Hepatocellular carcinoma (original) (raw)

• Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).
  PubMed Google Scholar
• Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019).
  CAS PubMed Google Scholar
• International Agency for Research on Cancer. GLOBOCAN 2018. IARC https://gco.iarc.fr/today/online-analysis-map?v=2020&mode=population&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=11&type=0&statistic=5&prevalence=0&population_groupearth&color_palette=default&map_scale=quantile&map_nb_colors=5&continent=0&rotate=%255B10%252C0%255D (2020).
• Akinyemiju, T. et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level. JAMA Oncol. 3, 1683 (2017).
  PubMed PubMed Central Google Scholar
• Kanwal, F. et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 153, 996–1005.e1 (2017).
  CAS PubMed Google Scholar
• Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).
  CAS PubMed Google Scholar
• Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505–511 (2015). A comprehensive genomic study conducted in HCC describing the landscape of mutations and mutational signatures.
  CAS PubMed PubMed Central Google Scholar
• Llovet, J. M., Montal, R., Sia, D. & Finn, R. S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599–616 (2018).
  PubMed Google Scholar
• Zucman-Rossi, J., Villanueva, A., Nault, J.-C. & Llovet, J. M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226–1239.e4 (2015).
  CAS PubMed Google Scholar
• Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).
  PubMed Google Scholar
• Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).
  CAS PubMed PubMed Central Google Scholar
• European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).
  Google Scholar
• Marrero, J. A. et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 68, 723–750 (2018).
  PubMed Google Scholar
• Simon, T. G. et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N. Engl. J. Med. 382, 1018–1028 (2020).
  CAS PubMed PubMed Central Google Scholar
• Llovet, J. M. et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. https://doi.org/10.1038/s41575-020-00395-0 (2020).
• Tabrizian, P. et al. A US multicenter analysis of 2529 HCC patients undergoing liver transplantation: 10-year outcome assessing the role of down-staging to within Milan criteria [abstract 15]. Hepatology 70, 10–11 (2019).
  Google Scholar
• Llovet, J. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37, 429–442 (2003). This paper is a meta-analysis of randomized studies providing the rationale to use transarterial chemoembolization in intermediate HCC as standard of care.
  CAS PubMed Google Scholar
• Salem, R. et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 151, 1155–1163.e2 (2016).
  PubMed Google Scholar
• Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020). This paper is the first study demonstrating survival benefit for any systemic therapies compared with the standard of care sorafenib in advanced HCC.
  CAS PubMed Google Scholar
• Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). The first study demonstrating survival benefit for systemic therapies (sorafenib) in advanced HCC compared with placebo.
  CAS PubMed Google Scholar
• Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018). This is the first study demonstrating a survival benefit similar to the standard of care sorafenib in advanced HCC compared with placebo.
  CAS PubMed Google Scholar
• Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017). The first study demonstrating survival benefit in second-line treatment for patients with advanced HCC progressing to sorafenib therapy.
  CAS PubMed Google Scholar
• Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
  CAS PubMed PubMed Central Google Scholar
• Zhu, A. X. et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 282–296 (2019).
  CAS PubMed Google Scholar
• El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).
  CAS PubMed PubMed Central Google Scholar
• Finn, R. S. et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38, 193–202 (2020).
  CAS PubMed Google Scholar
• McGlynn, K. A., Petrick, J. L. & London, W. T. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin. Liver Dis. 19, 223–238 (2015).
  PubMed PubMed Central Google Scholar
• Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).
  CAS PubMed Google Scholar
• Trinchet, J.-C. et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology 62, 737–750 (2015).
  PubMed Google Scholar
• Fracanzani, A. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non–iron-related chronic liver disease. Hepatology 33, 647–651 (2001).
  CAS PubMed Google Scholar
• Wang, J., Chenivesse, X., Henglein, B. & Bréchot, C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343, 555–557 (1990).
  CAS PubMed Google Scholar
• Kew, M. C. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int. 23, 405–409 (2003).
  CAS PubMed Google Scholar
• Chang, M. H. et al. Long-term effects of hepatitis B immunization of infants in preventing liver cancer. Gastroenterology 151, 472–480.e1 (2016).
  CAS PubMed Google Scholar
• Jain, M. K. et al. Evaluation of a multifaceted intervention to reduce health disparities in hepatitis C screening: a pre-post analysis. Hepatology 70, 40–50 (2019).
  PubMed Google Scholar
• Ioannou, G. N. et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology 157, 1264–1278.e4 (2019).
  CAS PubMed Google Scholar
• Llovet, J. M. & Villanueva, A. Effect of HCV clearance with direct-acting antiviral agents on HCC. Nat. Rev. Gastroenterol. Hepatol. 13, 561–562 (2016).
  CAS PubMed Google Scholar
• Puigvehí, M., Moctezuma-Velázquez, C., Villanueva, A. & Llovet, J. M. The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP Rep. 1, 120–130 (2019).
  PubMed PubMed Central Google Scholar
• Jepsen, P., Ott, P., Andersen, P. K., Sørensen, H. T. & Vilstrup, H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis. Ann. Intern. Med. 156, 841 (2012).
