{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:01Z","timestamp":1787027761269,"version":"build-2736575974"},"reference-count":107,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T00:00:00Z","timestamp":1711843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as \u201chepatocellular carcinoma\u201d, \u201cimmune checkpoint inhibitors\u201d, \u201csystemic therapy\u201d, \u201cportal hypertension\u201d, \u201cvariceal bleeding\u201d and \u201ctyrosine kinase inhibitors\u201d. Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab\/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.<\/jats:p>","DOI":"10.3390\/cancers16071388","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T05:42:43Z","timestamp":1711950163000},"page":"1388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives"],"prefix":"10.3390","volume":"16","author":[{"given":"Valeria","family":"De Gaetano","sequence":"first","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pallozzi","sequence":"additional","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6837-7582","authenticated-orcid":false,"given":"Lucia","family":"Cerrito","sequence":"additional","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1773-1171","authenticated-orcid":false,"given":"Francesco","family":"Santopaolo","sequence":"additional","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3431-0803","authenticated-orcid":false,"given":"Leonardo","family":"Stella","sequence":"additional","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6230-1779","authenticated-orcid":false,"given":"Antonio","family":"Gasbarrini","sequence":"additional","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"},{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Romana","family":"Ponziani","sequence":"additional","affiliation":[{"name":"Liver Unit, Centro Malattie dell\u2019Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41571-023-00825-3","article-title":"Global trends in hepatocellular carcinoma epidemiology: Implications for screening, prevention and therapy","volume":"20","author":"Singal","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ejca.2021.11.023","article-title":"Global, regional and national burden of primary liver cancer by subtype","volume":"161","author":"Rumgay","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1002\/cam4.4551","article-title":"Global burden of primary liver cancer by five etiologies and global prediction by 2035 based on global burden of disease study 2019","volume":"11","author":"Liu","year":"2022","journal-title":"Cancer Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1159\/000082895","article-title":"Endoscopic Prediction of Hepatocellular Carcinoma by Evaluation of Bleeding Esophageal Varices","volume":"70","author":"Nakayama","year":"2005","journal-title":"Digestion"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.jhep.2009.01.014","article-title":"Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis","volume":"50","author":"Ripoll","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"500","DOI":"10.5009\/gnl19155","article-title":"Treatment Outcomes and Prognostic Factors of Acute Variceal Bleeding in Patients with Hepatocellular Carcinoma","volume":"14","author":"Lee","year":"2020","journal-title":"Gut Liver"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S1089-3261(05)70186-0","article-title":"Natural history of portal hypertension in patients with cirrhosis","volume":"5","author":"Primignani","year":"2001","journal-title":"Clin. Liver Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.jhep.2021.12.022","article-title":"Baveno VII\u2014Renewing consensus in portal hypertension","volume":"76","author":"Bosch","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jhep.2014.03.014","article-title":"Inflammation and portal hypertension\u2014The undiscovered country","volume":"61","author":"Mehta","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.jhep.2012.03.007","article-title":"Functional aspects on the pathophysiology of portal hypertension in cirrhosis","volume":"57","author":"Bosch","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_12","first-page":"1378","article-title":"Prevalence and prognostic significance of the presence of esophageal varices in patients with hepatocellular carcinoma","volume":"4","author":"Giannini","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc."},{"key":"ref_13","first-page":"1734","article-title":"Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses\u2026","volume":"41","author":"Allaire","year":"2021","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100316","DOI":"10.1016\/j.jhepr.2021.100316","article-title":"Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy","volume":"3","author":"Iwakiri","year":"2021","journal-title":"JHEP Rep."