氨酰转移酶(GGT)、白细胞介素-2(IL-2)、IL-4、IL-6、IL-10、IFN-γ、TNF-α等指标水平.随访至2018年7月,观察患者肿瘤活性情况,分析不同标志物组合对AFP阴性HCC患者TACE术后疗效及预后的临床价值.结果 AFP阴性和阳性患者术前各项指标水平比较,差异均无统计学意义(P>0.05).IL-6联合GGT检测AFP阴性和阳性HCC患者TACE术后疗效及预后的灵敏度、特异度、阴性预测值、阳性预测值分别为95.2％、87.0％、87.0％、95.2％和85.7％、59.6％、70.1％、79.1％;IL-6对AFP阴性及阳性HCC患者预后的ROC曲线下面积分别为0.839和0.666.结论 血清IL-6联合GGT检测可作为一种预测AFP阴性HCC患者TA C E术后疗效及肿瘤活性的有效指标.

目的 探讨索拉非尼对中晚期肝癌介入治疗患者生存率及不良反应的影响.方法 按照随机数字表法将80例中晚期肝癌介入治疗患者均分为实验组和对照组.对照组行介入治疗,实验组在此基础上加用索拉非尼,对比2组患者临床疗效、临床症状改善情况、不良反应以及生存情况.结果 2组患者临床疗效对比,差异无统计学意义(P＞0.05).实验组患者食欲减退和肝区疼痛改善率均显著优于对照组,差异具有统计学意义(P＜0.05);实验组患者高血压、手足综合征及腹泻发生率显著高于对照组,差异具有统计学意义(P＜0.05).实验组患者6个月、12个月、24个月生存率以及中位无进展生存期均显著高于对照组,差异具有统计学意义(P＜0.05).结论 索拉非尼可延长中晚期肝癌介入治疗患者生存时间,改善临床症状,但会明显增加不良反应,临床用药需谨慎.

ABSTRACT Aim: To analyze the correlation between clinical features and hepatic dysfunction after transcatheter arterial chemoembolization in patients with primary liver cancer. Methods: 251 PLC patients treated by TACE were retrospectively analyzed. k2 test and Logistic regression model were used to assess the correlation between clinical features and hepatic dysfunction after TACE. Results: 40/251 patients(15.9%) presented with hepatic dysfunction after TACE. Univariate analysis showed that tumor diameter ≥ 10cm, Child-Pugh grade, cholinesterase level and portal vein tumor thrombosis(PVTT) were associated with hepatic dysfunction after TACE in PLC patients. Multivariate analysis showed that Child-Pugh grade B, tumor diameter ≥ 10cm and low cholinesterase level were risk factors associated with hepatic dysfunction after TACE in PLC patients. Conclusions: TACE should be carefully performed to avoid hepatic dysfunction in PLC patients with tumor diameter ≥ 10cm, Child-Pugh grade B, and low cholinesterase level. Disclosure: All authors have declared no conflicts of interest.

