肝细胞癌的免疫治疗

在过去的10年里,肝细胞癌(HCC)系统治疗的进步归功于分子靶向治疗的应用及免疫治疗的提高。HCC所处的免疫抑制微环境使肝癌细胞逃逸免疫系统的攻击,这亦为肝癌发展的重要原因,通过提高针对HCC的免疫杀伤能力,纠正免疫抑制状态是HCC免疫治疗的策略。HCC特异性抗原为基础的肿瘤疫苗治疗、基因工程改造的T淋巴细胞治疗、免疫检查点抑制剂的基础研究及临床转化使免疫治疗效果较过去有了显著提高。免疫治疗联合其他抗肿瘤治疗方法如局部消融、分子靶向治疗或肿瘤疫苗等综合治疗模式值得进一步探索。     

肝癌的免疫治疗进展

近年来,随着生物治疗技术的发展,免疫治疗成为了目前肿瘤治疗研究的热点。肝细胞癌(hepatocellular carcinoma,HCC)是最常见的肝脏恶性肿瘤,其治疗以手术、介入治疗、分子靶向治疗以及全身系统化疗等多种治疗手段联合应用,但效果不理想,无进展生存期及中位生存时间仍不尽人意。该文应用Pub Med数据库及中国期刊全文数据库(CNKI)检索系统,以"肝细胞癌、免疫治疗、免疫耐受"为关键词进行检索分析,总结了最近几年免疫疗法在肝癌治疗方面中的进展。重点是肝脏免疫系统的特殊性、HCC的免疫耐受性和HCC的免疫治疗策略,包括疫苗适应性治疗、免疫检查点抑制剂和细胞因子,以及靶向治疗联合免疫治疗在肝癌治疗中的应用等方面。希望能为临床医师了解肝癌免疫耐受的机制和HCC免疫治疗的进展和临床疗效提供参考。     

肝癌微波消融联合免疫治疗现状及前景

肝细胞肝癌在全球范围内的发生率呈逐年上升的趋势,在我国其死亡率已位居第3位。早期精准的诊断技术、各种手术治疗手段及放化疗等治疗方法的应用使得肝细胞肝癌的术后生存率得到显著的提高,但术后的高复发率及转移率成为制约其疗效的瓶颈。自从发现肝细胞肝癌具有免疫原性,微波消融能促进抗原释放,免疫治疗能激发特异性抗肿瘤免疫,微波消融联合免疫治疗很快被认为是治疗肝细胞肝癌最有前景的方法之一。现就目前研究的关于微波消融对机体免疫状态的影响、肿瘤相关抗原的释放及其作用机制和过继免疫治疗现状及前景作简要总结,为临床开展新型免疫治疗方法提供有力依据。     

肝癌围手术期的免疫治疗

肝细胞癌(以下简称肝癌)严重威胁我国人民的生命和健康。大多数肝癌患者在就诊时已处于中晚期,不适合接受根治性治疗;适合接受根治性治疗的早期肝癌患者仍然面临着术后较高的复发风险。鉴于以免疫检查点抑制剂为核心的免疫治疗方案在中晚期肝癌领域取得了重要进展,肝癌患者的围手术期免疫治疗也逐渐受到重视。在围手术期应用免疫治疗可以提高手术切除的可行性、降低手术切除后的复发率和延长患者生存。本文对以免疫检查点抑制剂为主的免疫治疗在肝癌围手术期中的应用和需要关注的问题进行探讨,希望能够为肝癌围手术期的免疫治疗提供新的思路。     

免疫治疗时代下的肝癌肝移植

我国大部分肝癌患者在就诊时不能获得根治性手术治疗,近年来肝癌免疫治疗的突破性进展为这些中晚期肝癌患者带来了曙光。在肝癌肝移植领域,免疫治疗更是因为在肿瘤免疫和移植免疫中扮演的双重角色而备受关注。在术前降期治疗和移植术后肿瘤复发的治疗中均有创新性的应用。在免疫治疗的时代下如何应用移植肿瘤学思维使肝癌肝移植患者获益是一个崭新的课题,这需要在临床实践中进行多学科团队协作,探讨最佳的肝癌肝移植患者治疗策略,最终改善中晚期肝癌患者的预后。     

