{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T18:41:49Z","timestamp":1773081709595,"version":"3.50.1"},"reference-count":102,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA254351"],"award-info":[{"award-number":["R01CA254351"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["R01CA260857"],"award-info":[{"award-number":["R01CA260857"]}]},{"name":"National Institute of Health","award":["R01CA247441"],"award-info":[{"award-number":["R01CA247441"]}]},{"name":"National Institute of Health","award":["R03CA256764"],"award-info":[{"award-number":["R03CA256764"]}]},{"name":"National Institute of Health","award":["P01CA261669"],"award-info":[{"award-number":["P01CA261669"]}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-21-1-0738"],"award-info":[{"award-number":["W81XWH-21-1-0738"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-19-1-0284"],"award-info":[{"award-number":["W81XWH-19-1-0284"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["Mildred-Scheel Postdoctoral Fellowship"],"award-info":[{"award-number":["Mildred-Scheel Postdoctoral Fellowship"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While the incidence of primary liver cancers has been increasing worldwide over the last few decades, the mortality has remained consistently high. Most patients present with underlying liver disease and have limited treatment options. In recent years, radiotherapy has emerged as a promising approach for some patients; however, the risk of radiation induced liver disease (RILD) remains a limiting factor for some patients. Thus, the discovery and validation of biomarkers to measure treatment response and toxicity is critical to make progress in personalizing radiotherapy for liver cancers. While tissue biomarkers are optimal, hepatocellular carcinoma (HCC) is typically diagnosed radiographically, making tumor tissue not readily available. Alternatively, blood-based diagnostics may be a more practical option as blood draws are minimally invasive, widely availability and may be performed serially during treatment. Possible blood-based diagnostics include indocyanine green test, plasma or serum levels of HGF or cytokines, circulating blood cells and genomic biomarkers. The albumin\u2013bilirubin (ALBI) score incorporates albumin and bilirubin to subdivide patients with well-compensated underlying liver dysfunction (Child\u2013Pugh score A) into two distinct groups. This review provides an overview of the current knowledge on circulating biomarkers and blood-based scores in patients with malignant liver disease undergoing radiotherapy and outlines potential future directions.<\/jats:p>","DOI":"10.3390\/ijms23041926","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T21:22:15Z","timestamp":1644441735000},"page":"1926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Leveraging Blood-Based Diagnostics to Predict Tumor Biology and Extend the Application and Personalization of Radiotherapy in Liver Cancers"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-7716","authenticated-orcid":false,"given":"Franziska","family":"Hauth","sequence":"first","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Radiation Oncology, University Clinic Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah J.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theodore S.","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-8797","authenticated-orcid":false,"given":"Dan G.","family":"Duda","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jhep.2019.08.025","article-title":"Epidemiology and surveillance for hepatocellular carcinoma: New trends","volume":"72","author":"Singal","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_3","first-page":"S0167-8140","article-title":"Ablative Radiotherapy for Liver Tumors Using Stereotactic MRI-Guidance: A Prospective Phase I Trial","volume":"21","author":"Wu","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_4","first-page":"55","article-title":"Marker-less online MR-guided stereotactic body radiotherapy of liver metastases at a 1.5 T MR-Linac\u2014Feasibility, workflow data and patient acceptance","volume":"26","author":"Gani","year":"2020","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Romesser, P.B., Tyagi, N., and Crane, C.H. (2021). Magnetic Resonance Imaging-Guided Adaptive Radiotherapy for Colorectal Liver Metastases. Cancers, 13.","DOI":"10.3390\/cancers13071636"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.2147\/JHC.S284403","article-title":"Current Understanding of Ablative Radiation Therapy in Hepatocellular Carcinoma","volume":"8","author":"Mathew","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ijrobp.2020.09.038","article-title":"Dose-Response Relationship in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: A Pooled Analysis of an Asian Liver Radiation Therapy Group Study","volume":"109","author":"Kim","year":"2021","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S0360-3016(02)02864-X","article-title":"Dose-response relationship in local radiotherapy for hepatocellular carcinoma","volume":"54","author":"Park","year":"2002","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1080\/02841860600897934","article-title":"Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study","volume":"45","author":"Romero","year":"2006","journal-title":"Acta Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.prro.2013.10.002","article-title":"A prospective feasibility study of respiratory-gated proton beam therapy for liver tumors","volume":"4","author":"Hong","year":"2014","journal-title":"Pr. Radiat. