Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma

Exosomes, extracellular vesicles with a diameter of 40 to 160 nm, are among the smallest extracellular vesicles released by cells. They deliver different cargoes, including proteins, DNAs, and RNAs, and facilitate communication between cells to coordinate a variety of physiological and pathological functions. Hepatocellular carcinoma (HCC) is the sixth common malignant tumor and the fourth leading cause of cancer-related death worldwide. Its molecular mechanism remains largely unknown, and there is a lack of reliable and noninvasive biomarkers for early diagnosis and prognosis prediction. Mounting evidence has shown that exosomes carry a variety of ncRNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which play critical roles in the occurrence and progression of HCC. In this review, we summarize the recent findings of exosomal miRNAs, lncRNAs, and circRNAs in HCC from their impact on the development of HCC to their potential applications in the diagnosis and treatment of HCC.     

系统炎症指数变化率在预测肝细胞肝癌复发中的意义

摘 要：［目的］ 探讨肝细胞肝癌（hepatocellular carcinoma,HCC）患者切除术前外周血系统炎症指数变化率（deltas ystematic inflammation index,Delta SII）对术后HCC复发的影响。［方法］回顾性分析接受HCC根治性切除术的患者123例。SII变化率（Delta SII）计算方式为：（术后SII-术前SII）/天数。术后SII为术后首次复查时采血检验所得数据。使用X-tile软件估算Delta SII对于术后复发的最佳决定值。Kaplan-meier法绘制生存曲线,Log-rank检验评估Delta SII在全部患者人群以及多种低危风险组中的价值。单因素Cox回归模型分析术前各临床参数对于术后复发的影响,有统计学意义的术前单因素进入Cox回归模型进行多因素分析。ROC曲线分析各参数对于复发预测的效能。［结果］截止2016年7月,123例患者中位随访时间43.60个月,共有55例（44.72%）患者复发。X-tile计算得到的Delta SII最佳切点为-2.64,其中 Delta SII≤-2.64患者98例（79.67%）,Delta SII>-2.64患者25例（20.33%）。单因素分析显示术前SII（P=0.041）、术后SII（P=0.035）以及Delta SII（P=0.027）是术后无瘤生存率的影响因素。多因素分析显示Delta SII是预测术后肿瘤复发的唯一独立危险因子（OR=2.49,95%CI：1.22～6.54,P=0.044）。对AFP阴性（≤400ng/ml）以及BCLC 0+A期的早期肝癌两个低复发风险亚组,Delta SII>-2.64依然是一个具有显著意义的复发评估指标（P均<0.05）。Delta SII>-2.64与多灶性肿瘤的发生具有显著的相关性（P=0.048）。ROC曲线分析显示Delta SII具有最大的复发预测效能。［结论］ Delta SII是一个简便、高效、易检测、低成本的HCC切除术后早期复发预测指标,Delta SII>-2.64的HCC患者术后早期复发风险显著增加,在临床工作中检测Delta SII有利于临床制定更加有效的HCC综合治疗监测方案。     

Epidemiology and Survival of Hepatocellular Carcinoma in the Central Region of Thailand

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in men and the third mostcommon cancer in woman in Thailand. This retrospective study was designed to assess the prevalence, clinicalmanifestations, treatment outcomes and prognosis of HCC in the central region of Thailand. Materials andMethods: The authors retrospectively reviewed all HCC patients aged more than 15 years old in Thammasatuniversity hospital (TUH) during the period from January 2007 to December 2012. Clinical information,biochemical tests and radiologic findings were collected from review of medical records. Results: There were308 patients with HCC, which accounted for the prevalence of 5.19% of all cancers diagnosed in TUH duringthe study period. Of these, 125 (40.5%) had complete information retrievable from their medical records andmet the inclusion criteria, 99 (79.2%) were males. The mean age was 57.4 years. A quarter of HCC patients inthis study presented without any symptom before diagnosis. The common clinical presentations in the remainingpatients were hepatomegaly 64/125 (51.2%), abdominal pain 56/125 (44.8%) and ascites 16/125 (20.8%). Cirrhosiswas seen in almost all patients (92.8%). The most common causes of HCC in this study were chronic hepatitisB (49.6%) and C (19.2%). Based on Barcelona Clinic Liver Cancer staging, 75.4% presented at intermediateor late stage. Patients receiving curative therapy with either surgical treatment or radiofrequency ablation hadsignificantly longer survival time after the HCC diagnosis than the palliative therapy group (11.0 months vs 4.0months, p value= 0.004). The mean survival time after the HCC diagnosis was 10.5 months. Conclusions: Thecommon causes of HCC in central region of Thailand were chronic hepatitis B and C. Surgical therapy or RFAseemed to provide better outcomes than other treatments but only in patients with early stage lesions. Most ofthe patients in this study presented with advanced diseases and had grave prognosis. Appropriate screeningpatients at risk for HCC might be an appropriate way to achieve early diagnosis and improve the treatmentoutcome.     