  PubMed Google Scholar
• Lin, C. W. et al. Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis. J. Hepatol. 58, 730–735 (2013).
  CAS PubMed Google Scholar
• Welzel, T. M. et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am. J. Gastroenterol. 108, 1314–1321 (2013).
  PubMed PubMed Central Google Scholar
• Kanwal, F. et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 155, 1828–1837.e2 (2018).
  PubMed Google Scholar
• Mittal, S. et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 14, 124–131.e1 (2016).
  CAS PubMed Google Scholar
• Rich, N. E., Yopp, A. C., Singal, A. G. & Murphy, C. C. Hepatocellular carcinoma incidence is decreasing among younger adults in the United States. Clin. Gastroenterol. Hepatol. 18, 242–248.e5 (2020).
  PubMed Google Scholar
• Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin. 68, 394–424 (2018).
  PubMed Google Scholar
• Rich, N. E. et al. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 17, 551–559.e1 (2019).
  PubMed Google Scholar
• Lee, Y.-C. A. et al. Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int. J. Epidemiol. 38, 1497–1511 (2009).
  PubMed Google Scholar
• Bravi, F., Bosetti, C., Tavani, A., Gallus, S. & La Vecchia, C. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin. Gastroenterol. Hepatol. 11, 1413–1421.e1 (2013).
  CAS PubMed Google Scholar
• Sia, D., Villanueva, A., Friedman, S. L. & Llovet, J. M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152, 745–761 (2017).
  CAS PubMed Google Scholar
• Pikarsky, E. Neighbourhood deaths cause a switch in cancer subtype. Nature 562, 45–46 (2018).
  CAS PubMed Google Scholar
• Seehawer, M. et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562, 69–75 (2018).
  CAS PubMed PubMed Central Google Scholar
• Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694–698 (2012).
  CAS PubMed PubMed Central Google Scholar
• Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).
  CAS PubMed PubMed Central Google Scholar
• Calderaro, J., Ziol, M., Paradis, V. & Zucman-Rossi, J. Molecular and histological correlations in liver cancer. J. Hepatol. 71, 616–630 (2019).
  CAS PubMed Google Scholar
• Hyman, D. M., Taylor, B. S. & Baselga, J. Implementing genome-driven oncology. Cell 168, 584–599 (2017).
  CAS PubMed PubMed Central Google Scholar
• Bressac, B., Kew, M., Wands, J. & Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431 (1991).
  CAS PubMed Google Scholar
• Wang, B. et al. Null genotypes of GSTM1 and GSTT1 contribute to hepatocellular carcinoma risk: Evidence from an updated meta-analysis. J. Hepatol. 53, 508–518 (2010).
  PubMed Google Scholar
• Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
  CAS PubMed PubMed Central Google Scholar
• Buch, S. et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat. Genet. 47, 1443–1448 (2015).
  CAS PubMed Google Scholar
• Paterlini-Bréchot, P. et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 22, 3911–3916 (2003).
  PubMed Google Scholar
• Nault, J.-C., Ningarhari, M., Rebouissou, S. & Zucman-Rossi, J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 16, 544–558 (2019).
  PubMed Google Scholar
• Bayard, Q. et al. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nat. Commun. 9, 5235 (2018).
  CAS PubMed PubMed Central Google Scholar
• Nault, J.-C. et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47, 1187–1193 (2015).
  CAS PubMed Google Scholar
• Letouzé, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017).
  PubMed PubMed Central Google Scholar
• Ng, A. W. T. et al. Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Sci. Transl. Med. 9, eaan6446 (2017).
  PubMed Google Scholar
• Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
  CAS PubMed PubMed Central Google Scholar
• Rebouissou, S. & Nault, J.-C. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J. Hepatol. 72, 215–229 (2020).
  CAS PubMed Google Scholar
• Hoshida, Y. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 69, 7385–7392 (2009).
  CAS PubMed PubMed Central Google Scholar
• Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341.e23 (2017).
  Google Scholar
• Lee, J.-S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12, 410–416 (2006).
  CAS PubMed Google Scholar
• Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007).
  CAS PubMed Google Scholar
• Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).
  CAS PubMed Google Scholar
• Lachenmayer, A. et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin. Cancer Res. 18, 4997–5007 (2012).
  CAS PubMed PubMed Central Google Scholar
• Ruiz de Galarreta, M. et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019).
  CAS PubMed Google Scholar
• Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
  PubMed Google Scholar
• Sutti, S. & Albano, E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 17, 81–92 (2020).
  CAS PubMed Google Scholar
• Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
  CAS PubMed PubMed Central Google Scholar
• Nishida, N. et al. Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 31, 1646–1653 (2016).
  CAS PubMed Google Scholar
• Tummala, K. S. et al. Inhibition of de novo NAD+ synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 26, 826–839 (2014).
  CAS PubMed Google Scholar
• Gomes, A. L. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30, 161–175 (2016).
  CAS PubMed Google Scholar
• Guri, Y. et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 32, 807–823.e12 (2017).
