Hepatocellular carcinoma： Therapy and prevention

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for the early detection of HCC in patients at risk, patient survival has not improved during the last three decades. This is due to the advanced stage of the disease at the time of clinical presentation and limited therapeutic options. The therapeutic options fall into five main categories: surgical interventions including tumor resection and liver transplantation, percutaneous interventions including ethanol injection and radiofrequency thermal ablation, transarterial interventions including embolization and chemoembolization, radiation therapy and drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomized controlled clinical trials that are the basis for therapeutic recommendations. Though surgery, percutaneous and transarterial interventions are effective in patients with limited disease (1-3 lesions, <5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality of HCC, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should allow to further elucidate the molecular events underlying HCC development and to identify novel diagnostic markers as well as therapeutic and preventive targets.     

Coexistence of hepatocellular carcinoma and gastrointestinal stromal tumor： A case report

Malignant gastrointestinal stromal tumors(GIST)are raremesenchymal tumors originating from the wall of thegastrointestinal tract.Their coexistence with other tumorsoriginating from other germ layers is unique.We havereported a case of a 63-year-old GIST patient presentingas an epigastric mass associated with hepatic tumor.Histologically,the mesenteric tumor was composed ofspindle cells showing both neural and smooth muscledifferentiation.Immunohistochemical examinationshowed positive staining for CD117,vimentin,S-100,and SMA,while CD34 antigen was negative.The hepatictumor was diagnosed as hepatocellular carcinoma(HCC).To the best of our knowledge,this is the first case ofGIST and HCC coexistence.The rarity of the case,however,should not lead to ignoring such a possibility indifferential diagnosis.     

Clinical practice guidelines for hepatocellular carcinoma： the first evidence based guidelines from Japan

TO THE EDITOR Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Japan, ranked 3rd in males and 5th in females.     

Direct invasion to the colon by hepatocellular carcinoma： Report of two cases

Although hepatocellular carcinoma （HCC） is a common tumor, direct invasion of the gastrointestinal tract by HCC is uncommon. Recently, we encountered two cases of HCC with direct invasion to the colon. The first patient was a 79-year-old man who underwent transarterial chemo-embolization （TACE） for HCC 1.5 years prior to admission to our hospital. Computed tomography （CT） showed a 7.5-cm liver tumor directly invading the transverse colon. Partial resection of the liver and transverse colon was performed. The patient survived 6 mo after surgery, but died of recurrent HCC. The second patient was a 69-year-old man who underwent TACE and ablation for HCC 2 years and 7 months prior to being admitted to our hospital for melena and abdominal distension. CT revealed a 6-cm liver tumor with direct invasion to the colon. The patient underwent partial resection of the liver and right hemicolectomy. The patient recovered from the surgery. But, unfortunately, he died of liver failure due to liver cirrhosis one month later. Although the prognosis of HCC that has invaded the colon is generally poor due to the advanced stage of the disease, surgical resection may be a favorable treatment option in patients with a good general condition.     

Hepatocellular carcinoma： Epidemiology, risk factors and pathogenesis

Hepatocellular carcinoma （HCC） is the commonest primary malignant cancer of the liver in the world. Given that the burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence and obesity-related fatty liver disease, it is expected that the incidence of HCC will also increase in the foreseeable future. This article summarizes the international epidemiology, the risk factors and the pathogenesis of HCC, including the roles of viral hepatitis, toxins, such as alcohol and aflatoxin, and insulin resistance.     

Management of hepatocellular adenoma： Solitary-uncomplicated, multiple and ruptured tumors

AIM: While hepatocellular adenomas (HAs) have often been studied as a unique entity, we aimed to better define current management of the various forms of HAs. METHODS: Twenty-five consecutive patients operated for solitary-uncomplicated (9), multiple (6), and ruptured (10) HAs were reviewed according to management strategies and outcomes. RESULTS: All solitary-uncomplicated HAs (ranged 2.2-14 cm in size) were removed. Out of 25 HAs, 2 (8%) included foci of carcinoma. In the multiple HA group, previously undiagnosed tumors were identified during surgery in 5/6 cases. In three cases with multiple spread HA, several lesions had to be left unresected. They remained unmodified after 4-, 6-, and 6-year radiological follow-up. Patients with ruptured HA (ranged 1.7-10 cm in size) were initially managed with hemodynamic support and angiography, allpwing the embolization of actively bleeding tumors in two patients. All ruptured tumors were subsequently removed 5.5 d (range 4-70 d) after admission. CONCLUSION: Tumors suspected of HA, regardless of the size, should be resected, because of high chances of rupture causing bleeding, and/or containing malignant foci. Although it is desirable to remove all lesions of multiple HA, this may not be possible in some patients, for whom long-term radiological follow-up is advised. Ruptured HA can be managed by hemodynamic support and angiography, allowing scheduled surgery.     

Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil： A pilot study

AIM： To investigate the poor prognosis of HCC with PVTT, we evaluated the efficacy by a new combination chemotherapy for advanced hepatocellular carcinoma （HCC） with portal vein tumor thrombus （PVTT）.
METHODS： From 2002 to 2007, a total of 10 consecutive patients with Stage IVA HCC accompanied by PVTT were studied prospectively to examine the efficacy of treatment by intra-arterial infusion of a chemotherapeutic agents consisting of etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil.
RESULTS： The mean course of chemotherapy was 14.4 （range, 9-21） too. One patient showed complete response （CR） with disappearance of HCC and PVI-F after treatment, and the two patients showed partial response （PR）, response rate （CR ＋ PR/All cases 30%）. The median survival time after the therapy was 457.2 d. The one-year survival rate was 70%. Adverse reactions were tolerable.
CONCLUSION： Although the prognosis of most patients with Stage IVA HCC by PVTT is poor, our combination chemotherapy may induces long-term survival and is an effective treatment and produced anti-tumor activity with tolerable adverse effects in patients for advanced Stage IVA HCC accompanied by PVTT.     

Intraperitoneal metastasis of hepatocellular carcinoma after spontaneous rupture： A case report

Rupture of hepatocellular carcinoma （HCC） is a lifethreatening complication. Peritoneal metastasis of HCC after spontaneous rupture was seldom noted. We report a case of intraperitoneal metastasis of HCC after spontaneous rupture. A previously asymptomatic 72-yearold man was admitted due to dull abdominal pain with abdominal fullness. He had a history of HCC rupture 10 mo ago and transarterial embolization was performed at that time. Abdominal computer tomograghy （CT） scan showed a huge peritoneal mass over the right upper quadrant area. Surgical resection was arranged and subsequent microscopic examination confirmed a diagnosis of moderately-differentiated HCC.     

Serum chromogranin-A in hepatocellular carcinoma： Diagnostic utility and limits

AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, renal, and heart functions influence circulating CgA. The aim of this study was to assess sensitivity and specificity of serum CgA as a marker of HCC in patients with liver cirrhosis (LC). METHODS: Serum CgA levels were measured by RIA in 339 patients of which 54 HCC, 132 LC, 45 chronic hepatitis (CH), 27 chronic heart failure (CHF), 36 chronic renal failure (CRF), 45 chronic inflammatory bowel disease (IBD) as disease controls and in 75 healthy controls. Patients with liver disease or IBD and concomitant renal and/or heart failure were excluded. Pearson correlation, non-parametric combination test and confidence interval analysis were used for statistical analysis. RESULTS: Serum CgA above normal values (100 ng/mL) were found in 83% of HCC patients, in 48% of LC patients, in 20% of CH patients, in 33% of IBD patients, in 92% of CRF patients, in 100% of CHF patients, and in none of the healthy controls. The mean CgA values in HCC (769±1046), in LC (249±369), in CH (87±94), in CRF (1390±1401), in CHF (577±539), in IBD (146±287) were significantly higher than those in healthy controls (48±18). HCC patients had higher CgA values (P<0.01) than LC, CH, and IBD patients but did not differ from those with CRF or CHF. The 95% CI for the mean (250-1289 ng/mL) in HCC patients was selected as a CgA range and the lower value of such range was assumed as cut-off. Sensitivity and specificity of CgA, calculated in relation to the cut-off in patients with cirrhosis and HCC, were respectively 61% (CI 48-73%) and 82% (CI 75-88%). Serum a-FP values were >200 ng/mL in 21% of the HCC patients and in none of the LC patients. No significant correlation was found between a-FP and CgA in patients with HCC and in patients with cirrhosis. CONCLUSION: When HCC is suspected and a-FP is normal or <200 ng/mL, CgA serum values represent a complementary diagnostic tool, unless kidney or heart failure is present.     

