肝癌的免疫治疗作为一种新的替代疗法引起研究者的广泛关注,免疫治疗的前提是利用宿主免疫系统的力量摧毁肿瘤细胞。免疫介导疗法的发展,如疫苗、自体免疫细胞过继转移和以肿瘤逃避机制为靶点刺激宿主免疫具有晚期肿瘤免疫治疗作用。此外,先天免疫和免疫逃避机制提高了对肝癌免疫的认识。临床前期和临床阶段免疫介导对肝癌患者的研究及治疗已显示出潜在的好处。该文总结了以肝细胞癌和胆管癌为重点的肿瘤免疫学研究进展。
原发性肝癌主要分为肝细胞癌(hepatocellular carcinoma,HCC)、胆管细胞癌(cholangiocarcinoma,CCA)和两者混合细胞的肝癌,其中肝细胞癌最多,占所有原发性肝癌的80%。肝细胞癌在导致全世界癌症相关死亡人数中排名第三[1]。原发性肝癌病因主要危险因素包括:感染肝炎病毒、黄曲霉毒素B、烟草、氯乙烯、摄入大量酒精、非酒精性脂肪性肝病、血色素沉着症和糖尿病。近来研究发现肝细胞死亡和代偿性肝细胞增生重复循环,影响突变因子和致癌基因突变对DNA损伤。这种毒性环境有利于肿瘤转化和肝癌的发生。HCC常常是在晚期诊断,预后极差,目前的大部分常规治疗方式无效。肿瘤切除、化学治疗(化疗)和放射治疗(放疗)、经皮无水乙醇注射、射频消融(RFA)、各种栓塞、索拉非尼被应用于临床治疗肝癌[1]。然而,手术切除后的复发率很高,手术后5年生存率30%~40%。
CCA是一种罕见的肿瘤,起源于胆管上皮细胞的恶性转化、肝内外胆管上皮细胞。这是最常见的胆道癌,占所有肝胆恶性肿瘤的10%~20%[2]。感染华支睾吸虫、肝炎病毒(HBV和HCV)和原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)是CCA的主要危险因素。CCA因早期难以诊断导致多数患者预后不良。CCA目前的治疗方案包括放射治疗和手术切除,但即使在这种有创性治疗后复发率也非常高。虽然手术在早期阶段被用作根治性治疗,但放疗更常用于治疗CCA。由于效果非常有限,化疗尚未成为治疗选择,仅用作最后的治疗方案。吉西他滨单独给药或与顺铂、卡培他滨和奥沙利铂组合显示有限的疗效。总体而言,肝移植仍然是 HCC和CCA的最佳可行治疗方案,但由于现有供体肝脏严重短缺,肝移植受限[3],因此免疫替代治疗显示出对肝癌治疗的必要性。
针对HCC的几种肿瘤相关抗原疫苗正在用于癌症治疗。其中研究发现Glypican3(GPC-3)是硫酸肝素硫酸蛋白聚糖片段的磷脂酰肌醇蛋白家族的成员,在HCC患者中被过表达,与预后有关[3]。在Ⅰ期临床试验中,当HLA-A*24阳性患者使用GPC3/298-306肽作为TAA,HLA-A*02阳性患者使用GPC3/144-152肽时,33例患者几乎所有患者均有明显的C
文献[3]报道了用于治疗HCC的原位癌症疫苗InCVAX的进展。InCVAX通过双管齐下的方法刺激强大的抗肿瘤免疫反应。这包括用激光治疗肿瘤的热处理,然后施用
过继细胞疗法(adoptive cell therapy,ACT)涉及到患者自身的免疫细胞,以识别和破坏其肿瘤。在这种方法中,收集来自健康患者血液的T细胞,并进行基因修饰以表达由参与T细胞信号传导的细胞表面分子特异性抗体的可变片段组成的人造受体。这种工程化受体(称为嵌合抗原受体(CAR))允许T细胞识别肿瘤细胞上的特异性抗原。CAR-T细胞然后在细胞培养物中繁殖直至数量达数十亿,并注射到患者血液中。输注后,CAR-T细胞设计用于识别肿瘤细胞并杀死它们。CAR-T细胞具有优于T细胞受体修饰的T(TCR-T)细胞的优点,因为它们识别没有MHC限制的肿瘤细胞[11],将允许改善患者靶向并克服MHC损失的肿瘤逃逸机制。急性淋巴细胞性白血病、急性骨髓性白血病和胃肠癌临床试验中[12],这种ACT方法显示出了希望[3]。应注意使用内源性T细胞的自体转移与同种异体的方法之间的明确区别。前一种方法涉及识别具有人类淋巴细胞抗原限制的肽的修饰的T细胞受体,而在后者中不存在人类淋巴细胞抗原限制,并且其涉及将细胞从免疫个体转移至非免疫接受者。这种差异对于评估与抗肿瘤外和靶向效应相关的毒性程度至关重要[3]。