  CAS PubMed Google Scholar
• Liu, D. et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci. Transl. Med. 10, eaap9840 (2018).
  PubMed Google Scholar
• Umemura, A. et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935–948 (2016).
  CAS PubMed PubMed Central Google Scholar
• Grohmann, M. et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 175, 1289–1306.e20 (2018).
  CAS PubMed PubMed Central Google Scholar
• Henderson, J. M., Zhang, H. E., Polak, N. & Gorrell, M. D. Hepatocellular carcinoma: mouse models and the potential roles of proteases. Cancer Lett. 387, 106–113 (2017).
  CAS PubMed Google Scholar
• Negro, F. Natural history of NASH and HCC. Liver Int. 40, 72–76 (2020).
  PubMed Google Scholar
• Rudalska, R. et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20, 1138–1146 (2014).
  CAS PubMed PubMed Central Google Scholar
• Martinez-Quetglas, I. et al. IGF2 is up-regulated by epigenetic mechanisms in hepatocellular carcinomas and is an actionable oncogene product in experimental models. Gastroenterology 151, 1192–1205 (2016).
  CAS PubMed Google Scholar
• Doudna, J. A. & Charpentier, E. The new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014).
  PubMed Google Scholar
• Cook, N., Jodrell, D. I. & Tuveson, D. A. Predictive in vivo animal models and translation to clinical trials. Drug Discov. Today 17, 253–260 (2012).
  PubMed Google Scholar
• Singh, M. & Ferrara, N. Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nat. Biotechnol. 30, 648–657 (2012).
  CAS PubMed Google Scholar
• Newell, P., Villanueva, A., Friedman, S. L., Koike, K. & Llovet, J. M. Experimental models of hepatocellular carcinoma. J. Hepatol. 48, 858–879 (2008).
  CAS PubMed PubMed Central Google Scholar
• Bresnahan, E., Ramadori, P., Heikenwalder, M., Zender, L. & Lujambio, A. Novel patient-derived preclinical models of liver cancer. J. Hepatol. 72, 239–249 (2020).
  CAS PubMed Google Scholar
• Moriya, K. et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med. 4, 1065–1067 (1998).
  CAS PubMed Google Scholar
• Hagel, M. et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 5, 424–437 (2015).
  CAS PubMed Google Scholar
• Day, C.-P., Merlino, G. & Van Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39–53 (2015).
  CAS PubMed PubMed Central Google Scholar
• Jayson, G. & Harris, J. How participants in cancer trials are chosen: ethics and conflicting interests. Nat. Rev. Cancer 6, 330–336 (2006).
  CAS PubMed Google Scholar
• Febbraio, M. A. et al. Preclinical models for studying NASH-driven HCC: how useful are they? Cell Metab. 29, 18–26 (2019).
  CAS PubMed Google Scholar
• Sharpless, N. E. & DePinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5, 741–754 (2006).
  CAS PubMed Google Scholar
• Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).
  CAS PubMed Google Scholar
• Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).
  CAS PubMed PubMed Central Google Scholar
• Malehmir, M. et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019).
  CAS PubMed Google Scholar
• Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
  CAS PubMed PubMed Central Google Scholar
• Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
  CAS PubMed Google Scholar
• Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O. & Kojiro, M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27, 407–414 (1998).
  CAS PubMed Google Scholar
• Yuan, D. et al. Kupffer cell-derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 31, 771–789.e6 (2017).
  CAS PubMed PubMed Central Google Scholar
• Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).
  CAS PubMed Google Scholar
• Horwitz, E. et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to Sorafenib treatment. Cancer Discov. 4, 730–743 (2014).
  CAS PubMed Google Scholar
• Finn, R. S. et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J. Clin. Oncol. 38, 2960–2970 (2020).
  PubMed PubMed Central Google Scholar
• Hou, J., Zhang, H., Sun, B. & Karin, M. The immunobiology of hepatocellular carcinoma in humans and mice: basic concepts and therapeutic implications. J. Hepatol. 72, 167–182 (2020).
  CAS PubMed Google Scholar
• Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359, 1995–2004 (2008). This study is the first molecular indication of the importance of the cancer field effect in the outcome of patients with HCC.
  CAS PubMed PubMed Central Google Scholar
• Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).
  CAS PubMed PubMed Central Google Scholar
• Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
  CAS PubMed Google Scholar
• Flecken, T. et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 59, 1415–1426 (2014).
  CAS PubMed Google Scholar
• Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).
  CAS PubMed Google Scholar
• Langhans, B. et al. Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Cancer Immunol. Immunother. 68, 2055–2066 (2019).
  CAS PubMed Google Scholar
• Garnelo, M. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66, 342–351 (2017).
  CAS PubMed Google Scholar
• Bruno, T. C. New predictors for immunotherapy responses sharpen our view of the tumour microenvironment. Nature 577, 474–476 (2020).
  CAS PubMed PubMed Central Google Scholar
• Schneider, C. et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61, 1733–1743 (2012).
  CAS PubMed Google Scholar
• Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).
  PubMed Google Scholar
• Calderaro, J. et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J. Hepatol. 70, 58–65 (2019).
