GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma

BACKGROUND/AIMS: Golgi protein-73 (GP73) is up-regulated in hepatocellular carcinoma (HCC). The aims of this study were to determine if GP73 is detected in the serum, and to establish the sensitivity and specificity of serum GP73 for diagnosing HCC. METHODS: Serum GP73 was detected by immunoblots and quantified by densitometric analysis. RESULTS: A total of 352 patients were studied. Serum GP73 levels were significantly higher in patients with HCC compared to those with cirrhosis (P < 0.001). GP73 had a sensitivity of 69% and a specificity of 75% at the optimal cutoff point of 10 relative units, with an area under the receiver operating curve of 0.79 vs. 0.61 for AFP (P = 0.001). GP73 levels had significantly higher sensitivity (62%) than AFP (25%) for diagnosing early HCC (P < 0.0001). Moreover, GP73 levels were elevated in the serum of 57% (32/56) of individuals with HCC who had serum AFP levels less than 20ng/ml. CONCLUSIONS: Higher levels of GP73 can be found in the serum of patients with HCC than of those without. GP73 was better than AFP for the diagnosis of early HCC. Further validation studies are needed to confirm the role of GP73 in the early detection of HCC.     

Tumour markers in the diagnosis of bronchial carcinoma: new options using fuzzy logic-based tumour marker profiles

The diagnosis of lung cancer and early knowledge of its histological type are very important; however, this is still a difficult subject for the physician. The aim of this study was to improve the diagnostic efficiency of tumour markers in the diagnosis of bronchial carcinoma by mathematical evaluation of a tumour marker profile employing fuzzy logic modeling. A panel of five tumour markers, including CYFRA 21-1, CEA, NSE, and five additional parameters was determined in 281 patients with confirmed primary diagnosis of bronchial carcinoma of different histology and stage. A further 131 persons, who had acute and chronic benign lung diseases, served as a control group. A classificator was developed using a fuzzy-logic rule-based system. The diagnostic value of the combined tumour markers was significantly better than that of the individual markers and of a combination of CYFRA 21-1, CEA, and NSE. The discrimination of malignant vs benign diseases was realized with a sensitivity of 87.5% and specificity of 85.5%. The rate of correct classification of small-cell vs non-small-cell lung carcinoma was 90.6% and 91.1%, respectively; for squamous cell carcinoma vs adenocarcinoma it was 76.8% and 78.8%, respectively. Our detailed analysis has shown that the fuzzy logic system improves diagnostic accuracy up to a rate of 20%, especially in early stages and in patients with all marker levels in the grey area. Our concept proved to be more powerful than measurement of single markers or the combination of CEA, CYFRA 21-1, and NSE. Its use may help in distinguishing between malignant and benign disease and make it possible to define different subgroups of patients earlier in the course of␣their disease. Received: 14 April 1998 / Accepted: 14 May 1998     

siRNA沉默AFP基因对肝癌细胞系EGHC-9901凋亡的影响

目的建立稳定表达针对AFP基因siRNA质粒的肝癌细胞模型并探讨对其凋亡的影响。方法构建针对AFP基因的siRNAs表达质粒,脂质体法将该质粒转染肝癌细胞系EGHC-9901,G418筛选4~5周后Western blot及RT-PCR检测靶基因抑制效果,细胞分组：实验组（siRNA-afp）,转染AFP-siRNA质粒组;载体对照组,转染空载体组;空白对照组,未做任何处理组。免疫荧光检测细胞在无血清状态下凋亡情况,Western blot及RT-PCR检测Caspase-3、Caspase-8等凋亡相关蛋白表达。结果在体外成功构建针对AFP的siRNA表达质粒并在体外建立稳定表达该质粒肝癌细胞系EGHC-9901,转染后细胞表达AFP近乎完全抑制;免疫荧光表明促进细胞在无血清状态下的实验组凋亡率为32%±4%,对照组凋亡率为17%±3%,差异有统计学意义（P〈0.05）;RT-PCR及Western blot检测凋亡相关蛋白表明实验组Caspase-3表达较对照组高,差异有统计学意义（P〈0.05）,而Caspase-8、Caspase-9、bcl-2表达无显著差异（P〉0.05）。结论在体外成功建立稳定表达针对AFP基因的siRNA肝癌细胞系,抑制AFP表达可能通过上调Caspase-3表达促进其凋亡。     