},{"key":"ref_15","first-page":"330","article-title":"The Molecular Basis of Portal Hypertension","volume":"128","author":"Rockey","year":"2017","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cuesta, \u00c1.M., Palao, N., Bragado, P., Gutierrez-Uzquiza, A., Herrera, B., S\u00e1nchez, A., and Porras, A. (2023). New and Old Key Players in Liver Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417152"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1136\/gut.50.4.571","article-title":"Hepatic stellate cells: Role in microcirculation and pathophysiology of portal hypertension","volume":"50","author":"Reynaert","year":"2002","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1177\/1535370219898141","article-title":"Mechanisms of liver fibrosis and its role in liver cancer","volume":"245","author":"Dhar","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41575-020-00411-3","article-title":"Role of liver sinusoidal endothelial cells in liver diseases","volume":"18","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jhep.2016.07.009","article-title":"Liver sinusoidal endothelial cells: Physiology and role in liver diseases","volume":"66","author":"Poisson","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s12072-015-9613-5","article-title":"New cellular and molecular targets for the treatment of portal hypertension","volume":"9","author":"Bosch","year":"2015","journal-title":"Hepatol. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1002\/hep.510280405","article-title":"Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats","volume":"28","author":"Gupta","year":"1998","journal-title":"Hepatol. Baltim. Md"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.jceh.2023.05.016","article-title":"Von Willebrand Factor as a Biomarker for Liver Disease\u2014An Update","volume":"13","author":"Elhence","year":"2023","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1182\/blood-2005-01-0152","article-title":"Localization of ADAMTS13 to the stellate cells of human liver","volume":"106","author":"Uemura","year":"2005","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1172\/JCI112736","article-title":"Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation","volume":"78","author":"Moake","year":"1986","journal-title":"J. Clin. Investig."},{"key":"ref_26","first-page":"1238","article-title":"Hepatic and portal vein thrombosis in cirrhosis: Possible role in development of parenchymal extinction and portal hypertension","volume":"21","author":"Wanless","year":"1995","journal-title":"Hepatol. Baltim. Md"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev-pathol-052016-100322","article-title":"The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer","volume":"12","author":"Affo","year":"2017","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hao, X., Sun, G., Zhang, Y., Kong, X., Rong, D., Song, J., Tang, W., and Wang, X. (2021). Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.775462"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00109-018-1731-9","article-title":"Cancer-associated fibroblasts promote the stemness of CD24+ liver cells via paracrine signaling","volume":"97","author":"Li","year":"2019","journal-title":"J. Mol. Med. Berl. Ger."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e146987","DOI":"10.1172\/JCI146987","article-title":"Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts","volume":"131","author":"Bhattacharjee","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_31","first-page":"302","article-title":"Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6\/STAT3\/Notch signaling","volume":"8","author":"Xiong","year":"2018","journal-title":"Am. J. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1158\/1078-0432.CCR-18-1254","article-title":"The Role of Angiogenesis in Hepatocellular Carcinoma","volume":"25","author":"Ma","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_33","first-page":"1845","article-title":"The role of liver sinusoidal endothelial cells in cancer liver metastasis","volume":"11","author":"Yang","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-3-030-11093-2_9","article-title":"Pericytes in the Liver","volume":"1122","author":"Kostallari","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1053\/jhep.2002.32524","article-title":"Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis","volume":"35","author":"Corpechot","year":"2002","journal-title":"Hepatol. Baltim. Md"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jhep.2008.09.019","article-title":"Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension","volume":"50","author":"Tiani","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nrd2115","article-title":"Angiogenesis: An organizing principle for drug discovery?","volume":"6","author":"Folkman","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00432-003-0530-y","article-title":"Angiogenesis in hepatocellular carcinoma: The retrospectives and perspectives","volume":"130","author":"Sun","year":"2004","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nrclinonc.2011.30","article-title":"HCC and angiogenesis: Possible targets and future directions","volume":"8","author":"Zhu","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10456-007-9074-0","article-title":"Angiogenesis and chronic inflammation: Cause or consequence?","volume":"10","author":"Costa","year":"2007","journal-title":"Angiogenesis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3389\/fimmu.2012.00021","article-title":"Hypoxia promotes tumor growth in linking angiogenesis to immune