迄今为止,很少有研究将CAR-T细胞应用于HCC和CCA免疫治疗。在一项研究中,表达针对GPC-3的CAR的T细胞在体外成功地消除了GPC3阳性细胞,并在小鼠的原位Huh-7异种移植物中成功消除。然而,大量的风险和毒性与使用CAR-T细胞有关,因为它们将大量的细胞因子释放到患者的血液中。这些包括但不限于细胞因子释放综合征、B细胞发育不全和肿瘤溶解综合征。使用CAR-T细胞的实体瘤的临床研究也显示出对正常组织的相当大的毒性[13]。在这方面,研究CAR-T细胞在动物模型中的有效性和安全性对于治疗实体肿瘤环境下CAR构建体的验证是必要的。区分肿瘤毒性的治疗效果对于ACT至关重要,CAR-T细胞的进一步修饰,有助于鉴定更好的靶标和优化改善预后的处理方案。
细胞因子诱导的细胞,包括活化的T细胞和自然杀伤细胞,在过继免疫治疗中已经显示临床益处。使用细胞因子诱导的杀伤(CIK)细胞的辅助免疫治疗的随机临床试验显示HCC的混合结果。在一项研究中,尽管无复发生存率增加,但仍未观察到患者存活率的改善,其他研究显示淋巴细胞输注(C
用CIK细胞免疫治疗进行的研究有限。在一项研究中,包含C
近年来,阻断针对肿瘤细胞的免疫应答(如PD-1、PD-L1和CTLA-4)的检查点分子已经成为肿瘤学中的新型治疗方法[19]。靶向这些分子的抗体已经开发出来,并且显示出显著的疗效。 其中彭博拉珠单抗(pembrolizumab)和nivolumab靶向于PD-1、tremelimumab和ipilimumab靶向于CTLA-4[20]。彭博拉珠单抗已被美国食品药品管理局(FDA)批准用于治疗转移性黑色素瘤(metastatic melanoma,MM)和非小细胞肺癌(NSCLC);MM、NSCLC和肾细胞癌的nivolumab和MM的ipilimumab作为单一药剂或组合使用[21]。 这些也被欧洲药物管理局批准[22]。
PD-1是跨膜受体的CD28免疫球蛋白超家族的阴性共刺激分子,是T细胞应答的强抑制剂。因此,阻止其功能是免疫治疗的策略。 B7共刺激分子家族的PD-L1和PD-L2是PD-1的配体。 PD-L1和PD-L2与PD-1的结合抑制C
研究发现CD160-共刺激分子与慢性HCV感染患者的T细胞耗尽相关,其中外周血中HCV特异性C
NK细胞受体2B4也被发现在慢性HCV患者的血液中过表达。其配体CD48与CD2(一种涉及NK和T细胞活化调节的分子)具有比2B4强6~8倍的亲和力。2B4对HCV特异性C
Tim-3通过其配体galectin-9的结合被鉴定为T辅助1型免疫的负调节物。在慢性HCV患者的C
原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)患者GP-2抗体升高,与患者生存率相关[29]。研究表明,高水平的抗GP2 IgA也与PSC患者的CCA发展相关。 因此,抗GP2 IgA可能是PSC患者危险分层的有价值工具。
血小板是存在于血液中的小的去核细胞。当发生血管损伤时,血小板被活化,导致生长因子如肝细胞生长因子(hepatocyte growth factor,HGF)、成纤维细胞生长因子(fibroblast growth factor,FGF)、胰岛素样生长因子(insulin-like growth factor,IGF)-1、VEGF、EGF和血小板衍生生长因子(PDGF)[30]增加,在血栓形成的过程中,血小板通过灭活HSC来减少胶原蛋白生成并促进肝脏再生来改善肝纤维化[31]。当血液中血小板数量升高时发生血小板增多症,并且在肝细胞癌和血小板增多症之间发现了强烈的关联。在1154例HCC患者的回顾性研究中,发现血小板增多症患者的AFP水平较高,肿瘤体积大,血小板数量高,存活率较低[31]。研究表明,高血小板计数可能是晚期HCC肝外转移的可靠标志物[32]。最近还报道了CCA的高血小板水平[33]。另一方面,血小板减少症(血小板计数低的病例)也显示与肝硬化背景下的HCC相关,与HCC患者的总体生存率降低相关[34]。这些结果表明血小板在预测肝癌患者的总生存率方面起重要作用。