广西新发现两个肝癌高发家族的病因学比较

目的 阐明在广西瑶族地区新发现的两个肝癌高发家族发生肝癌家族聚集性的危险因素。方法 以广西瑶族不同地区的两肝癌高发家族成员作为研究对象,应用ELISA法检测研究对象血清中HBV和HCV血清学标志物、采用PCR和RT-PCR技术分别检测HBV DNA和HCV RNA,结合流行病学调查结果进行综合分析。结果 两肝癌高发家族成员中HBsAg、HBsAb、HBeAg、HBeAb、HBcAb、HBV DNA、抗 HCV、HCV RNA的阳性率分别为45.0%(9/20)、35.0%(7/20)、15.0% (3/20)、25.0% (5/20)、45.0%(9/20)、25.0%(5/20)、0(0/20)、0(0/20)和9.52%(2/21)、42.9%(9/21)、4.8%(1/21)、4.8%(1/21)、23.8%(5/21)、9.52%(2/21)、0(0/21)、0(0/21)。其中HBsAg在两组间的差别具有统计学意义（P＝0.033）,A家族以山泉水作为饮用水,B家族十年前以塘水作为生活用水;其余因素差异未见统计学意义。结论 瑶族不同地区、不同家族成员发生肝癌家族聚集性的危险因素可以有所不同,HBV感染、饮用塘水等因素均可与遗传因素相互作用,从而导致肝癌家族聚集性的发生。     

肝细胞癌患者HBV,HCV感染状态的研究

收集浙医一院肿瘤科切除的肝癌病人31例，经病理证实均为肝细胞癌，83.87％伴结节性肝硬变。对照组17例。用ELISA法检测血清乙肝三系和HCV－Ab，用Nested－PCR法检测肝组织HBV-DNA和HCV-RNA。本研究得到以下结论：1）血清中抗HCV检测不能完全反映肝内是否曾有HCV感染情况。2）肝癌组织中确实存在HCV－RNA。3）肝细胞癌中，绝大多数存在乙型肝炎病毒感染的背景，血清、肝组织检测乙肝病毒标志均能反映其感染状态。4）肝癌中存在着HBV、HCV重叠感染的情况。     

Therapeutic Options in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is common in Africa as well as south eastern Asia, and is usually related to chronic hepatitis B virus infection although chronic hepatitis C virus infection and alcohol abuse also play a major role. Mass vaccination against the hepatitis B virus in neonates has been undertaken in Taiwan and South Africa with encouraging results. The treatment of choice for HCC is surgery, but radical resection is only feasible in a small percentage of patients because of the advanced nature of the disease and underlying liver cirrhosis. If surgical resection is not feasible, intra-arterial chemoembolization may reduce the size of tumors providing good palliation, and possibly render inoperable tumors operable. Locally ablative therapies including percutaneous ethanol injection, cryosurgery, microwave coagulation, and radiofrequency thermal ablation are useful in patients with limited disease, but are methods that are only feasible in highly specialized units. Liver transplantation, which is also only available in highly specialized centers, has unfortunately been disappointing. Unresectable HCC has a very poor prognosis, as the disease is highly refractory to most chemotherapy agents, possibly as a result of overexpression of the multidrug resistance gene, mdr1. Overall response rates of 10–15% have been reported with most chemotherapeutic agents, with doxorubicin probably being the most active agent. Other agents studied include fluorouracil as well as the newer oral fluoropyrimidines, etoposide, gemcitabine, anthracycline analogues including mitoxantrone, epirubicin, and pegylated liposomal doxorubicin, as well as cisplatin and the direct thymidylate synthase inhibitors raltitrexed and nolatrexed. Other agents including tamoxifen, tyrosine kinase inhibitors, thalidomide, interferons, and clofazimine have also been studied. Administration of viral vectors containing the p53 gene, or other tumor suppressor and suicide genes, is also a possible future therapy. Unfortunately as current approaches still remain unsatisfactory, especially in patients with advanced unresectable disease, newly diagnosed patients should, whenever available, be entered onto clinical studies with new agents which may result in better therapies for this highly refractory disease.     

Multicenter Epidemiologic Study on Hepatocellular Carcinoma in Turkey

Background: Hepatocellular cancer (HCC) is one of the important health problems in Turkey, being verycommon and highly lethal. The aim of this study was to determine clinical, demographic features and risk factors.Materials and Methods: Nine hundred and sixth-three patients with HCC from 13 cities in Turkey were includedin this study. Results: Only 205 (21%) of the 963 patients were women, with a male:female predominance of4.8:1 and a median age of 61 years. The etiologic risk factors for HCC were hepatitis B in 555 patients (57.6%),453 (81%) in men, and 102 (19%) in women, again with male predominance, hepatitis C in 159 (16.5%), (14.9%and 22.4%, with a higher incidence in women), and chronic alcohol abuse (more than ten years) in 137 (14.2%)(16.8% and 4.9%, higher in males). The Child-Pugh score paralleled with advanced disease stage amd also a highlevel of AFP. Conclusions: According to our findings the viral etiology (hepatitis B and hepatitis C infections)in the Turkish population was the most important factor in HCC development, with alcohol abuse as the thirdrisk factor. The Child-Pugh classification and AFP levels were determined to be important prognostic factors inHCC patients.     