  PubMed Google Scholar
• Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).
  CAS PubMed PubMed Central Google Scholar
• Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).
  CAS PubMed Google Scholar
• Higashi, T., Friedman, S. L. & Hoshida, Y. Hepatic stellate cells as key target in liver fibrosis. Adv. Drug Deliv. Rev. 121, 27–42 (2017).
  CAS PubMed PubMed Central Google Scholar
• Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).
  CAS PubMed PubMed Central Google Scholar
• Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).
  PubMed PubMed Central Google Scholar
• Hoshida, Y. et al. Prognostic gene expression signature for patients with hepatitis C–related early-stage cirrhosis. Gastroenterology 144, 1024–1030 (2013).
  CAS PubMed Google Scholar
• Budhu, A. et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10, 99–111 (2006).
  CAS PubMed Google Scholar
• Moeini, A. et al. An immune gene expression signature associated with development of human hepatocellular carcinoma identifies mice that respond to chemopreventive agents. Gastroenterology 157, 1383–1397.e11 (2019).
  CAS PubMed Google Scholar
• Singal, A. G., Lampertico, P. & Nahon, P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J. Hepatol. 72, 250–261 (2020).
  CAS PubMed PubMed Central Google Scholar
• Papatheodoridis, G. et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J. Hepatol. 64, 800–806 (2016).
  CAS PubMed Google Scholar
• Shinmura, R. et al. Cirrhotic nodules: association between MR imaging signal intensity and intranodular blood supply. Radiology 237, 512–519 (2005).
  PubMed Google Scholar
• van der Pol, C. B. et al. Accuracy of the liver imaging reporting and data system in computed tomography and magnetic resonance image analysis of hepatocellular carcinoma or overall malignancy — a systematic review. Gastroenterology 156, 976–986 (2019).
  PubMed Google Scholar
• Paisant, A. et al. Comparison of extracellular and hepatobiliary MR contrast agents for the diagnosis of small HCCs. J. Hepatol. 72, 937–945 (2020).
  CAS PubMed Google Scholar
• Kojiro, M. et al. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49, 658–664 (2009).
  Google Scholar
• Forner, A. et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 47, 97–104 (2007).
  Google Scholar
• Zhang, B.-H., Yang, B.-H. & Tang, Z.-Y. Randomized controlled trial of screening for hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 130, 417–422 (2004).
  PubMed Google Scholar
• Lederle, F. A. Screening for liver cancer: the rush to judgment. Ann. Intern. Med. 156, 387 (2012).
  PubMed Google Scholar
• Poustchi, H. et al. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology 54, 1998–2004 (2011).
  PubMed Google Scholar
• Singal, A. G., Pillai, A. & Tiro, J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 11, e1001624 (2014). This paper is a meta-analysis defining the accuracy of distinct surveillance strategies for the early detection of HCC.
  PubMed PubMed Central Google Scholar
• Andersson, K. L., Salomon, J. A., Goldie, S. J. & Chung, R. T. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 6, 1418–1424 (2008).
  PubMed PubMed Central Google Scholar
• Trinchet, J.-C. et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 54, 1987–1997 (2011).
  PubMed Google Scholar
• Atiq, O. et al. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. Hepatology 65, 1196–1205 (2017).
  CAS PubMed Google Scholar
• Marrero, J. A. et al. α-Fetoprotein, DES-γ carboxyprothrombin, and lectin-bound α-fetoprotein in early hepatocellular carcinoma. Gastroenterology 137, 110–118 (2009).
  CAS PubMed Google Scholar
• Pepe, M. S. et al. Phases of biomarker development for early detection of cancer. J. Natl. Cancer Inst. 93, 1054–1061 (2001).
  CAS PubMed Google Scholar
• Tzartzeva, K. et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 154, 1706–1718.e1 (2018).
  CAS PubMed Google Scholar
• Labgaa, I. et al. A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma. Oncogene 37, 3740–3752 (2018).
  CAS PubMed PubMed Central Google Scholar
• Kisiel, J. B. et al. Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation. Hepatology 69, 1180–1192 (2019).
  CAS PubMed Google Scholar
• Xu, R. et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat. Mater. 16, 1155–1161 (2017).
  CAS PubMed Google Scholar
• Qu, C. et al. Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy. Proc. Natl Acad. Sci. USA 116, 6308–6312 (2019).
  CAS PubMed PubMed Central Google Scholar
• Oh, C. R. et al. Genome-wide copy number alteration and VEGFA amplification of circulating cell-free DNA as a biomarker in advanced hepatocellular carcinoma patients treated with Sorafenib. BMC Cancer 19, 292 (2019).
  PubMed PubMed Central Google Scholar
• Torga, G. & Pienta, K. J. Patient-paired sample congruence between 2 commercial liquid biopsy tests. JAMA Oncol. 4, 868 (2018).
  PubMed Google Scholar
• Papatheodoridis, G. V., Chan, H. L.-Y., Hansen, B. E., Janssen, H. L. A. & Lampertico, P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J. Hepatol. 62, 956–967 (2015).