在肝窦内,循环C
肝癌的发病率正在迅速增加,HCC治疗的年度医疗保健费用正在攀升。在美国,照顾HCV相关HCC患者的总体中位数成本每年约1.8万美元[36]。因此,与肝癌相关的疾病的医疗费用高,需要开发新的疗法。目前正在对HCC和CCA进行一些临床试验,希望可以产生非常有效的免疫治疗[37,38]。
进一步研究的关键点是确定新的目标,这需要进行广泛的验证。例如,间皮素被报道为各种癌症中的潜在的免疫治疗靶标。靶向间皮素的硫酸酯酶-1的添加显示出这些细胞系非常高特异性的生长抑制,这表明它可能是CCA的潜在治疗剂[1]。尽管这一发现表明硫酸酯酶-1可以作为HCC中的肿瘤抑制因子,但在人肝癌样本中没有检测到间皮素的表达时,应谨慎解释。
TGN1412在20世纪90年代后期被开发为针对CD28的拮抗性单克隆抗体,CD28是T细胞应答的关键共刺激剂[39]。在使用该抗体的大鼠和小鼠中进行的实验研究工作已经显示出显著的希望来治疗自身免疫性和炎性疾病。然而,在临床前研究中将动物研究结果外推到人类具有潜在危险[1]。类似地,由于物种之间的差异,在CAR-T细胞,特别是HLA限制肽的情况下,从一个物种到另一个物种的数据类推可能是不可行的。
免疫治疗的最新进展不仅为治疗肿瘤复发,而且为防止肝硬化肝癌发展垫定了基础。 肝脏的免疫耐受性仍然是一个主要问题。然而,正在努力通过使用免疫检查点抑制药来规避这个问题。临床前研究和临床试验在这方面已经取得了有希望的成果。 目前,联合治疗如疫苗和(或)免疫检查点抑制药与局部烧蚀疗法是治疗肝癌的有吸引力的方法。在将这些免疫治疗干预措施应用于临床之前,必须解决临床试验中的安全性、毒性和疗效问题。
The authors have declared that no competing interests exist.
[1] |
In recent years, immunotherapy has gained renewed interest as an alternative therapeutic approach for solid tumors. Its premise is based on harnessing the power of the host immune system to destroy tumor cells. Development of immune-mediated therapies, such as vaccines, adoptive transfer of autologous immune cells, and stimulation of host immunity by targeting tumor-evasive mechanisms have advanced cancer immunotherapy. In addition, studies on innate immunity and mechanisms of immune evasion have enhanced our understanding on the immunology of liver cancer. Preclinical and clinical studies with immune-mediated therapies have shown potential benefits in patients with liver cancer. In this review, we summarize current knowledge and recent developments in tumor immunology by focusing on two main primary liver cancers: hepatocellular carcinoma and cholangiocarcinoma.