escape","volume":"3","author":"Chouaib","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S121","DOI":"10.1016\/j.jhep.2015.01.003","article-title":"Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments","volume":"62","author":"Bosch","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1136\/gut.48.1.87","article-title":"Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma","volume":"48","author":"Cramer","year":"2001","journal-title":"Gut"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1158\/1078-0432.CCR-11-0659","article-title":"Beyond VEGF: Inhibition of the fibroblast growth factor pathway and antiangiogenesis","volume":"17","author":"Lieu","year":"2011","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2174\/156800912798888956","article-title":"The critical role of vascular endothelial growth factor in tumor angiogenesis","volume":"12","author":"Amini","year":"2012","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jprot.2014.04.021","article-title":"The role of von Willebrand factor as a biomarker of tumor development in hepatitis B virus-associated human hepatocellular carcinoma: A quantitative proteomic based study","volume":"106","author":"Liu","year":"2014","journal-title":"J. Proteomics"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Takaya, H., Namisaki, T., Kitade, M., Kaji, K., Nakanishi, K., Tsuji, Y., Shimozato, N., Moriya, K., Seki, K., and Sawada, Y. (2019). VWF\/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma. BMC Gastroenterol., 19.","DOI":"10.1186\/s12876-019-1082-1"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1177\/2050640618779660","article-title":"von Willebrand factor is a useful biomarker for liver fibrosis and prediction of hepatocellular carcinoma development in patients with hepatitis B and C","volume":"6","author":"Takaya","year":"2018","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1158\/1055-9965.EPI-11-0464","article-title":"Prediction of Hepatocellular Carcinoma Development by Plasma ADAMTS13 in Chronic Hepatitis B and C","volume":"20","author":"Ikeda","year":"2011","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/hep.27387","article-title":"Chronic Passive Venous Congestion drives Hepatic Fibrogenesis via Sinusoidal Thrombosis and Mechanical Forces","volume":"61","author":"Simonetto","year":"2015","journal-title":"Hepatol. Baltim. Md"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.cld.2019.07.007","article-title":"Portal Hypertension: Pathogenesis and Diagnosis","volume":"23","author":"Turco","year":"2019","journal-title":"Clin. Liver Dis."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Papa, V., Schepis, T., Coppola, G., Chiappetta, M.F., Del Vecchio, L.E., Rozera, T., Quero, G., Gasbarrini, A., Alfieri, S., and Papa, A. (2023). The Role of Microbiota in Pancreatic Cancer. Cancers, 15.","DOI":"10.3390\/cancers15123143"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s40265-022-01827-8","article-title":"Tremelimumab: First Approval","volume":"83","author":"Keam","year":"2023","journal-title":"Drugs"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"(2017). Nivolumab Approved for Liver Cancer. Cancer Discov., 7, OF3.","DOI":"10.1158\/2159-8290.CD-NB2017-138"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/onco.13819","article-title":"FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib","volume":"26","author":"Saung","year":"2021","journal-title":"Oncologist"},{"key":"ref_57","unstructured":"US Food and Drug Administration (2019). FDA Grants Accelerated Approval to Pembrolizumab for Hepatocellular Carcinoma."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrclinonc.2018.29","article-title":"Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges","volume":"15","author":"Fukumura","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/sj.bjc.6603813","article-title":"Mechanisms of adverse effects of anti-VEGF therapy for cancer","volume":"96","author":"Kamba","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/15216540252774784","article-title":"VEGF receptor signaling and endothelial function","volume":"52","author":"Kliche","year":"2001","journal-title":"IUBMB Life"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jss.2005.05.006","article-title":"The Effects of ZD6474, an Inhibitor of VEGF Signaling, on Cutaneous Wound Healing in Mice1","volume":"129","author":"Ko","year":"2005","journal-title":"J. Surg. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3542","DOI":"10.1200\/JCO.2003.99.046","article-title":"Bevacizumab, bleeding, thrombosis, and warfarin","volume":"21","author":"Kilickap","year":"2003","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/S1470-2045(09)70222-0","article-title":"Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: A systematic review and meta-analysis of clinical trials","volume":"10","author":"Je","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0076-6879(05)07047-3","article-title":"Sorafenib (BAY 43-9006, Nexavar\u00ae), a Dual-Action Inhibitor That Targets RAF\/MEK\/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR\/PDGFR in Tumor Vasculature","volume":"Volume 407","author":"Adnane","year":"2006","journal-title":"Methods in Enzymology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11851","DOI":"10.1158\/0008-5472.CAN-06-1377","article-title":"Sorafenib blocks the RAF\/MEK\/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC\/PRF\/5","volume":"66","author":"Liu","year":"2006","journal-title":"Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.1158\/0008-5472.CAN-22-2639","article-title":"Revisiting