  PubMed Google Scholar
• Chang, M.-H. et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N. Engl. J. Med. 336, 1855–1859 (1997).
  CAS PubMed Google Scholar
• Singh, S., Singh, P. P., Singh, A. G., Murad, M. H. & Sanchez, W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144, 323–332 (2013).
  CAS PubMed Google Scholar
• Kennedy, O. J. et al. Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose–response meta-analysis. BMJ Open 7, e013739 (2017).
  PubMed PubMed Central Google Scholar
• Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology https://doi.org/10.1002/hep.31327 (2020).
  Article PubMed Google Scholar
• Llovet, J., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999). The first description of the BCLC classification widely used in guidelines of management of HCC.
  CAS PubMed Google Scholar
• D’Amico, G. et al. Clinical states of cirrhosis and competing risks. J. Hepatol. 68, 563–576 (2018).
  PubMed Google Scholar
• Llovet, J. M. et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 29, 62–67 (1999).
  CAS PubMed Google Scholar
• Shrager, B., Jibara, G., Schwartz, M. & Roayaie, S. Resection of hepatocellular carcinoma without cirrhosis. Ann. Surg. 255, 1135–1143 (2012).
  PubMed Google Scholar
• Viganò, L. et al. Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC. J. Hepatol. 63, 93–101 (2015).
  PubMed Google Scholar
• Piscaglia, F. et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 63, 827–838 (2016).
  PubMed Google Scholar
• Zhou, X.-D. et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 91, 1479–1486 (2001).
  CAS PubMed Google Scholar
• Johnson, P. J. et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach — the ALBI grade. J. Clin. Oncol. 33, 550–558 (2015).
  PubMed Google Scholar
• Pinato, D. J. et al. The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma. J. Hepatol. 66, 338–346 (2017).
  PubMed Google Scholar
• Roayaie, S. et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62, 440–451 (2015).
  CAS PubMed Google Scholar
• Berardi, G. et al. Development of a nomogram to predict outcome after liver resection for hepatocellular carcinoma in Child-Pugh B cirrhosis. J. Hepatol. 72, 75–84 (2020).
  PubMed Google Scholar
• Ishizawa, T. et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134, 1908–1916 (2008).
  PubMed Google Scholar
• Citterio, D. et al. Hierarchic interaction of factors associated with liver decompensation after resection for hepatocellular carcinoma. JAMA Surg. 151, 846–853 (2016).
  PubMed Google Scholar
• Vitale, A. et al. Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona clinic liver cancer stages: a multicentre study. J. Hepatol. 62, 617–624 (2015).
  PubMed Google Scholar
• Yin, L. et al. Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: a RCT. J. Hepatol. 61, 82–88 (2014).
  PubMed Google Scholar
• Kokudo, T. et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J. Hepatol. 65, 938–943 (2016).
  PubMed Google Scholar
• Roayaie, S., Jibara, G., Taouli, B. & Schwartz, M. Resection of hepatocellular carcinoma with macroscopic vascular invasion. Ann. Surg. Oncol. 20, 3754–3760 (2013).
  PubMed Google Scholar
• Roayaie, S. et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology 57, 1426–1435 (2013).
  PubMed Google Scholar
• Imamura, H. et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J. Hepatol. 38, 200–207 (2003).
  PubMed Google Scholar
• Shi, M. et al. Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial. Ann. Surg. 245, 36–43 (2007).
  PubMed PubMed Central Google Scholar
• Hidaka, M. et al. Impact of anatomical resection for hepatocellular carcinoma with microportal invasion (vp1): a multi-institutional study by the Kyushu study group of liver surgery. Ann. Surg. 271, 339–346 (2020).
  PubMed Google Scholar
• Samuel, M., Chow, P. K. H., Shih-Yen, E. C., Machin, D. & Soo, K. C. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst. Rev. 2009, CD001199 (2009).
  PubMed PubMed Central Google Scholar
• Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015).
  CAS PubMed Google Scholar
• Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).
  CAS PubMed Google Scholar
• Yin, J. et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J. Clin. Oncol. 31, 3647–3655 (2013).
  CAS PubMed Google Scholar
• Singal, A. G. et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 157, 1253–1263.e2 (2019).
  CAS PubMed Google Scholar
• Waziry, R. et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J. Hepatol. 67, 1204–1212 (2017).
  CAS PubMed Google Scholar
• Reig, M. et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J. Hepatol. 65, 719–726 (2016).
  CAS PubMed Google Scholar
• Tabrizian, P., Jibara, G., Shrager, B., Schwartz, M. & Roayaie, S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann. Surg. 261, 947–955 (2015).
  PubMed Google Scholar
• Ferrer-Fàbrega, J. et al. Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection. Hepatology 63, 839–849 (2016).
  PubMed Google Scholar
• Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–700 (1996). This is a landmark study establishing the criteria for liver transplantation in HCC.
  CAS PubMed Google Scholar
• Franssen, B., Jibara, G., Tabrizian, P., Schwartz, M. E. & Roayaie, S. Actual 10-year survival following hepatectomy for hepatocellular carcinoma. HPB 16, 830–835 (2014).
