Epigenetics of Sirtuins: Relevance to Hepatocellular Carcinoma

Sirtuins (SIRTs), members of the enzyme family found in yeast cells, are related to silent information regulator (SIR) 2 homologous to its gene family. SIRTs play an important role in many physiological functions from overexpression of gene silencing at the molecular level to the expression of related proteins and RNA to apoptosis. Studies have indicated that SIRTs may be related to the occurrence, development, and metastasis of cancer. However, the current mechanism of action of SIRTs in various diseases and the principle of molecular biology are not fully understood. Therefore, the present article discusses the main regulatory role and function of SIRTs in HCC and evaluates SIRTs as new targets for HCC treatment.     

吉西他滨联合多西紫杉醇方案治疗晚期肝癌的临床观察

目的评价吉西他滨联合多西紫杉醇治疗晚期肝细胞癌患者的疗效和不良反应。方法收集我科2006年2月-2010年2月间均诊断为晚期肝细胞癌患者42例。化疗方案剂量及方法设定：多西紫杉醇30 mg/m²,吉西他滨800 mg/m²在d1、d8天应用,静脉滴注。21天为 1周期,2周期后评价疗效。结果全组42例患者均可评价疗效。其中未见完全缓解患者,部分缓解率为21.4%(9/42),稳定47.6%(20/42),进展31.0%(13/42)。中位进展时间4.1月(95％CI：2.14~7.26月),中位生存时间9.2月(95％CI：4.25~18.12月)。无治疗相关死亡,主要不良反应为外周血粒细胞下降、血小板减少、轻度贫血、消化道反应、疲劳、外周神经毒性及偶发的腹泻和皮疹。结论吉西他滨联合多西他赛治疗晚期肝细胞癌具有显著的抗肿瘤作用,化疗期间出现血液学不良反应,食欲下降、乏力是普遍现象,需要临床重视。早期实施有效的干预可明显减少不良反应的发生率。     

Three Treatment Methods via the Hepatic Artery for Hepatocellular Carcinoma - A Retrospective Study

Background: To evaluate the relative effectiveness of different treatments of hepatocellular carcinoma(HCC) via the hepatic artery. Materials and Methods: The study sample group consisted of 418 patients whowere randomly selected from 2008 to 2012 with a first diagnosis of HCC and treated with transcatheter arterialchemoembolization (TACE) or without (TAE) chemotherapy or transcatheter arterial infusion (TAI). Wecollected data including tumor size preoperative and one month thereafter to compare change in areas acrossthe three groups, along with various laboratory indexes for comparison. Results: The overall average change ofareas was 240.8±72.1 mm2. In the three groups it was 265.0±58.0 mm2 vs. 250.5±51.9 mm2 vs. 123.7±26.2 mm2. Ingroups TACE and TAE values were larger than in group TAI (p<0.01), but the difference between the two wasnot statistically significant (p= 0.191). Additionally, U/L change of aspartate aminotransferase (AST) and alanineaminotransferase (ALT) in groups TACE and TAE was greater than in the TAI cases (24.0±13.5 vs. 20.9±12.1 vs.5.47±8.20 and 25.6±13.5 vs.23.2±12.28 vs.5.48±14.3) on the preoperative day and two days thereafter (p<0.01).Between the two groups there was no significant cariation (p= 0.320 and p= 0.609). However, the AST and ALTrecovered to normal levels one month later on therapy with liver protecting drugs. Conclusion: The groupsTACE and TAE demonstrated more effective reduction of tumor size than group TAI. While lipiodol causedacute liver function damage, this proved reversible.     

The Impact of Sorafenib in Combination with Transarterial Chemoembolization on the Outcomes of Intermediate-Stage Hepatocellular Carcinoma

