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Journal Watch: Dr Tu looks back at the most important research articles released in 2018 relating to models and biomarkers of hepatocellular carcinoma. 期刊观察:屠博士回顾了2018年发表的与肝细胞癌模型和生物标志物相关的最重要的研究文章。
IF 5 Q4 ONCOLOGY Pub Date : 2019-02-12 eCollection Date: 2019-03-01 DOI: 10.2217/hep-2019-0002
Thomas Tu
Wang G, Chow RD, Ye L et al. Mapping a functional cancer genome atlas of tumor suppressors in mouse liver using AAV-CRISPR-mediated direct in vivo screening. Sci. Adv. 4(2), eaao5508 (2018). Multiple putative hepatocellular carcinoma (HCC) driver mutations have been identified using next-generation sequencing, but the majority have not been confirmed in in vivo settings or in combination with each other. Wang et al. describe a high-throughput solution by transducing transgenic mice containing a Cre-dependent Cas9 with hepatocyte-specific adeno-associated virus vectors that encode for Cre recombinase, EGFP and a sgRNA from a library, targeting HCC candidate genes (49 genes drawn from online databases). Indels at target loci were then confirmed and quantified using multiplexed molecular inversion probe sequencing. Within 3 months of transduction, mice developed multifocal GFP-positive HCC, in which significant enrichment of Trp53, Setd2, Cic and Pik3R1 mutations were observed. Several pairs of mutations were significantly enriched, including Cdkn2a and Pten, B2m and Kansl1, and Arid2 and Cdkn2a. This exciting novel HCC model has the potential to confirm thousands of gene candidates identified by sequencing projects.
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引用次数: 0
Corrigendum. 勘误表。
IF 5 Q4 ONCOLOGY Pub Date : 2018-12-21 DOI: 10.2217/hep-2017-0017c1

[This corrects the article DOI: 10.2217/hep-2017-0017.].

[这更正了文章DOI: 10.2217/hep-2017-0017.]。
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引用次数: 0
Hepatocellular carcinoma treatment: hurdles, advances and prospects. 肝细胞癌治疗:障碍、进展和前景。
IF 1.2 Q4 ONCOLOGY Pub Date : 2018-09-28 eCollection Date: 2018-04-01 DOI: 10.2217/hep-2018-0002
Ratna Kumari, Manoj Kumar Sahu, Anindita Tripathy, Kanishka Uthansingh, Manas Behera

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality and is particularly refractory to the available chemotherapeutic drugs. Among various etiologies of HCC, viral etiology is the most common, and, along with alcoholic liver disease and nonalcoholic steatohepatitis, accounts for almost 90% of all HCC cases. HCC is a heterogeneous tumor associated with multiple signaling pathway alterations and its complex patho-physiology has made the treatment decision challenging. The potential curative treatment options are effective only in small group of patients, while palliative treatments are associated with improved survival and quality of life for intermediate/advanced stage HCC patients. This review article focuses on the currently available treatment strategies and hurdles encountered for HCC therapy. The curative treatment options discussed are surgical resection, liver transplantation, and local ablative therapies which are effective for early stage HCC patients. The palliative treatment options discussed are embolizing therapies, systemic therapies, and molecular targeted therapies. Besides, the review also focuses on hurdles to be conquered for successful treatment of HCC and specifies the future prospects for HCC treatment. It also discusses the multi-modal approach for HCC management which maximizes the chances of better clinical outcome after treatment and identifies that selection of a particular treatment regimen based on patients' disease stage, patients' ages, and other underlying factors will certainly lead to a better prognosis.