[本文引用:6]
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[3] |
Cholangiocarcinoma is a malignant tumor of the biliary system that can be classified into intrahepatic(i CCA),perihiliar(ph CCA) and distal. Initial experiences with orthotopic liver transplantation(OLT) for patientswith i CCA and ph CCA had very poor results and this treatment strategy was abandoned. In the last decade,thanks to a strict selection process and a neoadjuvant chemoradiation protocol,the results of OLT for patients with non-resectable phC CA have been shown to be excellent and this strategy has been extended worldwide in selected transplant centers. Intrahepatic cholangiocarcinoma is a growing disease in most countries and can be diagnosed both in cirrhotic and in non-cirrhotic livers. Even though OLT is contraindicated in most centers,recent investigations analyzing patients that were transplanted with a misdiagnosis of HCC and were found to have an iC CA have shown encouraging results. There is some information suggesting that patients with early stages of the disease could benefit from OLT. In this review we analyze the current stateof-the-art of OLT for cholangiocarcinoma as well as the new insights and future perspectives.
[本文引用:6]
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[9] |
Cholangiocarcinoma (CC) is a highly malignant epithelial cancer of the biliary tract, the cellular and molecular pathogenesis of which remains unclear. Malignant transformation of glandular epithelial cells is associated with the altered expression of mucin. We investigated the type of mucins expressed in CC. Twenty-six patients with histologically confirmed CC were included in this study. The expression of mucin was studied by immunohistochemistry using antibodies to MUC1, MUC1 core, MUC2, MUC3, MUC4, MUC5AC, and MUC6. There was extensive (>50%) expression of mucin, mainly MUC1 in 11/25 and MUC5AC in 12/26 cases. In the case of MUC3, 6/26 cases expressed mucin extensively, whilst only 1/26 had MUC2, MUC4, and MUC6 expression. Well-differentiated tumors significantly expressed MUC3 extensively compared to poor or moderately differentiated tumors ( p = 0.003). Fifteen of 25 cases had metastatic disease. MUC1 was extensively expressed in 9/15 cases with metastatic disease. In contrast, MUC1 expression was present in 2/10 cases where metastases were absent. Hilar lesions were less likely to express MUC1, but this was not statistically significant. Fifteen of 25 cases had metastatic disease. Extensive MUC3 expression was significantly associated with well-differentiated tumors, whilst there was an approaching significance between the extensive expression of MUC1 and metastasis in cholangiocarcinoma.
[本文引用:1]
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[19] |
Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non mall cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. PubMed was searched to identify relevant clinical studies of PD-1/PD-L1 argeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.
[本文引用:1]
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[20] |
Abstract Cancer cells express tumour-specific antigens derived via genetic and epigenetic alterations, which may be targeted by T-cell-mediated immune responses. However, cancer cells can avoid immune surveillance by suppressing immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. In recent years, the blockade of checkpoint molecules such as PD-1, PD-L1 and CTLA-4, with monoclonal antibodies has enabled the development of breakthrough therapies in oncology, and four therapeutic antibodies targeting these checkpoint molecules have been approved by the FDA for the treatment of several types of cancer. Here, we report the crystal structures of checkpoint molecules in complex with the Fab fragments of therapeutic antibodies, including PD-1/pembrolizumab, PD-1/nivolumab, PD-L1/BMS-936559 and CTLA-4/tremelimumab. These complex structures elucidate the precise epitopes of the antibodies and the molecular mechanisms underlying checkpoint blockade, providing useful information for the improvement of monoclonal antibodies capable of attenuating checkpoint signalling for the treatment of cancer.