Background: We investigated the treatment outcomes and hepatic reserve of transarterial chemoembolization (TACE)-refractory patients with recurrent advanced hepatocellular carcinoma (HCC) treated with TACE plus sorafenib. Methods: Forty-one patients with intermediate-stage HCC defined as being TACE refractory on imaging were treated with sorafenib and TACE between 2009 and 2012 and comprised the combination treatment group. Twenty-nine patients who received repeated TACE after becoming refractory to TACE between 2005 and 2008 comprised the TACE continuation group. Results: Although the interval between successive rounds of TACE was significantly shorter before the patients developed TACE refractoriness, it was significantly longer after the development of TACE refractoriness, in the combination treatment group compared with the TACE continuation group. The appearance of extrahepatic spread and/or vascular invasion differed significantly between the two groups. The median overall survival was significantly longer in the combination treatment group than in the TACE continuation group (20.5 vs. 15.4 months, respectively; hazard ratio = 2.04; 95% confidence interval = 1.20–3.48). The 3-year overall survival rate was 33.4% in the combination treatment group and 3.5% in the TACE continuation group. Downstaging of the Child–Pugh class was significantly less frequent in the combination treatment group than in the TACE continuation group. In COX proportional hazards analyses, sorafenib plus TACE resulted in a better prognosis compared with repeated TACE. Conclusions: Treatment with sorafenib plus TACE in TACE-refractory patients with intermediate-stage HCC resulted in longer intervals between TACE rounds, better maintenance of hepatic reserve, and significantly longer OS compared with repeated TACE.     

多结节和复发性肝细胞癌来源的临床研究

通过对１６０例肝细胞癌（ＨＣＣ）根治性切除者的随访，讨论了多结节ＨＣＣ中单中心与多中心起源者的不同临床特征，不同复发来源的ＨＣＣ的鉴别，同时性和异时性多中心ＨＣＣ的确定。由此提出了：同时癌或异时癌的生物学行为类似于单中心的单结节ＨＣＣ，应尽一切可能予以切除。有卫星灶的单中心ＨＣＣ，如能切除，应以肝叶切除为主。术后ＨＣＣ复发如属肝内转移者，应以局部灌注化疗为主。     

姜堰市男性原发性肝癌危险因素病例对照研究

目的 探讨姜堰市男性原发性肝癌的危险因素。方法 对姜堰市87例男性原发性肝癌进行1：1配对病例对照研究，通过条件Logistic回归单因素和多因素分析筛选主要危险因素。结果 乙型肝炎史和肿瘤家族史与原发性肝癌发生最为密切。结论 乙型肝炎史和肿瘤家族史为姜堰市男性原发性肝癌的危险因素。     

对巨大肝癌进行术前放射治疗的探讨

目的：探讨不能切除巨大肝癌经术前放射治疗缩小后切除的新途径。方法：术前放射治疗采用曾认为对肝癌疗效欠满意的放疗技术加以改良为全肝移动条野照射、缩野技术和分段放疗,放射总量达50—60Gy,放疗后3—4周,肝癌缩小后切除。结果：1987年6月-2000年12月,经放射治疗不能切除巨大肝癌84例,缩小后入选12例二步切除。此12例肝癌经术前放疗后,肿瘤最大径由11—18cm（中位14cm）缩小为6～8cm（中位7cm）;CT显示肝门淋巴结转移灶2cm、癌旁多个卫星病灶1—3cm各1例经放疗后病灶消失;1例AFP转阴者病理仍发现有存活的肝癌细胞。无手术死亡。未见放射性肝炎或术后严重并发症。随访：放射剂量〈50Gy者3例术后6—10月复发死亡;〉50Gy者生存1年以上9例（75．0％）,3年以上5例（41．6％）,5年以上4例（33．3％）,10年以上3例（25．0％）,17年以上1例仍健在。结论：术前放疗采用全肝移动条野照射、缩野技术和分段放疗是不能切除巨大肝癌的缩小后切除的新途径。采用放射剂量50—60Gy,放疗后3～4周手术可能比较适宜,远期随访结果令人鼓舞。     

原发性肝癌复发转移防治的临床与基础研究

简述近年复旦大学肝癌研究所获“九五”国家科技攻关等基金的资助对防治原发性肝癌复发转移的临床与基础研究课题的一些进展。在临床研究方面,亚临床复发作再切除手术是进一步提高疗效的主要途径,但预防复发则甚为困难。术后栓塞化疗（TACE）、生物治疗、术中肝动脉插管、冷冻肝切除等,可能有助于降低术后复发率。在实验研究方面,建立了人肝癌转移动物模型和细胞株。在分子水平对肝癌侵袭性作了研究,初步发现CerbB2、p12、p21、p53、mdm-2、VEGF、TGFα、EGF受体、MMP－2、uPA、uPA－R、ICAM－1与肝癌侵袭性呈正相关;nm23-H1、TIMP－2、Integrinα、E－cadherin、Kai-1则呈负相关。在实验性干预治疗方面,反义H－ras、Suramin、Heparin、抗肿瘤血管生成TNP－470、抗CD3／抗HBx的双特异抗体合并LAK治疗、基质金属蛋白酶抑制剂BBP－94及我所自行设计的β肽等对肝癌转移模型均有抑制转移的作用。预期生物治疗、转移复发的预测指标、多模式的干预治疗对防治肝癌转移甚为重要,其中抗肿瘤血管途径尤为突出。     