  PubMed Google Scholar
• Cucchetti, A. et al. The chances of hepatic resection curing hepatocellular carcinoma. J. Hepatol. 72, 711–717 (2020).
  PubMed Google Scholar
• Llovet, J. M., Fuster, J. & Bruix, J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30, 1434–1440 (1999).
  CAS PubMed Google Scholar
• Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 33, 1394–1403 (2001).
  CAS PubMed Google Scholar
• Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am. J. Transplant. 7, 2587–2596 (2007).
  CAS PubMed Google Scholar
• Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 10, 35–43 (2009).
  PubMed Google Scholar
• Commander, S. J. et al. A long-term experience with expansion of Milan criteria for liver transplant recipients. Clin. Transplant. 32, e13254 (2018).
  PubMed Google Scholar
• Ravaioli, M. et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am. J. Transpl. 8, 2547–2557 (2008).
  CAS Google Scholar
• Mazzaferro, V. et al. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma. Gastroenterology 154, 128–139 (2018).
  PubMed Google Scholar
• Hong, G. et al. Alpha-fetoprotein and 18F-FDG positron emission tomography predict tumor recurrence better than Milan criteria in living donor liver transplantation. J. Hepatol. 64, 852–859 (2016).
  CAS PubMed Google Scholar
• Kulik, L. et al. Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: a systematic review and meta-analysis. Hepatology 67, 381–400 (2018).
  CAS PubMed Google Scholar
• Yao, F. Y. et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology 61, 1968–1977 (2015).
  PubMed Google Scholar
• Cucchetti, A. et al. Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant. J. Hepatol. 73, 342–348 (2020).
  PubMed Google Scholar
• Halazun, K. J. et al. Is it time to abandon the Milan criteria? Results of a bicoastal US collaboration to redefine hepatocellular carcinoma liver transplantation selection policies. Ann. Surg. 268, 690–699 (2018).
  PubMed Google Scholar
• Kulik, L. M. et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am. J. Transpl. 12, 2997–3007 (2012).
  CAS Google Scholar
• Miltiadous, O. et al. Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J. Hepatol. 63, 1368–1377 (2015).
  PubMed Google Scholar
• Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma. Transplantation 100, 116–125 (2016).
  CAS PubMed Google Scholar
• Heimbach, J. K. et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67, 358–380 (2018).
  PubMed Google Scholar
• Lencioni, R. & Llovet, J. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).
  CAS PubMed Google Scholar
• Lencioni, R. New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma. Clin. Cancer Res. 19, 1312–1314 (2013).
  PubMed Google Scholar
• Llovet, J. M. & Lencioni, R. mRECIST for HCC: performance and novel refinements. J. Hepatol. 72, 288–306 (2020).
  PubMed Google Scholar
• Meyer, T. et al. mRECIST to predict survival in advanced hepatocellular carcinoma: analysis of two randomised phase II trials comparing nintedanib vs sorafenib. Liver Int. 37, 1047–1055 (2017).
  CAS PubMed Google Scholar
• Lencioni, R. et al. Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC. J. Hepatol. 66, 1166–1172 (2017).
  PubMed Google Scholar
• Kudo, M. et al. Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). J. Clin. Oncol. 37, 186–186 (2019).
  Google Scholar
• Lencioni, R. A. et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228, 235–240 (2003).
  PubMed Google Scholar
• Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W. & Chen, Y.-C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma ≤4 cm. Gastroenterology 127, 1714–1723 (2004).
  PubMed Google Scholar
• Shiina, S. et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129, 122–130 (2005).
  PubMed Google Scholar
• Ng, K. K. C. et al. Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma. Br. J. Surg. 104, 1775–1784 (2017).
  CAS PubMed Google Scholar
• Xu, X.-L., Liu, X.-D., Liang, M. & Luo, B.-M. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Radiology 287, 461–472 (2018).
  PubMed Google Scholar
• Izumi, N. et al. A multicenter randomized controlled trial to evaluate the efficacy of surgery vs. radiofrequency ablation for small hepatocellular carcinoma (SURF trial). J. Clin. Oncol. 37, 4002–4002 (2019).
  Google Scholar
• Xia, Y. et al. Long-term effects of repeat hepatectomy vs percutaneous radiofrequency ablation among patients with recurrent hepatocellular carcinoma. JAMA Oncol. 6, 255–263 (2020).
  PubMed Google Scholar
• Lencioni, R. et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 234, 961–967 (2005).
  PubMed Google Scholar
• Sala, M. et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 40, 1352–1360 (2004).
  PubMed Google Scholar
• Breen, D. J. & Lencioni, R. Image-guided ablation of primary liver and renal tumours. Nat. Rev. Clin. Oncol. 12, 175–186 (2015).
  PubMed Google Scholar
• Yu, J. et al. Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial. Gut 66, 1172–1173 (2017).
  PubMed Google Scholar
• Hu, J. et al. Image-guided percutaneous microwave ablation versus cryoablation for hepatocellular carcinoma in high-risk locations: intermediate-term results. Cancer Manag. Res. 11, 9801–9811 (2019).