Objective To investigate the proportion of CD4+ T cells, which express the granzyme A, B and perforin, in peripheral blood of patients with primary hepatocellular carcinoma (PHCC), and explore the correlation between CD4+ T and the course of PHCC. Methods Peripheral blood samples were obtained from 99 PHCC patients, 28 chronic hepatitis B (CHB) patients, and 40 healthy subjects (served as control), and CD4+ cytotoxic T cells in peripheral blood were quantitatively analyzed with flow cytometry. The difference of proportion of CD4+ T cells between early (n=29), intermediate (n=36) and progressive (n=34) stage of PHCC patients was also analyzed. Results It was revealed that the proportions of granzyme A+ CD4+ CTL, granzyme B+ CD4+ CTL and perforin+ CD4+ CTL were significantly higher in PHCC patients (15.38%±10.36%, 11.10%±8.43% and 7.42%±7.26%) compared with those in CHB patients (9.10%±5.80%, 6.16%±6.04% and 2.95%±3.34%) and healthy controls (10.25%±5.62%, 6.82%±6.12% and 3.14%±3.60%, P<0.05), but no statistical difference of the values existed between CHB patients and healthy controls. The proportions of granzyme A+ CD4+ CTL in early, intermediate and progressive stage of PHCC patients were 21.26%±12.61%, 14.54%±7.11% and 11.24%±9.04%, and of granzyme B+ CD4+ CTL were 15.35%±10.30%, 10.71%±6.06% and 7.90%±7.44%, and of perforin+ CD4+ CTL were 11.82%±9.17%, 7.16%±5.03% and 5.22%±6.58%, respectively. The proportions of CD4+ CTL declined along with the deterioration of PHCC. Conclusion The proportion of CD4+ CTL increases in the peripheral blood of PHCC patients, but it declines along with the deterioration of disease, implying that the CD4+ cytotoxic T may be closely associated with the deterioration of PHCC.

Objective To further confirm the upregulation expression of tumor suppressor,Dickkopf 1(DKK-1),in IFN-α treated HepG2 cells.Methods HepG2 cells were treated by various concentration of IFN-α of 1000U/ml,2000U/ml,respectively.At the time points of 6h、16h after IFN-α treatment,reversetranscription polymerase chain reaction(RT-PCR)and quantitative real-time PCR were performed to detect the expression of DKK-1 mRNA,western blot was used to observe the DKK-1 protein levels.Results Realtime PCR showed that HepG2 cells treated with 2000 U/ml IFN-αfor 16 h had higher DKK-1 mRNA expression0.00039± 0.000057 than cells in control group treated with 2000 U/ml for 6 h 0.000195± 0.000021 or 1000U/ml IFN-αfor 16 h 0.000307 ± 0.000012 P<0.05;Western blot further confirmed that IFN-treatment increased the expression of DKK-1 protein P<0.05.Conclusion IFN-α could induce the expression of DKK-1in HepG2 cells.DKK-1 may be a potential molecular target for IFN-α exerting its anti-proliferative function.

Objective To investigate the therapeutic effect of argon-helium cryoablation combined with sorafenib on hepatitis B-related advanced hepatocellular carcinoma(HCC) and to evaluate the role of microvessel density(MVD) in prognostic evaluation.Methods A total of 102 patients with advanced HCC were randomly divided into two groups,with 50 receiving sorafenib plus cryoablation(group SC) and 52 receiving only cryoablation(group C).The endpoint of the treatment was tumor progression or untolerable adverse reaction.Tumor tissues were obtained before treatment.MVD was evaluated by immunohistochemical analysis using CD34 antibody.The therapeutic effects were evaluated according to RECIST criterion every 4-6 weeks.The adverse events were observed in both groups;the therapeutic effect,overall survival time(OS),and time to progression(TTP) were compared between two groups.Results In group SC,complete response(CR) was achieved in 2 patients(4%),partial response(PR) in 9(18%),and stable disease(SD) in 22(44%),with the disease control rate(DCR) being 66% ;in group C,no CR,PR in 4(7.6%),and SD in 19(36.5%),with the DCR being 44.2%(P 0.05).The overall survival(OS) and the time to progression(TTP) were significantly longer in group SC than in group C(12.5 months vs 8.6 months,9.6 months vs 5.3 months;P 0.01).The mean MVD in group CRPR(111/0.74 mm2) was significantly lower than that in group PD(339/0.74 mm2,P 0.01).Patients with lower MVD receiving sorafenib plus cryoablation had longer OS and TTP than those only receiving cryoablation.The OS and TTP in patients with higher MVD had no significant difference between different groups.Conclusion Sorafenib plus cryoablation is a safe and effective therapy for patients with advanced HCC;it can improve the OS and TTP of patients.Patients with higher MVD have a lower response to therapy and poor prognosis.