Rare pulmonary and cerebral complications after transarterial chemoembolisation for hepatocellular carcinoma： A case report

We report a rare case of acute pulmonary and cerebral complication after transarterial chemoembolisation （TACE） for inoperable hepatocellular carcinoma. The case involved a large tumor and hepatic vein invasion. Nonspecific pulmonary and cerebral symptoms such as acute dyspnoea and transient consciousness loss developed in the patient, a 49-year-old woman, following the TACE due to pulmonary and cerebral oil embolism. The chest and brain conditions of this patient improved after some supportive therapies and nursing interventions. She also subsequently completed the other three procedures of TACE.     

Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

Hepatocellular carcinoma(HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancerrelated death. The difficulty to diagnose early cancer stages, the aggressive behaviors of HCC, and the poor effectiveness of therapeutic treatments, represent the reasons for the quite similar deaths per year and incidence number. Considering the fact that the diagnosis of HCC typically occurs in the advanced stages of the disease when the therapeutic options have only modest efficacy, the possibility to identify early diagnostic markers could be of significant benefit. So far, a large number of biomarkers have been associated to HCC progression and aggressiveness, but many of them turned out not to be of practical utility. This is the reason why active investigations are ongoing in this field. Given the huge amount of published works aimed at the identification of HCC biomarkers, in this review we mainly focused on the data published in the last year, with particular attention to the role of(1) molecular and biochemical cellular markers;(2) micro-interfering RNAs;(3) epigenetic variations; and(4) tumor stroma. It is worth mentioning that a significant number of the HCC markers described in the present review may be utilized also as targets for novel therapeutic approaches, indicating the tight relation between diagnosis and therapy. In conclusion, we believe that integrated researches among the different lines of investigation indicated above should represent the winning strategies to identify effective HCC markers and therapeutic targets.     

Hepatocellular carcinoma,hepatitis C virus infection and miRNA involvement: Perspectives for new therapeutic approaches

Chronic hepatitis C virus (HCV) infection is the principal etiology of cirrhosis and, ultimately, hepatocellular carcinoma (HCC). At present, approximately 71 million people are chronically infected with HCV, and 10%–20% of these are expected to develop severe liver complications throughout their lifetime. Scientific evidence has clearly shown the causal association between miRNAs, HCV infection and HCC. Although it is not completely clear whether miRNA dysregulation in HCC is the cause or the consequence of its development, variations in miRNA patterns have been described in different liver diseases, including HCC. Many studies have analyzed the importance of circulating miRNAs and their effect on cell proliferation and apoptosis. In this Review, we aim to summarize current knowledge on the association between miRNA, HCV and HCC from a diagnostic point of view, and also the potential implications for therapeutic approaches.     

Hsa-miR-93在肝癌中的作用机制研究

目的观察hsa-miR-93对肝癌细胞生长和细胞周期的影响，以分析其在肝癌中的作用机制。方法用real time RT-PCR法分析hsa-miR-93在人肝癌和癌旁肝组织的表达情况。此后构建hsa-miR-93过表达载体，同时合成二甲氧修饰的hsa-miR-93的反义核苷酸序列，二者转染肝癌细胞株观察它们对肝癌细胞生长及细胞周期的影响，分别以空载体和无关寡核苷酸序列为对照。转染后CCK-8法检测肝癌细胞生长情况，通过流式细胞仪分析细胞周期。结果hsa-miR-93在肝癌组织中表达明显高于癌旁肝组织。hsa-miR-93过表达载体可以促进肝癌细胞生长，促进细胞周期的G1／S期转换，而hsa-miR-93反义序列抑制肝癌细胞生长，使肝癌细胞阻滞于G1期（P〈0．05）。结论hsa-miR-93通过促进细胞周期的G1／S期转换而促进肝癌细胞生长，提示hsa-miR-93可能是肝癌的发病机制中一个重要分子。     

NAFLD与肝细胞癌的相关性研究进展*

非酒精性脂肪性肝病（NAFLD）已成为世界范围内最常见的慢性肝脏疾病,被认为是代谢综合征在肝脏的表现,其疾病谱从轻微肝细胞脂肪变性到非酒精性脂肪性肝炎（NASH）,进一步可发展为肝硬化或肝细胞癌（HCC）。随着肥胖及胰岛素抵抗问题的日益严重,NAFLD、NASH及其相关肝硬化、肝癌患者也日益增多。近年来研究表明,NASH可不经肝硬化阶段直接发展为HCC,具体机制尚不明确。     

Novel therapies for hemodialysis vascular access dysfunction: fact or fiction!

Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis population and contributes significantly to the overall cost of end-stage renal disease programs. At a histological level, most hemodialysis vascular access dysfunction (in both native arteriovenous fistulae and PTFE dialysis access grafts) is due to venous stenosis and thrombosis, secondary to venous neointimal hyperplasia. However, despite a wealth of experimental and clinical data on the use of novel therapeutic interventions that target neointimal hyperplasia in the setting of coronary artery disease, there are unfortunately no effective therapeutic interventions for hemodialysis vascular access dysfunction at the present time. This is particularly unfortunate, since neointimal hyperplasia in the setting of hemodialysis vascular access fistulae and grafts could be the ideal clinical model to test novel therapeutic interventions for neointimal hyperplasia.     

Imaging appearance of treated hepatocellular carcinoma

Surgical resection and imaging guided treatments play a crucial role in the management of hepatocellular carcinoma(HCC).Although the primary end point of treatment of HCC is survival,radiological response could be a surrogate end point of survival,and has a key role in HCC decision-making process.However,radiological assessment of HCC treatment efficacy is often controversial.There are few doubts on the evaluation of surgical resection;in fact,all known tumor sites should be removed.However,an unenhancing partial linear peripheral halo,in most cases,surrounding a fluid collection reducing in size during follow-up is demonstrated in successfully resected tumor with bipolar radiofrequency electrosurgical device.Efficacy assessment of locoregional therapies is more controversial and differs between percutaneous ablation(e.g.,radiofrequency ablation and percutaneous ethanol injection)and transarterial treatments(e.g.,conventional transarterial chemoembolization,transarterial chemoembolization with drug eluting beads and radioembolization).Finally,a different approach should be used for new systemic agent that,though not reducing tumor mass,could have a benefit on survival by delaying tumor progression and death.The purpose of this brief article is to review HCC imaging appearance after treatment.     

Innovative surgical approaches for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide,with an increasing diffusion in Europe and the United States.The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC.In this review,we will analyze the modern concept of preoperative management,the role of laparoscopic and robotic surgery,the intraoperative use of three dimensional models and augmented reality,as well as the potential application of fluorescence.     

规则性肝切除术治疗原发性肝癌的分析

目的:随机对照观察规则性肝切除术治疗原发性肝癌的安全性以及临床疗效,探讨治疗肝癌合理的手术方式.方法:将38例肝切除术治疗原发性肝癌的患者随机分为2组:规则性肝切除术15例.非规则性肝切除术23例,对两组病例的手术和随访情况进行分析评价.结果:两组均无手术死亡,术中出血、并发症发生率、住院时间无显著差异.规则性肝切除标本切缘满意率(大于2cm)较高,术后近期复发率显著降低,一年无瘤生存率高于非规则性肝切除.结论:规则性肝切除是治疗原发性肝癌安全有效的术式,对有适应证的病例应尽可能采用此种手术方式,有望获得较好的疗效.     

肝细胞癌的非手术治疗

肝细胞癌（HCC）是原发性肝癌的最主要类型。肝切除术可根治 HCC,使患者长期生存,但肝切除术受到一定的限制,主要在于：（1）肿瘤细胞恶性程度高、病情进展快,极易发生播散和转移;（2）HCC 患者多存在严重的肝硬化基础,因为肝功能失代偿而无法手术;（3）大部分肿瘤为多中心发生,很难切除完全。因此,切除率低和复发率高乃是制约手术治疗 HCC 患者的主要障碍。联合应用手术治疗与各种非手术治疗,多种方案的优化组合将成为综合治疗 HCC 患者的优先选择,提高疗效[1,2]。目前,常用的非手术治疗方法主要有肝动脉化疗栓塞（TACE）、局部消融、放射治疗、系统化疗和分子靶向治疗等。