Advances in Management of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most frequent type of malignant liver tumor and a high impact health problem worldwide. The prevalence of HCC is particularly high in many Asian and African countries. Some HCC patients have no symptoms prior to diagnosis and many of them therefore present at late stage and have a grave prognosis. The well-established causes of HCC are chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection or alcoholic cirrhosis and nonalcoholic steatohepatitis. The Barcelona Clinic Liver Cancer (BCLC) Staging System remains the most widely used for HCC management guidelines. To date, the treatments for HCC are still very challenging for physicians due to limited resources in many parts of the world, but many options of management have been proposed, including hepatic resection, liver transplantation, ablative therapy, chemoembolization, sora nib and best supportive care. This review article describes the current evidence-based management of HCC with focus on early to advance stages that impact on patient overall survival.     

Cancer Stem Cells in Hepatocellular Carcinoma

Background

Hepatocellular carcinoma is one of the most common cancers and the second leading cause of cancer-related deaths worldwide. Only a small proportion of patients benefit from curative treatment and the prognosis is very poor for the majority of cases due to late presentation, resistance to chemotherapy and high recurrence rate. In recent years, progress in stem cell biology allowed us to explain that hierarchically organized cancer stem cells (CSCs) drive histological and functional heterogeneity of hematological malignancies and solid tumors.

Methods and Results

Also referred to as tumor-initiating cells, CSCs have been isolated from both hepatocellular carcinoma (HCC) cell lines and primary tumors by using hepatic progenitor markers. Although there is still no consensus on cancer stem cell phenotype in HCC, single or combined use of CSC markers defines a minor population of tumor cells with the capacity of self-renewing and the ability to recapitulate the original tumor heterogeneity.

Conclusions

This review focuses on the biological features of CSCs and their potential as diagnostic/prognostic tools and therapeutic targets in HCC.

     

Burden of Hepatocellular Carcinoma in Asian

Hepatocellular carcinoma (HCC), the sixth most prevalent cancer worldwide, continues to have high prevalence in many countries of Asia. The main challenge is the high prevalence of chronic hepatitis and aflatoxin, for example in China. HBV vaccination should be the major preventive tactic in Asian countries. The burden of HCC is low in Iran because most cases are due to HBV and this infection was less common. Although in Iran, a mass vaccination program started in 1993, its impact on decreasing the burden of HCC due to HBV can onlybe expected in future decades.     

Update on Embolization Therapies for Hepatocellular Carcinoma

Purpose of Review

The purpose of the review is to summarize the latest applications for embolotherapy in the management of patients with HCC according to BCLC stage.

Recent Findings

While traditionally reserved for patients with unresectable HCC and stage B disease, there is an important role for embolization therapies in earlier stage patients as an adjunct to ablation, bridging, or downstaging therapy, as a means to improve safety of resection, and potentially as an arterial ablative option in the case of radioembolization. Newer applications of radioembolization such as radiation segmentectomy have the potential to provide cure in localized unifocal disease, and transarterial chemoembolization–portal vein embolization and radiation lobectomy may provide a combination of treatment and future liver remnant hypertrophy for planned hepatic resection. There is also an increasing role for embolization in the treatment of stage C disease, and recent data suggest it can be used in combination with sorafenib with the potential for survival benefit over sorafenib alone, even in the case of portal vein tumor thrombus.

Summary

Embolization therapies play an increasingly important role in patients with BCLC stage A–C hepatocellular carcinoma. While different therapies may be offered on a patient-specific basis, there are limited prospective RCT data to support superiority of one technique over another.

     

肝细胞癌中表观遗传改变对免疫治疗的影响

肝细胞癌是最常见的恶性肿瘤之一,早期诊断困难,致死率高,相对于其他恶性肿瘤而言欠缺有效的治疗方法。近年来,表观遗传机制被广泛研究,与基因突变不同,表观遗传改变是动态的、可靶向修正的,且表观遗传失调对肿瘤免疫也产生影响。靶向修正表观遗传能够改善肿瘤免疫,增强免疫治疗效果,为探索新型联合治疗带来希望。全文主要讨论肝细胞癌发生发展过程中表观遗传的主要变化以及表观遗传对肿瘤免疫的影响,探索联合靶向表观遗传和免疫治疗新疗法。