Objective To investigate the correlation between the percentage of peripheral regulatory T cells (Tregs) and the course of hepatocellular carcinoma (HCC),and analyze the prognostic implication of Tregs in HCC patients undergone argon-helium cryoablation.Methods The percentage of Tregs was determined by flow cytometry,and the correlation between the percentage of Tregs and progression of HCC was then studied.Of 101 patients with HCC,34 underwent argon-helium cryoablation.The Tregs percentage and alpha fetoprotein (AFP) levels in peripheral blood were detected before and after the cryoablation.Subsequently,the variation of Tregs percentage and AFP levels,and the correlation between their variation and the course of HCC was analyzed.Results According to the Barcelona-Clinic Liver Cancer (BCLC) classification,the Tregs was 6.89%±1.27% in patients in early-stage of HCC,9.13%±1.36% in intermediate-stage,10.12%±2.04% in advanced-stage,and 13.4%±2.81% in terminal-stage.After argon-helium cryoablation,the Tregs percentage in 17 patients with regressive tumor was lowered compared with that before cryoablation,and among them both the AFP level and Tregs percentage declined in 7 cases with pre-AFP level >20ng/ml.In addition,the Tregs percentage increased obviously in 14 patients with progression of tumor growth after cryoablation compared with that before cryoablation.Among them both the AFP level and Tregs percentage increased accompanying with the tumor progression in 9 cases with pre-AFP level >20ng/ml.Conclusions The Tregs percentage may increase accompanying progression of the tumor.Argon-helium cryoablation may reduce the Tregs percentage in HCC patients.Increased percentage of Tregs may be considered as a sign for tumor progression,while AFP can not precisely indicate tumor progression in AFP-negative HCC patients.

Objective:To observe the efficacy of endothelial progenitor cells carrying hIFN-γ(EPCs-hIFN-γ) in cancer maintenance therapy after chemotherapy.Methods: MTT was used to examine the inhibitory effects of hIFN-γ and/or C225 against colorectal cancer LoVo cells after treatment with CPT-11.The in vivo inhibitory effects of EPCs-hIFN-γ and/or C225 on LoVo tumors and their effects on survival of LoVo tumor-bearing nude mice were investigated after mice had been treated with CPT-11.Results: In vitro,hIFN-γ and/or C225 further inhibited the growth of cancer cells after CPT-11 treatment.In vivo,after 50 mg/kg CPT-11 treatment,EPCs-hIFN-γ,C225 and EPCs-hIFN-γ+C225 inhibited the growth of tumors in LoVo tumor-bearing nude mice(mean tumor volumes: [2024.28±1048.40] mm3 vs [764.94±720.14],[233.85±186.97],[186.95±133.43],[163.9±173.39] mm3;P0.05).EPCs-hIFN-γ,C225 and EPCs-hIFN-γ+C225 treatment also increased the survival of tumor-bearing mice(median survival: 34.2 d vs 39.4,44.5,48.5,51.3 d;P0.05 or P0.01).Conclusion: EPC-hIFN-γ can inhibit the tumor growth and prolong the survival of tumor-bearing mice in cancer maintenance therapy after chemotherapy.