肝细胞癌(HCC)是导致癌症相关死亡的主要原因之一,对现有的化疗药物尤其难治。在 HCC 的各种病因中,病毒病因最为常见,与酒精性肝病和非酒精性脂肪性肝炎一起,几乎占所有 HCC 病例的 90%。HCC 是一种与多种信号通路改变相关的异质性肿瘤,其复杂的病理生理学使治疗决策充满挑战。潜在的根治性治疗方案仅对一小部分患者有效,而姑息治疗则能提高中晚期 HCC 患者的生存率和生活质量。这篇综述文章重点介绍了目前可用的治疗策略以及治疗 HCC 所遇到的障碍。讨论的根治性治疗方案包括手术切除、肝移植和局部消融疗法,这些方案对早期 HCC 患者有效。讨论的姑息治疗方案包括栓塞疗法、全身疗法和分子靶向疗法。此外,这篇综述还重点讨论了成功治疗 HCC 需要克服的障碍,并明确了 HCC 治疗的未来前景。它还讨论了治疗 HCC 的多模式方法,这种方法能最大限度地提高治疗后临床疗效,并指出根据患者的疾病分期、年龄和其他潜在因素选择特定的治疗方案必将带来更好的预后。
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引用次数: 0
Transcatheter arterial chemoembolization combined with radiofrequency or microwave ablation for hepatocellular carcinoma: a review. 经导管动脉化疗栓塞联合射频或微波消融治疗肝细胞癌:综述。
IF 5 Q4 ONCOLOGY Pub Date : 2018-09-28 eCollection Date: 2018-04-01 DOI: 10.2217/hep-2018-0001
Nikolaos Galanakis, Elias Kehagias, Nikolas Matthaiou, Dimitrios Samonakis, Dimitrios Tsetis

Hepatocellular carcinoma (HCC) is the sixth most common type of malignancy. Several therapies are available for HCC and are determined by stage of presentation, patient clinical status and liver function. Local-regional treatment options, including transcatheter arterial chemoembolization, radiofrequency ablation or microwave ablation, are safe and effective for HCC but are accompanied by limitations. The synergistic effects of combined transcatheter arterial chemoembolization and radiofrequency ablation/microwave ablation may overcome these limitations and improve the therapeutic outcome. The purpose of this article is to review the current literature on these combined therapies and examine their efficacy, safety and influence on the overall and recurrence-free survival in patients with HCC.

肝细胞癌(HCC)是第六大最常见的恶性肿瘤。肝细胞癌有几种治疗方法,根据表现阶段、患者临床状态和肝功能而定。局部区域治疗方案,包括经导管动脉化疗栓塞、射频消融或微波消融,对HCC是安全有效的,但也有局限性。经导管动脉化疗栓塞联合射频消融/微波消融的协同作用可能克服这些局限性,改善治疗效果。本文的目的是回顾目前关于这些联合治疗的文献,并检查它们的有效性、安全性以及对HCC患者总生存率和无复发生存率的影响。
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引用次数: 23
Selective internal radiation therapy: an effective treatment for hormonal syndromes in pancreatic neuroendocrine tumors. 选择性内放射治疗:胰腺神经内分泌肿瘤激素综合征的有效治疗方法。
IF 5 Q4 ONCOLOGY Pub Date : 2018-09-28 eCollection Date: 2018-04-01 DOI: 10.2217/hep-2017-0025
Leyre Zubiri, José I Bilbao, Javier Rodríguez, Bruno Sangro

The hormone secretion in pancreatic neuroendocrine tumors (pNET) causes an important interference in patients' quality of life. We present two cases of pNET metastatic to the liver (a pancreatic endocrine carcinoma with a severe hormonal syndrome and an insulinoma with severe crisis of hypoglycemia and coma) refractory to conventional treatments, which were finally solved with selective internal radiation therapy (SIRT), a nonstandard level 1 therapy. We show two examples of an excellent control of symptoms together with a long survival after treatment with SIRT. The evidence supporting the use of this therapy is level 2. Our case reports strongly support the use of SIRT for the severe clinical syndrome in pNET metastatic to the liver and refractory to somatostatin analogs.