Hepatocellular carcinoma review: Current treatment,and evidence-based medicine

We read with great interest the recent article entitled “Hepatocellular carcinoma review: Current treatment, and evidence-based medicine” by Raza et al, published in World Journal of Gastroenterology. Authors evaluated treatments for early and advanced stage hepatocellular carcinoma based on an extensive review of the relevant literature. They reported that radiofrequency ablation is the most effective local ablative therapy. They concluded that RF ablation is equivalent to surgical resection in well selected patients with early stage hepatocellular carcinoma. In addition, we want to mention microwave ablation besides RF ablation.     

Elevated serum alpha fetoprotein levels promote pathological progression of hepatocellular carcinoma

AIM:To investigate the biological role of alpha fetoprotein (AFP) and its clinical signif icance in carcinogenesis of hepatocellular carcinoma (HCC).METHODS:Clinical analysis of HCC patients and im-munohistochemical examination were conducted to evaluate the relationship between serum AFP level and patient mortality. Confocal microscopy,Western blotting, dimethylthiahzolyl-2,5-diphenyl-tetrazolium bromide,Cell Counting Kit-8 assays and flow cytometry were performed to explore the possible mechanism.RESULTS:...     

Surveillance for hepatocellular carcinoma

When hepatocellular carcinoma presents with symptoms cure is seldom possible and death usually follows within months. However, it is possible to detect HCC early, at which stage it is curable. This requires a surveillance program. The components of such a program include: identification of the at risk population, provision of appropriate surveillance tests, and an appropriate method of determining whether the abnormalities found on screening are cancer or not. Surveillance for liver cancer meets all these criteria. Unfortunately high quality evidence showing benefit of liver cancer surveillance is lacking, but lesser quality evidence is plentiful, including several cost efficacy analyses that all show that surveillance does decrease mortality. Therefore all the continental liver disease societies and all national liver disease societies have recommended that surveillance should be undertaken.     

CT灌注成像在AFP阴性及增强CT表现不典型的HCC诊断中的价值

目的探讨CT灌注成像在AFP阴性及增强CT表现不典型的肝细胞癌（HCC）诊断及鉴别诊断中的应用价值。方法从2011年9月至2013年9月收治的HCC患者中随机选择14例进行研究,均予以64层螺旋CT灌注成像扫描。结果 HCC组病灶的平均通过时间（MTT）为（8.6±4.8）s,血管表面通透性（PS）为（28.8±19）mL·100 mL^-1·min^-1,较之非病灶区的（14.5±8.1）s和（59.1±26）mL·100 mL^-1·min^-1,均呈现出显著减少的情况;HCC组病灶的肝动脉灌注分数（HAF）为0.432±0.197,较之非病灶区的0.105±0.113,则呈现出显著增加的情况（均P〈0.05）。HCC组病灶的肝血容量（HBV）（30±20）mL/100 mL和肝血流量（HBF）（232±170）mL·100 mL^-1·min^-1较之非病灶区（25±16）mL/100 mL、（175±76）mL·100 mL^-1·min^-1差异均无统计学意义（均P〉0.05）。在HBF方面,肝血管瘤组病灶与HCC组病灶之间存在显著差异。肝局灶性结节增生与非结节区的各灌注参数大小基本一致,但肝局灶性结节增生的HAF小于非结节区。HCC组病灶灌注参数合患者血清AFP之间不存在明显的相关性,PS（r=-0.1022,P=0.7520）;HAF（r=-0.3138,P=0.2964）;MTT（r=0.0416,P=0.8926）;HBV（r=-0.2170,P=0.4765）;HBF（r=-0.2152,P=-0.4801）。结论 CT灌注成像在AFP阴性及增强CT表现不典型的HCC诊断及鉴别诊断中具有重要的应用价值。     

Hepatocellular carcinoma treated with transarterial chemoembolization: dynamic perfusion-CT in the assessment of residual tumor

AIM: To asses the value of computed tomography (CT)-perfusion in the detection of residual hepatocellular carcinoma (HCC) vascularization after transarterial chemoembolization (TACE). METHODS: Thirty-two consecutive patients were pro-spectively included in this study. All patients had liver cirrhosis and a conf irmed HCC lesion which was treated with TACE. One month after treatment, perfusion measurements of treated lesions were carried out. The CTperfusion (CT-p) protocol was performed with 16 slice multid...     