Background and purpose:Recently,a few studies suggested that effective effects of Sorafenib combined argonhelium cryoablation on hepatitis B-related advanced hepatocellar carcinoma(AHCC).However,the prognosis of the patients has a substantial difference.Advanced liver cancer prognostic systems(ALCPS),Model for endstage liver disease(MELD) and Child-Pugh scoring system has shown some value in the assessment of therapeutic effects for AHCC.Unfortunately,there were few comparative studies of these different scoring systems.This study was aimed to identify the potential predictive scoring system for the therapeutic response of argonhelium cryoablation when combined with sorafenib on hepatitis Brelated AHCC.Methods:Fifty patients with AHCC who underwent sorafenib combined with cryoablation were enrolled in this study.The therapeutic effect,overall median survival(OS) and time of progression(TTP) were compared in different groups and were later divided using Child-Pugh,model for endstage liver disease(MELD) and advanced liver cancer prognostic systems(ALCPS) scoring systems.The significance of predicting the prognoses by Child-Pugh,MELD and ALCPS scoring systems were respectively analyzed.Results:Median overall survival(OS) and time of progression(TTP) were 11.0 months and 6.0 months,respectively.Complete response (CR) was observed in 2 patients(4%),partial response(PR) in 8(16%),stable disease(SD) in 23(46%) and therapeutic effective rate was 66%.According to the ALCPS,patients with a score of ≤8,9-15 and ≥16 had different OS(16.5,8.6,and 6.8 months,respectively(P0.05),different TTP(12.0months,6.0 months,and 2.0month,respectively(P0.01) and different therapeutic effective rates(94.1%,70.6%,and 31.3%,respectively(P0.01).OS and TTP of patients with a MELD score of ≤7 was 16.5 months and 10.0 months,which were longer than patients with a MELD score of 7(7.8months,2.5months).The respective therapeutic effective rates were 78.2% versus 41.2% in the two groups.The OS and TTP of Child-pugh class A or B patients had no significant difference(P0.05),but the therapeutic effective rates for Child-pugh class A patients were higher than that of class B patients(69.2% vs 54.6%,P0.05).Conclusion:Sorafenib combined with cryoablation on AHCC has advantages of prolonging OS and TTP.ALCPS,MELD and Child-Pugh scoring systems can be used to predict the feasibility and efficacy of that treatment on AHCC.ALCPS seems to be the most sensitive and specific predictor in patients with AHCC who underwent the treatment.

Objective To evaluate the therapeutic effect and safety of argon-helium cryoablation combined with sorafenib in the treatment of hepatitis B-related advanced hepatocellular carcinoma(HCC).Methods Out of 102patients,50receiving sorafenib combining with cryoablation were assigned into Group S+C,while 52receiving cryoablation alone were into Group C.Therapeutic effects were evaluated every 4to 6weeks according to the Response Evaluation Criteria in Solid Tumors(RECIST).The primary endpoints were tumor progression and intolerable toxicity.Adverse events were assessed in both groups according to the National Cancer Institute-Common Toxicity Criteria(NCI-CTC).The results of follow-up for overall survival time(OS)and time to progression(TTP)in both groups were performed and compared.Results In Group S+C,complete response(CR)was achieved in 2cases,partial response(PR)in 9cases, stable disease(SD)in 22cases,contributing to a disease control rate(DCR)of 66.0%.In Group C,4patients showed PR,19showed SD,and no CR was observed,resulting in a DCR of 44.2%.The mean OS and TTP were 11.0and 6.0months in Group S+C,and 7.5 and 3.5months in Group C,respectively.The incidence of complications,such as sorafenib related skin rash,hypertension,hand-foot skin reaction,diarrhea,abnormities in liver function,leucopenia,and gastrointestinal hemorrhage,was 62%,54%,42%,42%,34%,20% and 12%,respectively,in patients of group S+C,and in those patients with the same adverse events,which were severer than Grade 3, was 4%,2%,22%,6%,6%,4%and 6%,respectively.Conclusion Sorafenib combining cryoablation is safe and effective for patients with advanced hepatocellular carcinoma,contributing to a significant increase in OS and TTP.

Objective To evaluate the clinical effect of argon-helium cryosurgical ablation system to treat early-stage hepatocellular carcinoma.Methods Totally 48 early-stage hepatocellular carcinoma patients were treated.Clinical symptom,tumor size,AFP,complications and survival time were analysised.Results At the end of the study,23 patients survived and 25 patients died.Survival time was(33.91±1.39)month,survival rates of 1,2,3,4 year were 81.3%,62.1%,47.6% and 44.4%,respectively.Conclusion To early-stage hepatocellular carcinoma patients with severe liver cirrhosis,argon-helium cryosurgical ablation therapy is a ideal alternative with the advantage of few complications and good outcome.