胰腺神经内分泌肿瘤(pNET)的激素分泌是影响患者生活质量的重要因素。我们报告了2例pNET转移到肝脏的病例(1例胰腺内分泌癌伴严重激素综合征,1例胰岛素瘤伴严重低血糖和昏迷危像),常规治疗难治性,最终通过选择性内放射治疗(SIRT)解决,这是一种非标准的1级治疗。我们展示了两个在SIRT治疗后症状得到良好控制和长期生存的例子。支持使用这种疗法的证据是2级。我们的病例报告强烈支持使用SIRT治疗pNET转移到肝脏和对生长抑素类似物难治的严重临床综合征。
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引用次数: 3
Molecular heterogeneity in hepatocellular carcinoma. 肝细胞癌的分子异质性。
IF 5 Q4 ONCOLOGY Pub Date : 2018-09-11 eCollection Date: 2018-01-01 DOI: 10.2217/hep-2018-0005
Shijia Zhu, Yujin Hoshida
Recent successful clinical trials have led to or likely lead to the regulatory approval of several molecular targeted agents for firstand second-line treatment of hepatocellular carcinoma (HCC), including multikinase inhibitors, lenvatinib, regorafenib and cabozantinib, as well as immune checkpoint inhibitors nivolumab and pembrolizumab [1–5]. However, objective response rates to these agents are only 20% at maximum and patient survival benefit is no more than a few months despite the high cost of the drugs. A recent simulation-based analysis has reported that regorafenib treatment for advanced-stage HCC patients is not cost-effective with an incremental cost-effectiveness ratio (ICER) of $224,396 per quality-adjusted life year gained, which far exceeds the widely accepted incremental cost-effectiveness ratio cutoff of $50,000 [6]. Given that only small proportion of the patients respond to each therapy, it is critical to identify potential responders to avoid prescribing the drugs to patients who will not benefit from the treatment and enable cost-effective patient management [7]. However, no biomarker of drug response is available for any of the approved drugs for HCC to date.
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引用次数: 18
De novo hepatocellular carcinoma occurrence in hepatitis C cirrhotics treated with direct-acting antiviral agents. 直接作用抗病毒药物治疗丙型肝炎肝硬化中新发肝细胞癌的发生率。
IF 5 Q4 ONCOLOGY Pub Date : 2018-07-25 eCollection Date: 2018-01-01 DOI: 10.2217/hep-2018-0003
Gabriela Kuftinec, Thomas Loehfelm, Michael Corwin, Blythe Durbin-Johnson, MarieChristi Candido, Rebecca Hluhanich, Souvik Sarkar

Aim: Recent studies raise concerns for higher incidence of hepatocellular carcinoma (HCC) after direct-acting antiviral therapy for hepatitis C virus (HCV).

Methods: In this study, using analysis of liver imaging pre- and post-DAA treatment, we queried new occurrence or 'de novo' of HCC in patients with HCV-cirrhosis treated with DAAs. Of 150 patients who met study criteria, 7 (4.7%; 95% CI: 2.1-9.5%) patients developed de novo HCC which did not differ from historical rates of 3% (p = 0.22).

Results: Notably, patients with decompensated cirrhosis had significantly higher rate of de novo HCC (9.3%; 95% CI: 3.12-22.2%; p = 0.04).

Conclusion: Our data support the need for continued surveillance for HCC in HCV cirrhotics even after successful therapy.

目的:最近的研究引起了对丙型肝炎病毒(HCV)直接抗病毒治疗后肝细胞癌(HCC)发生率增高的关注。方法:在本研究中,通过分析daa治疗前后的肝脏影像学,我们询问肝细胞癌新发或“新生”的hcv -肝硬化患者接受daa治疗。在150例符合研究标准的患者中,7例(4.7%;95% CI: 2.1-9.5%),与历史发生率3% (p = 0.22)无差异。结果:值得注意的是,失代偿期肝硬化患者的新发HCC发生率明显较高(9.3%;95% ci: 3.12-22.2%;p = 0.04)。结论:我们的数据支持HCV肝硬化患者即使在治疗成功后仍需要继续监测HCC。
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引用次数: 6
The impact of antiviral therapy on hepatocellular carcinoma epidemiology. 抗病毒治疗对肝细胞癌流行病学的影响。
IF 5 Q4 ONCOLOGY Pub Date : 2018-05-10 eCollection Date: 2018-01-01 DOI: 10.2217/hep-2017-0024
Massimo Colombo, Ana Lleo

The development of nucleos(t)ide analogs and direct antiviral agents has revolutionized the management of chronic infection with HBV and HCV, respectively. These regimens allow to expand treatment to virtually all infected, including those with poor hepatic reserve and those with severe comorbidities. As a result, permanent suppression of HBV and eradication of HCV has been achieved in almost all treated patients, resulting in substantial clinical benefits. In several cohorts, these successes have translated into a reduction of the incidence of hepatocellular carcinoma that was more frequently observed in patients with less advanced hepatitis, whereas liver cancer was more often associated with male gender, cirrhosis, alcohol abuse and diabetes.