Clinicopathologic Study on Lymph Node Metastasis of Hepatocellular Carcinoma: A Retrospective Study of 660 Consecutive Autopsy Cases

There have been few reports in the literature concerning lymphnode metastasis (LM) in hepatocellular carcinoma (HCC). Nowadays,hepatectomy has become one of the most popular treatments forHCC, and understanding LM in HCC is indispensable at surgeryfor improving the patient's prognosis. In the present study,the authors verified this using autopsy cases. The clinicopathologiccharacteristics of LM have been studied in 660 consecutive autopsycases of HCC at Kurume University Hospital during the past 22years. LM was noted in 168 (25.5%) of the 660 cases, and wasmost frequent (66.7%) in HCCs of the pedunculated type. Theincidence of LM was significantly higher in the massive typeof HCC (30.1%) than the nodular type (19.9%) (P<0.05). Theincidence of LM was also higher in non-cirrhotic (34.8%) thancirrhotic cases (23.5%) (P<0.05). No metastasis was foundin tumors less than 3 cm in diameter. The metastasis rate increasedto 40% in tumors larger than 10 cm in diameter. The LM siteswere peripancreatic, 13.6%; hepatic hilar, 13.5% and perigastric,10.8%. The incidence of LM in the perigastric nodes was significantlyhigher in tumors located in the left hepatic lobe. LM was notfound in well-differentiated HCCs but was frequently found inpoorly-differentiated HCCs. Extensive LM was found in 60% ofHCCs with sinusoidal tumor growth and in 57% of cases showingsarcomatous changes.     

肝癌患者脾脏免疫状态的研究

对16例肝癌病人外周血及脾静脉血T淋巴细胞亚群检测结果：1）肝癌患者较对照组外周血CD 3、CD 4细胞及CD4／CD8比值降低，CD 8细胞升高。2）肝癌患者脾静脉血较外周血CD 3、CD 4阳性细胞、CD4／CD8比例明显降低，CD 8显著升高。认为随着病程进展，脾脏不但不起正性免疫作用，反而转向负性免疫状态。同时，还对肝癌患者的脾脏手术问题进行了讨论。     

肝细胞癌患者血清血管内皮生长因子测定的临床意义

目的　探讨肝细胞癌患者血清血管内皮生长因子 (vascularendothelialgrowthfactor ,VEGF)表达情况的临床意义。方法　选择 5 0例肝细胞癌和 2 5例正常对照血清标本 ,采用定量ELISA法检测血清VEGF含量。记录肝细胞癌组临床特征 ,与血清VEGF水平做相关性分析。结果　肝细胞癌组血清VEGF显著高于正常对照组 (P <0 0 5 )。肿瘤的生长方式对VEGF的表达有重要意义 (P <0 0 5 ) ;伴有远处转移患者血清VEGF水平明显增高 (P <0 0 5 ) ,TNMⅢ、Ⅳ期患者血清VEGF浓度也明显高于TNMⅠ、Ⅱ期患者 (P <0 0 5 )。结论　血清VEGF水平可作为肝细胞癌诊断和预后评价的重要指标     

肝癌患者粘附性LAK细胞制备及抗瘤活性研究

本研究在常规LAK细胞制备基础上进行改进，用苯丙氨酸甲酯(PME)去除肝癌患者外周血中抑制LAK细胞活性的单核巨噬细胞。制备抗癌活性较高扩增迅速的粘附性LAK细胞，从实验结果分析。外周血处理后粘附性LAK细胞较未粘性LAK细胞具有较强的扩增能力，最大扩增倍数23～243倍，同时粘附性LAK细胞中TH细胞亚群有增加趋势，Ts细胞亚群有碱少趋势，其IL-2R^ 表达增加至64．3%。此外,在抗瘤活性方面粘附性LAK细胞与非粘附性LAK细胞存在一定差别，分别为64．6%和42．8%．因此。从临床实用出发。制备相对高效的粘附性LAK细胞可以提高LAK疗法的治疗效果。     