Argon-helium cryosurgical system has been widely used in the treatment of tumors in recent years,the basic mechanism is that the ultra low temperature(-140 ℃) can act on the tissues and result in the formation of ice crystals in exterior and interior of cells and cellular dehydration,which will produce a series of physical and chemical changes and then result in the cell necrosis of tumor tissues.Recent studies revealed that the freezing immune efficacy resulting from the therapy is another important anti-tumor principle of Argon-helium cryosurgical system.The animal and clinical researches showed that specific antibody could be found after cryotherapy,and necrotic tumor cells after cryotherapy can result in T cell mediated killing of tumor cells as tumor vaccine.But,part of trials showed that cryotherapy could result in immune inhibition,the possible causes maybe the high-zone immune tolerance.In general,therapy with argon-helium cryosurgical system has some advantages that surigical therapy can not have,such as releving the tumor load,reducing the immune inhibitor produced bny tumor,slight postoperative stress reaction,slight body immunosuppression,activation of the body immune function by the antigen released from necrotic tumor.,which is the reliable therapeutic method for the advanced tumor patients.

OBJECTIVE:To explore the separation and culture method of adult hepatocytes.METHODS:The isolated adult hepatocytes were cultivated by RPMI 1640 medium at 37 degrees C in vitro. The characteristics of the growing hepatocytes were observed. Their synthesis of urea was detected. The transformation efficiency and density's change of lidocaine were analyzed.RESULTS:Hepatocytes were successful separated from adult liver. And they were cultivated in common condition and hollow fiber reactor. The functional capacity of hepatocytes was for lidocaine metabolism and urea excretion.CONCLUSION:The adult hepatocytes have been successful separated from liver. And they can be cultivated in common condition and hollow fiber reactor. And it could provide a great quantity and high activity of hepatocytes for bioartificial liver.

目的 评价经皮氩氦刀治疗原发性肝癌(HOC)的疗效、安全性及并发症.方法 采用氩氦超导手术系统,在B超引导下经皮氩氦刀治疗300例HOC患者,观察其治疗效果及随访情况.结果 165例患者的223个瘤体(直径7.2±2.8cm,5.0～15cm)未被彻底毁损,135例的185个瘤体(直径5.6±0.8cm,1.9～7.0cm)被完全毁损,两组肿瘤直径差异显著(P=0.0001).265例患者随访中位时间为31.2(6～63)个月,彻底毁损组(经氩氦刀治疗后肿瘤被完全毁损)肿瘤原位复发率为16.3%(22/135),肝动脉化疗栓塞(TACE)组(经氩氦刀治疗后肿瘤未被完全毁损,再联合TACE治疗)原位复发率为47.1%(41/87),两组肿瘤原位复发率差异显著(P=0.0001).早期、中期、进展期肝癌(巴塞罗纳肝癌分期标准)术后生存期分别为38.7±3.8、26.5±4.2、16.9±1.4个月.17例(5.7%)发生严重并发症,包括冷休克6例(2.0%)、肝癌破裂出血5例(1.7%)、应激性胃黏膜出血4例(1.3%)、肝功能衰竭2例(0.7%).术后肝功能多有轻度损害,2周左右恢复至术前的基线水平.结论 经皮氩氦刀治疗肝癌是一种较安全有效的方法 ,肿瘤直径和肿瘤分期是影响疗效的主要因素.