Neutrophil to lymphocyte ratio and albumin bilirubin grade in hepatocellular carcinoma: A systematic review

BACKGROUND Hepatocellular carcinoma(HCC) is a frequent cause of cancer related death globally. Neutrophil to lymphocyte ratio(NLR) and albumin bilirubin(ALBI) grade are emerging prognostic indicators in HCC.AIM To study published literature of NLR and ALBI over the last five years, and to validate NLR and ALBI locally in our centre as indicators of HCC survival.METHODS A systematic review of the published literature on PubMed of NLR and ALBI in HCC over the last five years. The search followed the guidelines of the preferred reporting items for systematic reviews and meta-analyses. Additionally, we also investigated HCC cases between December 2013 and December 2018 in our centre.RESULTS There were 54 studies describing the relation between HCC and NLR and 95 studies describing the relation between HCC and ALBI grade over the last five years. Our local cohort of patients showed NLR to have a significant negative relationship to survival(P = 0.011). There was also significant inverse relationship between the size of the largest HCC nodule and survival(P = 0.009). Median survival with alpha fetoprotein(AFP) 10 KU/L was 20 mo and with AFP 10 KU/L was 5 mo. We found that AFP was inversely related to survival, this relationship was not statically significant(P = 0.132). Mean survival for ALBI grade 1 was 37.7 mo, ALBI grade 2 was 13.4 months and ALBI grade 3 was 4.5 mo. ALBI grades performed better than Child Turcotte Pugh score in detecting death from HCC.CONCLUSION NLR and ALBI grade in HCC predict survival better than the conventional alpha fetoprotein. ALBI grade performs better than Child Turcotte Pugh score. These markers are done as part of routine clinical care and in cases of normal alpha fetoprotein, these markers could give a better understanding of the patient disease progression. NLR and ALBI grade could have a role in modified easier to learn staging and prognostic systems for HCC.     

Hepatocellular carcinoma: Mechanisms of progression and immunotherapy

Liver cancer is one of the most common malignancies,and various pathogenic factors can lead to its occurrence and development.Among all primary liver cancers,hepatocellular carcinoma(HCC)is the most common.With extensive studies,an increasing number of molecular mechanisms that promote HCC are being discovered.Surgical resection is still the most effective treatment for patients with early HCC.However,early detection and treatment are difficult for most HCC patients,and the postoperative recurrence rate is high,resulting in poor clinical prognosis of HCC.Although immunotherapy takes longer than conventional chemotherapy to produce therapeutic effects,it persists for longer.In recent years,the emergence of many new immunotherapies,such as immune checkpoint blockade and chimeric antigen receptor T cell therapies,has given new hope for the treatment of HCC.     

Hepatocellular carcinoma and evidence-based surgery

Transplantation cannot be considered the most important therapeutic procedure for hepatocellular carcinoma (HCC). In France, no more than 2% of patients with HCC undergo a transplantation. Randomized controlled trial must assess the benefit to risk ratio of various potentially “curative” treatment procedures (transplantation, resection, radio-frequency ablation).     

Hepatocellular carcinoma review:Current treatment,and evidence-based medicine

Hepatocellular carcinoma(HCC)is the fifth most common tumor worldwide.Multiple treatment options are available for HCC including curative resection,liver transplantation,radiofrequency ablation,trans-arterial chemoembolization,radioembolization and systemic targeted agent like sorafenib.The treatment of HCC depends on the tumor stage,patient performance status and liver function reserve and requires a multidisciplinary approach.In the past few years with significant advances in surgical treatments and locoregional therapies,the short-term survival of HCC has improved but the recurrent disease remains a big problem.The pathogenesis of HCC is a multistep and complex process,wherein angiogenesis plays an important role.For patients with advanced disease,sorafenib is the only approved therapy,but novel systemic molecular targeted agents and their combinations are emerging.This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature.     