  CAS PubMed PubMed Central Google Scholar
• Cheng, R. G., Bhattacharya, R., Yeh, M. M. & Padia, S. A. Irreversible electroporation can effectively ablate hepatocellular carcinoma to complete pathologic necrosis. J. Vasc. Interv. Radiol. 26, 1184–1188 (2015).
  PubMed Google Scholar
• Sutter, O. et al. Safety and efficacy of irreversible electroporation for the treatment of hepatocellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center case series. Radiology 284, 877–886 (2017).
  PubMed Google Scholar
• Peng, Z.-W. et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J. Clin. Oncol. 31, 426–432 (2013).
  PubMed Google Scholar
• Tak, W. Y. et al. Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. Clin. Cancer Res. 24, 73–83 (2018).
  CAS PubMed Google Scholar
• Wang, C. et al. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology 61, 1579–1590 (2015).
  PubMed Google Scholar
• Xu, J. et al. Radiofrequency ablation vs. cryoablation for localized hepatocellular carcinoma: a propensity-matched population study. Anticancer. Res. 38, 6381–6386 (2018).
  PubMed Google Scholar
• Di Costanzo, G. G. et al. Radiofrequency ablation versus laser ablation for the treatment of small hepatocellular carcinoma in cirrhosis: a randomized trial. J. Gastroenterol. Hepatol. 30, 559–565 (2015).
  PubMed Google Scholar
• Bujold, A. et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J. Clin. Oncol. 31, 1631–1639 (2013).
  PubMed Google Scholar
• Hong, T. S. et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 34, 460–468 (2016).
  CAS PubMed Google Scholar
• Tse, R. V. et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 26, 657–664 (2008).
  PubMed Google Scholar
• Yang, J.-F. et al. Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis. Radiat. Oncol. 14, 180 (2019).
  PubMed PubMed Central Google Scholar
• Wahl, D. R. et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J. Clin. Oncol. 34, 452–459 (2016).
  CAS PubMed Google Scholar
• Shen, P. C. et al. Comparison of stereotactic body radiation therapy and transarterial chemoembolization for unresectable medium-sized hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 105, 307–318 (2019).
  PubMed Google Scholar
• Kim, T. H. et al. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial. J. Hepatol. https://doi.org/10.1016/j.jhep.2020.09.026 (2020)
• Llovet, J. M. et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359, 1734–1739 (2002).
  PubMed Google Scholar
• Lo, C. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35, 1164–1171 (2002).
  CAS PubMed Google Scholar
• Vogel, A. et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29 (Suppl. 4), iv238–iv255 (2018).
  Google Scholar
• Lencioni, R., de Baere, T., Soulen, M. C., Rilling, W. S. & Geschwind, J.-F. H. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 64, 106–116 (2016).
  CAS PubMed Google Scholar
• Meyer, T. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 2, 565–575 (2017).
  PubMed Google Scholar
• Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 60, 1697–1707 (2014).
  CAS PubMed Google Scholar
• Okusaka, T. et al. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J. Hepatol. 51, 1030–1036 (2009).
  CAS PubMed Google Scholar
• Chau, I. et al. Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study. Br. J. Cancer 119, 19–26 (2018).
  CAS PubMed PubMed Central Google Scholar
• Lammer, J. et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc. Intervent. Radiol. 33, 41–52 (2010).
  PubMed Google Scholar
• Varela, M. et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J. Hepatol. 46, 474–481 (2007).
  CAS PubMed Google Scholar
• Burrel, M. et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using drug eluting beads. Implications for clinical practice and trial design. J. Hepatol. 56, 1330–1335 (2012).
  PubMed Google Scholar
• Vincenzi, B. et al. Prognostic relevance of objective response according to EASL criteria and mRECIST criteria in hepatocellular carcinoma patients treated with loco-regional therapies: a literature-based meta-analysis. PLoS ONE 10, e0133488 (2015).
  PubMed PubMed Central Google Scholar
• Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol. 64, 1090–1098 (2016).
  CAS PubMed Google Scholar
• Kudo, M. et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol. Hepatol. 3, 37–46 (2018).
  PubMed Google Scholar
• Kudo, M. et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol. Hepatol. 3, 424–432 (2018).
  PubMed Google Scholar
• Park, J. W. et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J. Hepatol. 70, 684–691 (2019).
  CAS PubMed Google Scholar
• Kudo, M. et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur. J. Cancer 47, 2117–2127 (2011).
  CAS PubMed Google Scholar
• Hilgard, P. et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 52, 1741–1749 (2010).
  CAS PubMed Google Scholar
• Salem, R. et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 138, 52–64 (2010).
  CAS PubMed Google Scholar
• Mazzaferro, V. et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 57, 1826–1837 (2013).
  CAS PubMed Google Scholar
• Vilgrain, V. et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 18, 1624–1636 (2017).
  CAS PubMed Google Scholar
• Chow, P. K. H. et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J. Clin. Oncol. 36, 1913–1921 (2018).