BACKGROUND:Hepatocyte transplantation has attracted more and more attention as a therapeutic measure for liver failure and genetic metabolic liver diseases.OBJECTIVE:TO evaluate the efficacy and safety of human hepatocyte transplantation in treating hepatitis B related liver failure in one case by a 2-year follow-up.DESIGN:A case-report of 2-year follow-up.SETTING:No.9 Department of Infectious Diseases,Bioengineering Research Room,the 302 Hospital of Chinese PLA.PARTICI PANT:One inpatient with hepatitis B related liver failure was selected from the 302 Hospital of Chinese PLA.and she was diagnosed according the laboratory tests.The transplanted hepatocytes were originated frOm the healthy liver of a 24-year-old man,who had signed the protocol for liver donation before death.METHODS:The hepatocyte transplantation was completed in the Department of Radiology,the 302 Hospital of Chinese PLA in December 2004.Liver was isolated to obtain human primary hepatocytes, and then cryopreserved.The hepatocytes were transplanted into recipient spleen via femoral vein after resuscitation.The clinical symptoms,changes of blood biochemical indexes,and changes of spleen MRI signals were observed before and after operation.The patient was reexamined every half a year after operation, including liver function, blood coagulation function,B-mode ultrasonography,gastroscopy and MRI,and she was followed up for 2 years. MAIN OUTCOME MEASURES:Liver function,blood coagulation function, imaging indexes, immunological indexes,complication and rejection.RESULTS:①Totally(1-2)×1010 hepatocytes were harvested,and the viability of rewarmed hepatocytes was 60%,and finally 2×109 hepatocytes were transplanted.②Two months later,the clinical symptoms of the recipient were obviously ameliorated,and serum bilirubin and aspartate aminotransferase(AST)were obviously decreased,while prothrombin activity was markedly increased.20 months later,the MRI results showed that there was hepatocyte image in spleen.Two years after operation.the total bilirubin level was 20 μmol/L,direct bilirubin level was 7 μmol/L, alanine aminotransferase was 416.75 nkat/L,AST was 533.44 nkat/L,albumin was 37 g/L,prothrombin activity was 90%,which were all obviously ameliorated as compared with those before operation(474.5 μmol/L,340.3 μmol/L,400.08 nkat/L,1 200.24 nkat/L,38 g/L,25%).The patient left the hospital 2 months later and could do light-burdened job.No complications of hydroperitonia and liver function failure, etc.were observed,and no rejection occurred.Several reexaminations by B-mode ultrasonography all indicated the further aggravations of liver cirrhosis and esophageal varices.She was admitted to hospital for twice because of esophageal varices bleeding,and cured by endoscopic variceal sclerosis therapy.CONCLUSION:Hepatocyte transplantation can ameliorate liver function without rejection,but it cannot relieve portal hypertension.

我科曾于2004年12月成功完成一例肝细胞体内移植术,目前患者已存活2年,现将该患者情况报道如下.

Objective To investigate the effects and safety of human hepatocytes transplantation in vivo for the treatment of liver failure. Methods The primary human hepatocytes were collected from normal liver tissue donated by healthy volunteers and preserved by cryopreservation technique. After thawing, the hepatocytes were transplanted into the spleen of patients with severe hepatitis through catheterization of the femoral artery. Then the changes in clinical symptoms, serum biochemical indexes and MRI signals of the spleen were observed in the patients. Results A total of 2×10 10 hepatocytes were isolated from normal liver tissue of healthy volunteers and 75% of the hepatocytes were alive after cryopreservation and thawing. The number of transplanted hepatocytes was 2×109. In the recipients, the clinical symptoms were markedly improved, serum levels of bilirubin, NH_3, ALT and AST were significantly reduced, but that of PTA remarkably increased, after hepatocyte transplantation. The follow-up examination was performed 80d and 270d after discharge from the hospital, and it was showed that all the serum biochemical indexes returned to normal and signals of the hepatocytes were found in the spleen. Conclusions Hepatocyte transplantation is a safe and effective therapy for severe hepatitis. The transplanted hepatocytes can proliferate and differentiate in the spleen to replace or partially compensate the liver function of synthesis, detoxication and metabolism. Contrast enhanced MRI can be a new method for follow-up study of transplanted hepatocytes.