肝癌局部消融治疗引起的热休克蛋白70增强免疫研究进展

肝癌仍严重威胁人类健康,探索治疗肝癌的新型微创方法迫在眉睫。系统回顾了肝癌在我国的一般情况,叙述了肝癌目前的局部消融及免疫治疗方法。介绍了纳秒脉冲治疗肝癌的基本原理和热休克蛋白70在抗肿瘤免疫中的作用机制。提出纳秒脉冲作为一种外源性电刺激会使机体中的热休克蛋白7表达升高,来加强机体的抗肿瘤免疫。完善了纳秒脉冲治疗肝癌的免疫学机制,并为肝癌的免疫治疗提供了新思路。     

肠道菌群与肝癌免疫治疗的研究进展

肠道菌群对人类的健康发挥了重要作用.研究发现,肠道菌群在肿瘤的发生和肿瘤免疫治疗中也起着关键作用.目前,免疫治疗在肝癌治疗领域取得了重要进展.尽管免疫治疗可以提高肝癌患者的生存,但是目前其疗效仍不够满意.调节肠道菌群组成,特别是使有助于免疫治疗效果的菌群在肠道富集,可能会使得肝癌免疫治疗的效果得到提高.本文就肠道菌群与肝癌免疫治疗的相关研究进展进行综述.     

原发性肝癌淋巴细胞表型变化与转移和复发的关系

原发性肝癌是最常见的恶性肿瘤之一 ,虽然手术是其首选有效的治疗方法 ,但由于患者多合并肝硬化 ,且易发生肝内及远处转移 ,能获手术治疗者仅占 2 0 %左右 ,放、化疗难以彻底消灭肿瘤细胞 ,同时易损伤正常组织 ,降低全身和肝脏局部免疫力。因此 ,近年来生物免疫治疗已渐成为肿瘤治疗的第四模式。为探讨免疫治疗与介入治疗对原发性肝癌患者淋巴细胞表型的影响及其临床相关性 ,2 0 0 0～2 0 0 1年 ,我们对 42例中晚期原发性肝癌患者采用动脉栓塞 (TACE)与干扰素联合治疗 ,现报告如下。1　资料与方法1 .1　一般资料　本文中晚期原发性肝癌患…     

肝细胞癌细胞免疫治疗的研究进展

肝细胞癌(HCC)的治疗目前主要采用以手术为主、配合局部放疗和化疗的综合治疗措施,但多数患者经综合治疗后也容易复发,缺乏有效的治疗药物和手段,总体治疗效果并不理想。越来越多的证据表明,肝癌的发生、发展、转移和复发与机体免疫系统有密切的关系。因此,免疫治疗特别是细胞免疫治疗可以调节机体免疫功能,诱导特异性肿瘤免疫,达到治疗肝癌、减少肝癌复发和转移的目的,已成为肝癌综合治疗的重要组成部分。对细胞免疫治疗在HCC中的临床前研究和临床试验取得的成果进行综述,并讨论当前存在的问题。     

原发性肝癌的非手术治疗

近年来,原发性肝癌的诊断和治疗取得了长足的进步,尤其是分子靶向治疗和免疫治疗等非手术治疗领域进展迅速。本文围绕原发性肝癌介入治疗、放射治疗、靶向治疗和免疫治疗等近3年来的最新数据和前沿研究进行回顾和总结。     

Effect of interferon therapy on first and second recurrence after resection of hepatitis C virus-related hepatocellular carcinoma

Aim: Several investigators have shown that interferon (IFN) therapy can suppress the recurrence of hepatocellular carcinoma (HCC) after curative treatment. We investigated the effect of IFN therapy on the first and second HCC recurrence following hepatic resection of hepatitis C virus (HCV)-related HCC. Methods: Subjects included 166 patients who had undergone curative resection for a single HCV-related HCC. We analyzed the outcome after initial hepatic resection and risk factors of a second HCC recurrence following treatment for the first HCC recurrence. Results: Using multivariate analysis, a non-sustained virological response (non-SVR) was significantly associated with a high incidence of first HCC recurrence. The rate of second HCC recurrence tended to be higher in the non-SVR group than in the SVR group. In the patients with recurrence of multiple tumors or who received non-curative treatment for recurrent HCC, the second HCC recurrence rates were significantly higher. Multivariate analysis demonstrated that non-curative treatment for first HCC recurrence was an independent risk factor for a second HCC recurrence. Among the patients who received curative treatment for their first HCC recurrence, the rates of second recurrence were significantly higher in the non-SVR group than in the SVR group. Multivariate analysis also revealed that SVR was independently associated with prevention of a second HCC recurrence. Conclusions: These results suggest that on first HCC recurrence, a curative treatment should be considered in order to prevent a second recurrence if possible. In addition, IFN therapy contributes to improved prognosis after curative treatment, even in patients with recurrent HCC.     