Antiangiogenic Multikinase Inhibitors in the Era of Immune Checkpoint Blockade: The Case of Sorafenib","volume":"82","author":"Duda","year":"2022","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/hep.22758","article-title":"Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats","volume":"49","author":"Mejias","year":"2009","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1002\/hep.21785","article-title":"Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats","volume":"46","author":"Fernandez","year":"2007","journal-title":"Hepatology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.jhep.2009.06.024","article-title":"Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats","volume":"51","author":"Reiberger","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Coriat, R., Gouya, H., Mir, O., Ropert, S., Vignaux, O., Chaussade, S., Sogni, P., Pol, S., Blanchet, B., and Legmann, P. (2011). Reversible decrease of portal venous flow in cirrhotic patients: A positive side effect of sorafenib. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016978"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1365-2036.2011.04896.x","article-title":"The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma\u2014A pilot study","volume":"35","author":"Pinter","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1111\/hepr.13294","article-title":"Long-term antitumor effect of lenvatinib on unresectable hepatocellular carcinoma with portal vein invasion","volume":"49","author":"Takeda","year":"2019","journal-title":"Hepatol. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s10637-022-01248-0","article-title":"Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience","volume":"40","author":"Wu","year":"2022","journal-title":"Investig. New Drugs"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4429","DOI":"10.2147\/DDDT.S386829","article-title":"Risk Factors for Hepatic Encephalopathy in Hepatocellular Carcinoma After Sorafenib or Lenvatinib Treatment: A Real-World Study","volume":"16","author":"Chen","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1111\/hepr.13531","article-title":"Portal hemodynamic effects of lenvatinib in patients with advanced hepatocellular carcinoma: A prospective cohort study","volume":"50","author":"Hidaka","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1111\/hepr.13537","article-title":"Therapeutic efficacy of lenvatinib in hepatocellular carcinoma patients with portal hypertension","volume":"50","author":"Maesaka","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1111\/liv.15458","article-title":"A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC","volume":"42","author":"Larrey","year":"2022","journal-title":"Liver Int."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.jhep.2022.11.019","article-title":"Treatment of portal hypertension in patients with HCC in the era of Baveno VII","volume":"78","author":"Thabut","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1002\/hep.32468","article-title":"Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study","volume":"76","author":"Fulgenzi","year":"2022","journal-title":"Hepatology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.2169\/internalmedicine.6535-20","article-title":"Rapid Progression of Liver Fibrosis Induced by Acute Liver Injury Due to Immune-related Adverse Events of Atezolizumab","volume":"60","author":"Honma","year":"2021","journal-title":"Intern. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s12328-022-01605-9","article-title":"Two cases of rapid progression of esophageal varices after atezolizumab-bevacizumab treatment for hepatocellular carcinoma","volume":"15","author":"Furusawa","year":"2022","journal-title":"Clin. J. Gastroenterol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1128569","DOI":"10.3389\/fonc.2023.1128569","article-title":"Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors","volume":"13","author":"Wu","year":"2023","journal-title":"Front. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.jhep.2019.10.021","article-title":"Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma","volume":"72","author":"Sangro","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.jhep.2023.10.040","article-title":"Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours","volume":"80","author":"Celsa","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1002\/cncr.32206","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series","volume":"125","author":"Kambhampati","year":"2019","journal-title":"Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Choi, W.M., Lee, D., Shim, J.H., Kim, K.M., Lim, Y.S., Lee, H.C., Yoo, C., Park, S.R., Ryu, M.H., and Ryoo, B.Y. (2020). Effectiveness and Safety of Nivolumab in Child\u2013Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study. Cancers, 12.","DOI":"10.3390\/cancers12071968"},{"key":"ref_87","first-page":"EVIDoa2100070","article-title":"Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma","volume":"1","author":"Lau","year":"2022","journal-title":"NEJM Evid."