MicroRNA-215 as a Diagnostic Marker in Egyptian Patients with Hepatocellular Carcinoma

Background: MicroRNAs are mentioned as a small non-coding RNAs groups and aberrant miRNA expression wasfound in hepatocellular carcinoma (HCC) patients. Aim: To evaluate role of plasma MicroRNA-215 as a diagnostictool in HCC patients. Methods: A prospective study included 195 subjects: healthy controls (group I), cirrhotic patients(group II), and patients with HCC (group III). Clinical examination, radiological and laboratory investigations whichincluded quantification of miR-215 by Real-time qPCR were done for all cases. Results: Spearman’s rank correlationrevealed that in HCC group, there was a negative correlation between MiRNA-215 and serum AFP levels and focal sizelesion (cm) (rs = -0.72, - 0.94 respectively, p<0.001). Receiver operating characteristics analysis for discriminationbetween cirrhosis and HCC groups regarding microRNA-215 displayed 78.3% sensitivity, 88.0% specificity at cutoffvalue of ≤ 1.90. Area under the curve (AUC) was 0.87 (p< 0.001). As regards AFP, it had a sensitivity of 81.7%, aspecificity of 66.7 at cutoff value of ≥ 11.50 (ng/mL). Conclusions: Plasma level of miR-215 may be a promisingbiomarker in HCC diagnosis. Moreover, if miR-215 combined with AFP, it can be used as a diagnostic biomarker, forearly detection of HCC.     

Clinical Significance of MiR-130b and MiR-125b as Biomarkers in Hepatocellular Carcinoma

Objective: This study aimed to assess the role of miR-130b and miR-125b expression in Hepatocellular Carcinoma (HCC) progression. Subjects and Methods: This study was carried out on 150 subjects classified into three groups: Group I, 50 healthy controls; Group II, 50 patients with liver cirrhosis; Group III, 50 patients with HCV related HCC. The controls were frequency matched based on age and sex with the other groups. All individuals were subjected to testing for liver function, alpha-fetoprotein (AFP), and viral markers. miR-130b and miR-125b were detected in plasma using a quantitative real-time RT-PCR. Results: miR-130b was significantly upregulated, whereas miR-125b was significantly downregulated in HCC patients compared with cirrhotic patients and healthy controls. There was a significant correlation between miR-130b and AFP and tumor size. Receiver operating curve (ROC) analyses suggested that plasma miR-130b had a significant diagnostic value for HCC with a sensitivity of 92% and a specificity of 77.5%.  A sensitivity of 85.5% and a specificity of 82.5% was observed for  miR-125b for HCC. Conclusion: Plasma miR-130b and miR-125b may play a role in disease progression and development of HCC and may act as potential biomarkers for the diagnosis of HCC.     

Asparagus Polysaccharide and Gum with Hepatic Artery Embolization Induces Tumor Growth and Inhibits Angiogenesis in an Orthotopic Hepatocellular Carcinoma Model

Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is anurgent need for the development of novel therapies for this deadly disease. It has been proven that asparaguspolysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notableantitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvantfor liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form,asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE)therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesisand promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functionsand showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparaguspolysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancerTACE therapy.     

Outcomes of Geriatric Patients with Hepatocellular Carcinoma

Background: The treatment modalities and outcomes of geriatric patients with hepatocellular carcinoma (HCC) remain controversial. This retrospective observational cohort study compared the outcomes of HCC between geriatric and younger patients. Methods: The medical records of patients with HCC managed between January 2001 and December 2017 were retrieved from the Chang Gung Memorial Hospital Research Database. Patients were stratified by age into two groups: a geriatric group (65–75 years) and a younger group (<65 years). The two groups were matched through 1:2 propensity score matching (PSM) according to sex, cardiovascular disease, cerebrovascular attack, diabetes mellitus, cirrhosis, hepatitis, and hypertension. Results: Of the 11,033 patients with HCC, 2147 patients aged 65–75 years and 4294 patients aged <65 years were identified after 1:2 PSM. The Kaplan–Meier model revealed that the HCC outcomes in patients older than 65 years were not significantly different after 3 years (p = 0.060). Consistent results were also obtained when the laboratory data associated with HCC incidence were included in the Fine–Gray competing risk model after 1:2 PSM (p = 0.1695). The major risk factors for HCC survival were systemic immune-inflammation index (SII) ≥ 610 × 10⁹ cells/L, advanced tumor stage, and model for end-stage liver disease (MELD) score, etc. Conclusion: Age was not an independent factor for mortality in patients with HCC in the first 3 years. Geriatric patients with HCC should be as aggressively managed as younger patients.     