[本文引用:1]
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[21] |
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[22] |
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[23] |
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[24] |
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[27] |
DOI:10.1111/jgh.13017
URL
[本文引用:2]
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[28] |
DOI:10.1172/JCI43127
URL
[本文引用:1]
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[29] |
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[30] |
Hepatocellular carcinoma (HCC) is the commonest type of liver cancer and has a high mortality rate. Currently treatment options are limited and new therapies are urgently needed. Platelets are enucleated small cells, derived from mature megakaryocytes and besides their role in thrombosis; they actively take part in carcinogenesis and metastasis. Platelet number in the blood is associated with disease progression, overall survival and HCC subgrouping. Both thrombocytosis and thrombocytopenia are associated with HCC phenotype and size, related with other factors like cirrhosis background. Platelet counts and also platelet-to-lymphocyte ratio (PLR) and neutrophil-tolymphocyte ratio (NLR) are considered in decision making in management. Since platelets also take up nucleotides and cytokines from tumor cells, isolating and studying platelets might provide valuable information for understanding tumor cells and may help to develop personalized treatment. Anticoagulants and antiplatelet agents are commonly used potential cancer therapeutics, which are also being studied for HCC treatment. Thus, platelets are one aspect of a complex microenvironmental milieu, the affects the biology of HCC and other tumors.
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[31] |
Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease.
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[32] |
Abstract Background & Aims Thrombocytosis is associated with metastasis in many human cancers. Most hepatocellular carcinomas (HCC) develop in cirrhotic livers, which are characterized by thrombocytopenia. We aimed to elucidate the pretreatment platelet count in prediction of extrahepatic metastasis of HCC during the follow-up. Methods Three cohorts containing 1660, 480 and 965 HCC patients enrolled from three hospitals were used for discovery and validation respectively. Pretreatment clinical factors associated with extrahepatic metastasis during follow-up up to 502years were identified using multivariate Cox regression model. Results <p>In early-stage HCC (BCLC stage 0-A), pretreatment platelet count (hazard ratio [HR], 1.04 per 10,000/μl; 95% CI, 1.01–1.07; P =020.010) and serum alpha-foetoprotein (AFP) >10002ng/ml (HR, 1.70; 95% CI, 1.04–2.78; P =020.033) were the only two independent factors associated with extrahepatic metastasis. Receiver operating characteristic evidenced that pretreatment platelet count predicted metastasis better than AFP did. Survival tree analysis identified platelet counts 212,000/μl (HR, 2.12; 95% CI, 1.67–2.70; P Conclusions Pretreatment platelet count is a reliable marker to predict extrahepatic metastasis of early-stage HCC following curative treatment. Cirrhotic thrombocytopenia contributes to relatively low metastasis incidence of HCC than many other cancers. High platelet count identifies a subgroup of HCC patients at high risk of metastasis, who might benefit from adjuvant therapies following initial curative treatment.
[本文引用:1]
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[33] |
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[34] |
Thrombocytopenia has been acknowledged to be a crucial risk factor for cirrhosis formation and hepatocarcinogenesis in chronic liver diseases. However, to date, the association between platelet count (PLT) and the prognosis of hepatocellular carcinoma (HCC) remains inconsistent and controversial. The aim of the present study was to determine whether PLT could be used as a useful predictor of survival in patients with HCC. We performed systematic review in online databases, including PubMed, EmBase, and Web of Science, from inception until 2014. Studies were included if a statistical relationship was investigated between PLT and survival for HCC, and hazard ratio (HR) and 95% confidence intervals (CIs) for overall survival (OS) or recurrence-free survival (RFS) were provided. The quality of each included study was assessed by Newcastle–Ottawa scale score. To synthesize these studies, a random-effects model or a fixed-effects model was applied as appropriate. Then, we calculated heterogeneity, performed sensitivity analysis, tested publication bias, and did subgrouped and meta-regression analysis. Finally, we identified 33 eligible articles (published from 1998 to 2014) involved 5545 patients by retrieval. A low level of preoperative PLT was found to be significantly associated with apoorsurvival of HCC. Irrespective of the therapy used, the pooled HRs for OS and RFS were 1.41 (95% CI, 1.14–1.75) and 1.44 (95% CI, 1.13–1.83), respectively. Specifically, in patients who underwent liver resection, the pooled HRs for OS and RFS were 1.67 (95% CI, 1.22–2.27) and 1.44 (95% CI, 1.04–1.99), respectively. Furthermore, patients with preoperative thrombocytopenia (PLT66<6610066×66109/L) had a worse OS (HR: 1.73, 95% CI, 1.29–2.32) and RFS (HR: 1.57, 95% CI, 1.31–1.87) in comparison with patients without thrombocytopenia. All our findings showed no significant changes due to the removal of any study or the use of an opposite-effects model, and there was no significant publication bias. The limitations of this meat-analysis were nonuniform cut-off values of PLT, high between-study heterogeneities, potential confounders, and a bias of publication year. A low preoperative PLT level results in an unfavorable outcome in HCC. PLT is a simple, inexpensive, and useful predictor of survival in patients with HCC.