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1016\/j.ejca.2013.05.028","article-title":"Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study","volume":"49","author":"Bruix","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"36220","DOI":"10.18632\/oncotarget.26333","article-title":"The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension","volume":"9","author":"Uschner","year":"2018","journal-title":"Oncotarget"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"788","DOI":"10.4251\/wjgo.v11.i10.788","article-title":"Targeted agents for second-line treatment of advanced hepatocellular carcinoma","volume":"11","author":"Personeni","year":"2019","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Pavlovic, N., Rani, B., Gerwins, P., and Heindryckx, F. (2019). Platelets as Key Factors in Hepatocellular Carcinoma. Cancers, 11.","DOI":"10.3390\/cancers11071022"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1111\/apt.16490","article-title":"Nonselective beta-blockers are associated with a lower risk of hepatocellular carcinoma among cirrhotic patients in the United States","volume":"54","author":"Wijarnpreecha","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1080\/00365521.2020.1762919","article-title":"Beta-adrenergic receptor blockers and liver cancer mortality in a national cohort of hepatocellular carcinoma patients","volume":"55","author":"Udumyan","year":"2020","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1111\/j.1572-0241.2004.40336.x","article-title":"Outcomes of patients with hepatocellular carcinoma presenting with variceal bleeding","volume":"99","author":"Lang","year":"2004","journal-title":"Am. J. Gastroenterol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"17588359211031141","DOI":"10.1177\/17588359211031141","article-title":"Immunotherapy in hepatocellular carcinoma: Evaluation and management of adverse events associated with atezolizumab plus bevacizumab","volume":"13","author":"Hsu","year":"2021","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"102059","DOI":"10.1016\/j.clinre.2022.102059","article-title":"Screening and management of portal hypertension in advanced hepatocellular carcinoma: A French practice survey","volume":"47","author":"Allaire","year":"2023","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.dld.2019.06.019","article-title":"Ulcer bleeding after band ligation of esophageal varices: Risk factors and prognosis","volume":"52","author":"Cachero","year":"2020","journal-title":"Dig. Liver Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jvir.2012.08.032","article-title":"Hepatotoxicity after Transarterial Chemoembolization and Transjugular Intrahepatic Portosystemic Shunt: Do Two Rights Make a Wrong?","volume":"24","author":"Naeger","year":"2013","journal-title":"J. Vasc. Interv. Radiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1053\/j.gastro.2020.09.026","article-title":"Effects of Early Placement of Transjugular Portosystemic Shunts in Patients With High-Risk Acute Variceal Bleeding: A Meta-analysis of Individual Patient Data","volume":"160","author":"Han","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/cam4.4906","article-title":"Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis","volume":"12","author":"Chapin","year":"2023","journal-title":"Cancer Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/S1470-2045(23)00469-2","article-title":"Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): A randomised, double-blind, phase 3 trial","volume":"24","author":"Llovet","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/hep.27729","article-title":"Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib","volume":"62","author":"Iavarone","year":"2015","journal-title":"Hepatology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"101110","DOI":"10.1016\/j.aohep.2023.101110","article-title":"Liver decompensation is a frequent cause of treatment discontinuation and prognostic factor in intermediate-advanced HCC","volume":"28","author":"Anders","year":"2023","journal-title":"Ann. Hepatol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Kondo, T., Koroki, K., Kanzaki, H., Kobayashi, K., Kiyono, S., Nakamura, M., Kanogawa, N., Saito, T., Ogasawara, S., and Ooka, Y. (2022). Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0261619"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.jhep.2016.07.020","article-title":"Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEO study","volume":"65","author":"Marrero","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2018.09.031","article-title":"Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma\u2014A meta-analysis","volume":"105","author":"Nuttall","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Tampaki, M., Papatheodoridis, G.V., and Cholongitas, E. (2023). Management of Hepatocellular Carcinoma in Decompensated Cirrhotic Patients: A Comprehensive Overview. Cancers, 15.","DOI":"10.3390\/cancers15041310"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/7\/1388\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:21:58Z","timestamp":1760106118000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/7\/1388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,31]]},"references-count":107,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["cancers16071388"],"URL":"https:\/\/doi.org\/10.3390\/cancers16071388","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,31]]}}}