肝癌组织中三个MAGE家族基因的克隆

目的:从肝癌组织中克隆肿瘤相关抗原基因MAGE-1的全长cDNA,为该基因及其编码抗原应用于肝癌的免疫治疗奠定基础.方法:根据MAGE-1编码区上、下游序列设计一对引物,用RT-PCR方法从肝癌组织中扩增该基因的全长cDNA,酶切产生粘性末端后连接入PUC19质粒.经初步酶切鉴定后,通过DNA序列分析获取所克隆基因片断的核苷酸序列.结果:成功地克隆了MAGE-1基因的全长cDNA,同时还获得一约750bp的MAGE-3基因片段及一与MAGE-6和MAGE-12高度同源的基因的克隆.此与MAGE-6,-12高度同源的基因可能为一未知MAGE家族成员.结论:肝癌组织中表达多种MAGE家族基因,甚至可能存在未知MAGE家族基因的表达,这将为寻找肝癌免疫治疗的攻击靶点开辟新的途径.     

应用端粒重复序列扩增法检测原发性肝癌组织端粒酶活性的研究

目的：检测原发性肝癌及癌旁组织端粒酶活性并探讨端粒酶活性在原发性肝癌中的临床意义。方法：应用端粒重复序列扩增法（TRAP）检测36例原发性肝癌及癌旁组织和3例正常肝组织端粒酶活性。结果：36例原发性肝癌组织有29例（80.6%）阳性。而36例癌旁组织只有4例（11.1%）阳性。3例正常肝组织均阴性。4例癌旁组织端粒酶阳性的患者均于术后半年内复发。结论：原发性肝癌癌旁组织端粒酶活性可望成为预测原发性肝癌术后复发的重要指标,对患者术后治疗方案的选择以及术后随访观察具有一定的指导意义。     

Significant SNPs Related to Telomere Length and Hepatocellular Carcinoma Risk in Chronic Hepatitis B Carriers

Chronic hepatitis B virus (HBV) infection increases the risk of developing cirrhosis and hepatocellular carcinoma(HCC) with suspected interactions between virus replication and host immune responses. A number of reports havesuggested that telomerase function may be involved in chronic hepatitis B (CHB) pathogenesis, but positive or negativeassociations with HCC risk remain for discussion. Mean telomere length is an indicator of biological aging and it hasbeen reported that reduction in NBV carriers compared to normal individuals. In somatic cells, telomeres containsimple, tandemly repeated G-rich sequences that frequently are reduced by 50 to 200 base pairs at each cell division.Several genome-wide association studies (GWAS) in diverse ethnic populations have revealed eleven single nucleotidepolymorphisms (SNPs) linked to telomere length. Two of these, rs398652 and rs621559, have prognostic value and couldbe used as genetic markers. This review describes current knowledge concerning telomerase activity and telomere lengthas well as significant polymorphisms in HBV-related HCC patients. In particular, to cast light on genotype-phenotypeinteractions, we used SNPnexus to evaluate effects of the two SNPs on risk of disease and complex disorders.     

原发性肝癌患者血清丙型肝炎病毒抗体测定及其临床意义

作者应用抗丙型肝炎病毒(HCV)酶联免疫分析(EIA)试剂盒,对50例原发性肝细胞癌(HCC)患者作了抗HCV检测;同时以40例健康成年献血员作为对照组。血清抗HCV罹患率在对照组为5％(2/40),而在HCC组为10％(5/50)。两组之间无明显差异(P>0.05),但HCC组5例抗HCV阳性者均伴有HBV感染。因此建议今后在对健康献血员作肝功能及HBV系列测定的同时,应作抗HCV测定;对抗HCV阳性者,应进一步作HCV的PCR检测,并应极治疗。