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[35] |
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[36] |
BACKGROUND Hepatitis C virus (HCV) is the commonest cause of hepatocellular carcinoma (HCC) in the United States. The benefits of HCV therapy may be measured in part by the prevention of HCC and other complications of cirrhosis. The true cost of care of the HCV patient with HCC is unknown. METHODS One hundred patients were randomly selected from a cohort of all HCC patients with HCV at a US transplant center between 2003 and 2013. Patients were categorized by the primary treatment modality, Barcelona class, and ultimate transplant status. Costs included the unit costs of procedures, imaging, hospitalizations, medications, and all subsequent care of the HCC patient until either death or the end of follow-up. Associations with survival and cost were assessed in multivariate regression models. RESULTS Overall costs included a median of $176,456 (interquartile range [IQR], $84,489-$292,192) per patient or $6279 (IQR, $4043-$9720) per patient-month of observation. The median costs per patient-month were $7492 (IQR, $5137-$11,057) for transplant patients and $4830 for nontransplant patients. The highest median monthly costs were for transplant patients with Barcelona A4 disease ($11,349) and patients who received chemoembolization whether they underwent transplantation ($10,244) or not ($8853). Transarterial chemoembolization and radiofrequency ablation were independently associated with a 28% increase and a 22% decrease in costs, respectively, with adjustments for the severity of liver disease and Barcelona class. CONCLUSIONS These data represent real-world estimates of the cost of HCC care provided at a transplant center and should inform economic studies of HCV therapy. Cancer 2016;122:852 8. 2015 American Cancer Society .
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[37] |
Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.
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[38] |
Abstract Cholangiocarcinoma (CCA) is an epithelial cell malignancy arising from bile ducts and/or peribiliary glands. Even though it is considered as a rare neoplasm, its incidence is raising, particularly in developed countries. Prognosis is generally poor with few patients who present the inclusion criteria for surgery (the mainstay treatment for this tumour). Several genetic alterations potentially driving tumour progression have been described, representing a possible target for new compounds. Areas covered: A clinical trial search in Clinicaltrials.gov encompassing a literature search in PubMed and ASCO/ESMO Websites was undertaken in March 2016. Expert opinion: Notwithstanding a large number of drug tested, results are still disappointing. The main reasons could be the low number of patients enrolled in trials, and the lack of a patient selection based on the biological profile of the tumours. Potential active drugs could have been discharged simply because beneficial in a particular subgroup of patients and not in un unselected population. The future direction of the research should consider biomarker evaluation in order to describe the genetic alteration/s that drive tumour progression and aggressiveness and the mechanisms of drug resistance. Finally, it will be of great interest to consider the results of immunotherapy whenever available.
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[39] |
Abstract Two decades ago, we discovered “superagonistic” monoclonal antibodies specific for the CD28 molecule which are able to polyclonally activate T-cells, in particular regulatory T-cells, and are therapeutically active in many rodent models of autoimmunity, inflammation, transplantation and tissue repair. A phase I trial of the human CD28 superagonist TGN1412 failed in 2006 due an unexpected cytokine release syndrome, but after it became clear that dose-reduction allows to preferentially address regulatory T-cells also in humans, clinical development was resumed under the name TAB08. Here, I recount the story of CD28 superagonist development from a personal perspective with an emphasis on the dramatic events during and after the 2006 phase I trial, the reasons for the failure of preclinical research to warn of the impending cytokine storm, and on the research which allowed resumption of clinical development. This article is protected by copyright. All rights reserved.
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