Tertiary Prevention of HBV-related HCC in Asia

Chronic hepatitis B is the leading cause of hepatocellular carcinoma (HCC) in Asia. Despite liver resection or local ablation therapy, up to 70 % of patients will have HCC recurrence. While early HCC recurrence within 2 years of index treatment is mainly associated with tumor characteristics such as vascular invasion and tumor number, late recurrence arises due to field effect and is associated with high hepatitis B virus DNA level and hepatic necroinflammation. Although current data suggest that antiviral therapy can reduce the risk of cirrhosis and incident HCC, its role in preventing HCC recurrence after curative treatment remains controversial. In recent years, knowledge on the signaling pathways of HCC has led to exciting development in targeted therapy, with sorafenib being the first to be registered for the treatment of advanced HCC. Further studies are needed to clarify the role of targeted therapy in the adjuvant setting to prevent HCC recurrence.     

肝细胞癌患者肝移植术后肿瘤复发转移的防治

肝细胞癌(HCC)仍是目前发病率较高的消化道肿瘤,肝移植能从根本上切除肿瘤病灶,是HCC综合治疗方案中的主要手段之一。移植后肿瘤的复发和转移问题,是影响受体长期生存的主要因素。近年来,得益于全球范围的技术改进和经验积累,在HCC的诊疗方面取得了的长足的发展和进步。针对HCC肝移植适应证、复发转移预测、肝移植围手术期干预和术后HCC复发的综合治疗等方面进行探讨。     

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation

AIM: To evaluated patterns and outcomes of hepatocellular carcinoma(HCC) recurrence after living donor liver transplantation(LDLT).METHODS: From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54(18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mT OR inhibitor.RESULTS: The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence 12 mo(P = 0.048), multiple recurrences at HCC recurrence(P = 0.038), and palliative treatment for recurrent tumors(P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showedsurvival benefits in the palliative treatment group(P = 0.005).CONCLUSION: Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an m TOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.     

Current status and prospect of treatments for recurrent hepatocellular carcinoma

Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

Impact of diabetes on recurrence of hepatocellular carcinoma after surgical treatment in patients with viral hepatitis

OBJECTIVES: Consensus has been reached that diabetes is a risk factor for development of HCC, but the impact on postoperative recurrence is still controversial. To clarify this point, we analyzed the relationship of postoperative recurrence rate of HCC and coexistence of diabetes in the patients with viral hepatitis. METHODS: A total of 90 patients who had undergone curative resection for HCC were analyzed. They were divided into two groups with and without diabetes, and the recurrence-free survival rates after surgical treatment and the factors contributing to recurrence were examined. RESULTS: Kaplan-Meier survival analysis showed the recurrence-free survival rates in the diabetic group were significantly lower than those in the nondiabetic group (P= 0.005) and overall survival rates in the diabetic group were significantly lower than those in the nondiabetic group (P= 0.005). These results were emphasized in the analysis of patients infected with hepatitis C virus. Univariate and multivariate analyses showed diabetes was a significant factor contributing to HCC recurrence after treatment. Furthermore, multivariate analysis in HCC patients with diabetes showed Child-Pugh classification B (P= 0.001) and insulin therapy (P= 0.049) were significant factors contributing to HCC recurrence after treatment. CONCLUSIONS: The results of the present study suggest that diabetes is a risk factor for the recurrence of HCV-related HCC and decreases the overall survival rates after surgical treatment. HCV-related HCC patients with diabetes should be closely followed for postoperative recurrence.     

Predictors of early and late hepatocellular carcinoma recurrence

Hepatocellular carcinoma(HCC) is the most frequent liver neoplasm, and its incidence rates are constantly increasing. Despite the availability of potentially curative treatments(liver transplantation, surgical resection, thermal ablation), long-term outcomes are affected by a high recurrence rate(up to 70% of cases 5 years after treatment). HCC recurrence within 2 years of treatment is defined as “early” and is generally caused by the occult intrahepatic spread of the primary neoplasm and relate...