Hepatocellular carcinoma surveillance:An evidence-based approach

Hepatocellular carcinoma(HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound(US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease(NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection.Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as nonCaucasian race and low socioeconomic status.     

hAFP增强子调控的肝癌特异性基因治疗载体的构建及活性测定

目的:构建新型AFP顺式作用元件调控的基因表达载体,检测该调控元件的特异性和活性表达.方法:设计含有特定酶切位点的引物,采用PCR法从HepG2细胞中克隆AFP启动子及增强子基因亚区片段.启动子与增强子长、短片段分别与含有报告基因荧光素酶基因的载体pGL-3的多克隆位点连接,构建不同长度hAFP增强子调控的肝癌特异性Luciferase表达载体APSE-Luc/APLE-Luc.经测序,PCR及酶切鉴定各重组体.用脂质体法将表达载体转染表达或不表达AFP的肿瘤细胞系进行荧光强度及特异性表达测定.结果:成功地将AFP基因启动子、增强子克隆到报告基因载体pGL-3的多克隆位点,构建成为不同长度hAFP增强子调控的肝癌特异性Luciferase表达载体APSE-Luc/APLE-Luc,酶切鉴定和DNA序列分析无误.转染APLE-Luc质粒的细胞中Luciferase表达量明显高于转染APSE-Luc质粒的细胞,其在HepG2细胞中的表达明显高于SMMC7721细胞及Hela细胞.结论:成功构建AFP启动子与增强子联合调控载体APSE-Luc/APLE-Luc.AFP增强子能够特异性地增强目的基因在AFP阳性细胞中表达,并且不同的亚区活性不同,长片段的活性明显高于短片段.     

AFP阴性肝癌的肿瘤标志物诊断的研究进展

甲胎蛋白(alpha-fetoprotein,AFP)是肝细胞癌(hepatocellular carcinoma,HCC)的主要标志物,测定血清AFP水平是目前诊断HCC的主要手段.约1/3的HCC患者血清AFP水平正常,即所谓的AFP阴性肝癌,这部分患者的诊断是目前肝癌诊断中需解决的关键问题.多年来,人们一直在寻找能弥补AFP不足的肝癌标志物,以提高HCC的诊断水平.本文综述了有关AFP阴性肝癌的肿瘤标志物诊断研究进展,主要内容包括传统肝癌标志物对AFP阴性肝癌的诊断价值,新肝癌标志物对AFP阴性肝癌的诊断价值,以及对AFP阴性HCC具有潜在诊断价值的生物标志物.     

Hepatocellular carcinoma in viral hepatitis: Improving standard therapy

The prognosis of hepatocellular carcinoma (HCC) patients depends not only on tumour stage but also on the background liver function reservoir. For years, surgical resection has been considered as the sole potentially curative option, but currently it competes with transplantation and percutaneous ablation. Resection is usually indicated in patients with solitary HCC and preserved liver function. In cases of poor liver function reservoir and/or multiplicity of lesions, liver transplantation is the treatment option of choice. However, liver transplantation is frequently not feasible because of the shortage or absence of a donor or the condition of the recipient. Image-guided local ablation therapies, such as percutaneous ethanol injection and radiofrequency ablation, have been playing important roles because they are potentially curative, less invasive, and easily repeatable. TACE has been widely performed for unresectable HCC. However, complete necrosis of whole lesions is rarely achieved, and TACE should be indicated for advanced HCC that cannot be treated by resection or ablation. Recently, various agents that interfere with VEGFR signalling are being investigated, although their safety and effectiveness have yet to be confirmed. Short-term prognosis of HCC patients has been much improved recently due to advances in early diagnosis and treatment. However, long-term prognosis is as yet far from satisfactory, as indicated by the fact that overall survival at 10 years after apparently curative treatment of HCC is as low as 22–35%. Prevention of recurrence of HCC is one of the most challenging tasks in current hepatology.

• hepatocellular carcinoma (HCC) is one of the most common cancers worldwide.

• the prognosis of HCC patients depends not only on tumour stage but also on the background liver function reservoir.

• the short-term prognosis of HCC patients has been much improved recently by advances in early diagnosis and treatment.

• the choice of optimal treatment for individual patients, especially those at an earlier cancer stage, is sometimes controversial.

• prevention of recurrence of HCC, or tertiary prevention, is one of the most challenging tasks in current hepatology.

MicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma

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