  CAS PubMed Google Scholar
• Ricke, J. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J. Hepatol. 71, 1164–1174 (2019).
  CAS PubMed Google Scholar
• Bruix, J. et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J. Hepatol. 67, 999–1008 (2017).
  CAS PubMed Google Scholar
• Finn R. S. et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib(sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J. Clin. Oncol. 39, (suppl 3; abstr 267) (2021).
• Yau, T. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 6, e204564 (2020).
  PubMed PubMed Central Google Scholar
• Zhu, A. X. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19, 940–952 (2018).
  PubMed Google Scholar
• Llovet, J. M., Montal, R. & Villanueva, A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J. Hepatol. 70, 1262–1277 (2019).
  PubMed Google Scholar
• Office of the Commissioner. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma (2020).
• Yau, T. et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann. Oncol. 30, v874–v875 (2019).
  Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04039607 (2019).
• Zappasodi, R., Merghoub, T. & Wolchok, J. D. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581–598 (2018).
  CAS PubMed PubMed Central Google Scholar
• Rahma, O. E. & Hodi, F. S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 25, 5449–5457 (2019).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03713593 (2018).
• US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03755791 (2018).
• Bergerot, P., Lamb, P., Wang, E. & Pal, S. K. Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol. Cancer Ther. 18, 2185–2193 (2019).
  CAS PubMed Google Scholar
• Ott, P. A., Hodi, F. S., Kaufman, H. L., Wigginton, J. M. & Wolchok, J. D. Combination immunotherapy: a road map. J. Immunother. Cancer 5, 16 (2017).
  PubMed PubMed Central Google Scholar
• Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
  CAS PubMed PubMed Central Google Scholar
• Kelley, R. K. et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J. Clin. Oncol. 38, 4508–4508 (2020).
  Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03298451 (2017).
• Schmidt, E. V. et al. Assessment of clinical activity of PD-1 checkpoint inhibitor combination therapies reported in clinical trials. JAMA Netw. Open 3, e1920833 (2020).
  PubMed Google Scholar
• Montal, R. et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br. J. Cancer 121, 340–343 (2019).
  CAS PubMed PubMed Central Google Scholar
• Galle, P. R. et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int. 39, 2214–2229 (2019).
  PubMed Google Scholar
• Teufel, M. et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology 156, 1731–1741 (2019).
  CAS PubMed Google Scholar
• Pinyol, R. et al. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut 68, 1065–1075 (2019).
  PubMed Google Scholar
• Li, X.-S., Li, J.-W., Li, H. & Jiang, T. Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis. Biosci. Rep. 40, BSR20200459 (2020).
  CAS PubMed PubMed Central Google Scholar
• Kim, R. D. et al. First-in-human phase I study of Fisogatinib (BLU-554) validates aberrant fibroblast growth factor 19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9, 1696–1707 (2019).
  CAS PubMed Google Scholar
• Lim, H. Y. et al. Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular carcinoma. Clin. Cancer Res. 24, 4650–4661 (2018).
  CAS PubMed Google Scholar
• Rimassa, L. et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 19, 682–693 (2018).
  CAS PubMed Google Scholar
• Tapper, E. B. & Asrani, S. K. The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care. J. Hepatol. https://doi.org/10.1016/j.jhep.2020.04.005 (2020).
  Article PubMed PubMed Central Google Scholar
• US Census Bureau. Coronavirus (COVID-19) pandemic. US Census Bureau https://www.census.gov/coronavirus (2020).
• Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).
  CAS PubMed PubMed Central Google Scholar
• International Liver Cancer Association. Management of HCC during COVID-19: ILCA guidance. ILCA https://ilca-online.org/news/management-of-hcc-during-covid-19-ilca-guidance/ (2020).
• Cheng, A. L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009).
  CAS PubMed Google Scholar
• Sangro, B. et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J. Hepatol. 72, 320–341 (2020).
  CAS PubMed PubMed Central Google Scholar
• Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 312, 57–67 (2014).
  PubMed Google Scholar
• Blazeby, J. M. et al. Development of a questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-HCC18. Eur. J. Cancer 40, 2439–2444 (2004).
  PubMed Google Scholar
• Heffernan, N. et al. Measuring health-related quality of life in patients with hepatobiliary cancers: the functional assessment of Cancer Therapy-Hepatobiliary Questionnaire. J. Clin. Oncol. 20, 2229–2239 (2002).
  PubMed Google Scholar
• Fan, S. Y., Eiser, C. & Ho, M. C. Health-related quality of life in patients with hepatocellular carcinoma: a systematic review. Clin. Gastroenterol. Hepatol. 8, 559–564 (2010).
  PubMed Google Scholar
• Diouf, M. et al. The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma. J. Hepatol. 58, 509–521 (2013).
  PubMed Google Scholar
• Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).
  CAS PubMed PubMed Central Google Scholar
• Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
  CAS PubMed Google Scholar
• Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).
  CAS PubMed Google Scholar
• Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res. 38, 255 (2019).
  PubMed PubMed Central Google Scholar
• Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).
  PubMed Google Scholar