核苷(t)类似物和直接抗病毒药物的发展分别彻底改变了HBV和HCV慢性感染的管理。这些方案可以将治疗范围扩大到几乎所有感染者,包括肝储备不良者和有严重合并症者。因此,几乎所有接受治疗的患者都实现了HBV的永久抑制和HCV的根除,从而产生了可观的临床效益。在一些队列中,这些成功转化为肝细胞癌发病率的降低,肝细胞癌在较不严重的肝炎患者中更为常见,而肝癌通常与男性、肝硬化、酗酒和糖尿病有关。
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引用次数: 17
How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma. Rap及其gef如何控制肝脏生理和癌症发展。C3G在人肝癌中的改变。
IF 5 Q4 ONCOLOGY Pub Date : 2018-04-16 eCollection Date: 2018-01-01 DOI: 10.2217/hep-2017-0026
Celia Sequera, Sara Manzano, Carmen Guerrero, Almudena Porras

Rap proteins regulate liver physiopathology. For example, Rap2B promotes hepatocarcinoma (HCC) growth, while Rap1 might play a dual role. The RapGEF, Epac1, activates Rap upon cAMP binding, regulating metabolism, survival, and liver regeneration. A liver specific Epac2 isoform lacking cAMP-binding domain also activates Rap1, promoting fibrosis in alcoholic liver disease. C3G (RapGEF1) is also present in the liver, but mainly as shorter isoforms. Its function in the liver remains unknown. Information from different public genetic databases revealed that C3G mRNA levels increase in HCC, although they decrease in metastatic stages. In addition, several mutations in RapGEF1 gene are present, associated with a reduced patient survival. Based on this, C3G might represent a new HCC diagnostic and prognostic marker, and a therapeutic target.

Rap蛋白调节肝脏的生理病理。例如,Rap2B促进肝癌(HCC)的生长,而Rap1可能发挥双重作用。RapGEF, Epac1,通过cAMP结合激活Rap,调节代谢、存活和肝脏再生。缺乏camp结合域的肝脏特异性Epac2异构体也激活Rap1,促进酒精性肝病纤维化。C3G (RapGEF1)也存在于肝脏中,但主要以较短的亚型存在。它在肝脏中的功能尚不清楚。来自不同公共遗传数据库的信息显示,C3G mRNA水平在HCC中升高,尽管它们在转移期降低。此外,存在几种RapGEF1基因突变,与患者生存率降低有关。基于此,C3G可能是一种新的HCC诊断和预后指标,也是一种治疗靶点。
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引用次数: 22
Molecular classification of hepatocellular adenomas: impact on clinical practice. 肝细胞腺瘤的分子分型:对临床的影响。
IF 5 Q4 ONCOLOGY Pub Date : 2018-04-09 eCollection Date: 2018-01-01 DOI: 10.2217/hep-2017-0023
Anne-Laure Védie, Olivier Sutter, Marianne Ziol, Jean-Charles Nault

Hepatocellular adenomas are rare benign liver tumors usually developing in young women using oral contraception. The two main complications are hemorrhage (10-20%) and malignant transformation into hepatocellular carcinoma (<5%). A molecular classification has been recently updated in six major subgroups, linked to risk factors, histology, imaging and clinical features: adenomas inactivated for HNF1A, inflammatory adenomas, β-catenin-activated adenomas mutated in exon 3, β-catenin-activated adenomas mutated in exon 7-8, sonic hedgehog adenomas, and unclassified adenomas. Indeed, β-catenin-mutated adenomas in exon 3 are associated with malignant transformation, and sonic hedgehog adenomas with bleeding. This new nosology of hepatocellular adenomas will help to stratify patients according to risk of complications and will guide therapeutics in the future.

肝细胞腺瘤是一种罕见的良性肝脏肿瘤,通常发生在使用口服避孕药的年轻女性中。两种主要并发症是出血(10-20%)和恶性转化为肝细胞癌(HNF1A、炎性腺瘤、外显子3突变的β-catenin激活的腺瘤、外显子7-8突变的β-catenin激活的腺瘤、音刺猬腺瘤和未分类腺瘤)。事实上,外显子3上β-连环蛋白突变的腺瘤与恶性转化和伴有出血的超音刺猬腺瘤有关。这种新的肝细胞腺瘤分类学将有助于根据并发症的风险对患者进行分层,并将指导未来的治疗方法。
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引用次数: 34
期刊
Hepatic Oncology
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