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.semradonc.2011.05.003","article-title":"Hepatic radiation toxicity: Avoidance and amelioration","volume":"21","author":"Guha","year":"2011","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/S0360-3016(02)02846-8","article-title":"Analysis of radiation-induced liver disease using the Lyman NTCP model","volume":"53","author":"Dawson","year":"2002","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fitch, M.I., Sharp, L., Hanly, P., and Longo, C.J. (2021). Experiencing financial toxicity associated with cancer in publicly funded healthcare systems: A systematic review of qualitative studies. J. Cancer Surviv., 1\u201315.","DOI":"10.1007\/s11764-021-01025-7"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.3748\/wjg.v25.i40.6041","article-title":"Role of liver biopsy in hepatocellular carcinoma","volume":"25","author":"Spadaccini","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1055\/s-2007-1007122","article-title":"Prognosis of hepatocellular carcinoma: The BCLC staging classification","volume":"19","author":"Llovet","year":"1999","journal-title":"Semin. Liver Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1200\/JCO.2014.59.0521","article-title":"Addressing the interplay of liver disease and hepatocellular carcinoma on patient survival: The ALBI scoring model","volume":"33","author":"Knox","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1002\/jso.24992","article-title":"ALBI versus Child-Pugh grading systems for liver function in patients with hepatocellular carcinoma","volume":"117","author":"Na","year":"2018","journal-title":"J. Surg. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1002\/bjs.10095","article-title":"Albumin-bilirubin versus Child-Pugh score as a predictor of outcome after liver resection for hepatocellular carcinoma","volume":"103","author":"Wang","year":"2016","journal-title":"Br. J. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1200\/JCO.2014.57.9151","article-title":"Assessment of liver function in patients with hepatocellular carcinoma: A new evidence-based approach-the ALBI grade","volume":"33","author":"Johnson","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1111\/jgh.13608","article-title":"ALBI and PALBI grade predict survival for HCC across treatment modalities and BCLC stages in the MELD Era","volume":"32","author":"Liu","year":"2017","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1007\/s10637-015-0292-9","article-title":"Liver function assessment according to the Albumin-Bilirubin (ALBI) grade in sorafenib-treated patients with advanced hepatocellular carcinoma","volume":"33","author":"Ogasawara","year":"2015","journal-title":"Invest. New Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.hbpd.2018.07.011","article-title":"Post-operative albumin-bilirubin grade predicts long-term outcomes among Child-Pugh grade A patients with hepatocellular carcinoma after curative resection","volume":"17","author":"Amisaki","year":"2018","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.ijrobp.2018.04.011","article-title":"Baseline Albumin-Bilirubin (ALBI) Score in Western Patients with Hepatocellular Carcinoma Treated with Stereotactic Body Radiation Therapy (SBRT)","volume":"101","author":"Murray","year":"2018","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ijrobp.2017.04.036","article-title":"Comparison Between Child-Turcotte-Pugh and Albumin-Bilirubin Scores in Assessing the Prognosis of Hepatocellular Carcinoma After Stereotactic Ablative Radiation Therapy","volume":"99","author":"Lo","year":"2017","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.prro.2016.10.003","article-title":"Assessment of hepatic function decline after stereotactic body radiation therapy for primary liver cancer","volume":"7","author":"Toesca","year":"2017","journal-title":"Pr. Radiat. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"28818","DOI":"10.18632\/oncotarget.25522","article-title":"Comparison of platelet-albumin-bilirubin (PALBI), albumin-bilirubin (ALBI), and child-pugh (CP) score for predicting of survival in advanced hcc patients receiving radiotherapy (RT)","volume":"9","author":"Ho","year":"2018","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13014-019-1251-y","article-title":"Albumin\u2014bilirubin (ALBI) versus Child-Turcotte-Pugh (CTP) in prognosis of HCC after stereotactic body radiation therapy","volume":"14","author":"Su","year":"2019","journal-title":"Radiat. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ijrobp.2021.04.012","article-title":"The Potential for Midtreatment Albumin-Bilirubin (ALBI) Score to Individualize Liver Stereotactic Body Radiation Therapy","volume":"111","author":"Jackson","year":"2021","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00066-017-1256-0","article-title":"The role of albumin-bilirubin grade and inflammation-based index in patients with hepatocellular carcinoma treated with stereotactic body radiotherapy","volume":"194","author":"Gkika","year":"2018","journal-title":"Strahlenther Onkol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1001\/archsurg.1984.01390150006002","article-title":"Indocyanine green. Its use as an early indicator of hepatic dysfunction following injury in man","volume":"119","author":"Gottlieb","year":"1984","journal-title":"Arch. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.jceh.2018.09.004","article-title":"Correlation of baseline Portal pressure (hepatic venous pressure gradient) and Indocyanine Green Clearance Test With Post-transarterial Chemoembolization Acute Hepatic Failure","volume":"9","author":"Khisti","year":"2019","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1097\/MEG.0000000000000611","article-title":"Indocyanine green retention test (ICG-r15) as a noninvasive predictor of portal hypertension in patients with different severity of cirrhosis","volume":"28","author":"Pind","year":"2016","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"416","DOI":"10.3748\/wjg.v27.i5.416","article-title":"Comparative study of indocyanine green-R15, Child-Pugh score, and model for end-stage liver disease score for prediction of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt","volume":"27","author":"Wang","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/SLA.0b013e31825d5d47","article-title":"Physiological and biochemical basis of clinical liver function tests: A review","volume":"257","author":"Hoekstra","year":"2013","journal-title":"Ann. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.radonc.2014.04.007","article-title":"Estimating functional liver reserve following hepatic irradiation: Adaptive normal tissue response models","volume":"111","author":"Stenmark","year":"2014","journal-title":"Radiother. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ijrobp.2008.04.035","article-title":"Radiotherapeutic parameters predictive of liver complications induced by liver tumor radiotherapy","volume":"73","author":"Lee","year":"2009","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ijrobp.2017.09.032","article-title":"Using Indocyanine Green Extraction to Predict Liver Function After Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma","volume":"100","author":"Suresh","year":"2017","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1001\/jamaoncol.2017.2303","article-title":"Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage: A Phase 2 Clinical Trial","volume":"4","author":"Feng","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ijrobp.2020.08.046","article-title":"Individualized Adaptive Radiation Therapy Allows for Safe Treatment of Hepatocellular Carcinoma in Patients With Child-Turcotte-Pugh B Liver Disease","volume":"109","author":"Jackson","year":"2020","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.tranon.2019.04.003","article-title":"Serum Levels of Hepatocyte Growth Factor and CD40 Ligand Predict Radiation-Induced Liver Injury","volume":"12","author":"Cuneo","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41698-018-0065-y","article-title":"Pretreatment plasma HGF as potential biomarker for susceptibility to radiation-induced liver dysfunction after radiotherapy","volume":"2","author":"Hong","year":"2018","journal-title":"NPJ Precis. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.ijrobp.2017.10.005","article-title":"Modeling of Normal Tissue Complications Using Imaging and Biomarkers After Radiation Therapy for Hepatocellular Carcinoma","volume":"100","author":"Johansson","year":"2018","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1200\/CCI.20.00118","article-title":"Toward Personalized Radiation Therapy of Liver Metastasis: Importance of Serial Blood Biomarkers","volume":"5","author":"Ajdari","year":"2021","journal-title":"JCO Clin. Cancer Inf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.3748\/wjg.v23.i11.2077","article-title":"Multi-analyte analysis of cytokines that predict outcomes in patients with hepatocellular carcinoma treated with radiotherapy","volume":"23","author":"Cha","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41698-020-0124-z","article-title":"Association of pro-inflammatory soluble cytokine receptors early during hepatocellular carcinoma stereotactic radiotherapy with liver toxicity","volume":"4","author":"Ng","year":"2020","journal-title":"NPJ Precis. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100950","DOI":"10.1016\/j.tranon.2020.100950","article-title":"TNFR1 and the TNF\u03b1 axis as a targetable mediator of liver injury from stereotactic body radiation therapy","volume":"14","author":"Cousins","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1016\/j.ijrobp.2018.04.026","article-title":"Differential Association Between Circulating Lymphocyte Populations with Outcome After Radiation Therapy in Subtypes of Liver Cancer","volume":"101","author":"Grassberger","year":"2018","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.adro.2017.08.003","article-title":"Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer","volume":"2","author":"Gustafson","year":"2017","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9691067","DOI":"10.1155\/2019\/9691067","article-title":"Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival","volume":"2019","author":"Zhang","year":"2019","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1007\/s00066-019-01462-5","article-title":"Acute severe lymphopenia by radiotherapy is associated with reduced overall survival in hepatocellular carcinoma","volume":"195","author":"Byun","year":"2019","journal-title":"Strahlenther Onkol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"896","DOI":"10.3389\/fonc.2019.00896","article-title":"Association Between Circulating Lymphocyte Populations and Outcome After Stereotactic Body Radiation Therapy in Patients with Hepatocellular Carcinoma","volume":"9","author":"Zhuang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s13014-017-0824-x","article-title":"Radiation-related lymphopenia is associated with spleen irradiation dose during radiotherapy in patients with hepatocellular carcinoma","volume":"12","author":"Liu","year":"2017","journal-title":"Radiat. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.2147\/JHC.S334933","article-title":"Dynamic Changes in Neutrophil-to-Lymphocyte Ratio are Associated with Survival and Liver Toxicity Following Stereotactic Body Radiotherapy for Hepatocellular Carcinoma","volume":"8","author":"Hsiang","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2147\/JHC.S282062","article-title":"Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy","volume":"8","author":"De","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.4155\/fmc-2021-0128","article-title":"The role of HGF\/MET in liver cancer","volume":"13","author":"Gupta","year":"2021","journal-title":"Futur. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s12032-020-01350-4","article-title":"Activation of the HGF\/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression","volume":"37","author":"Fu","year":"2020","journal-title":"Med. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/cas.12891","article-title":"Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells","volume":"107","author":"Koc","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1080\/10408363.2019.1653821","article-title":"HGF\/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers","volume":"56","author":"Moosavi","year":"2019","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Dayyani, F., Zurita, J., Nogueras-Gonz\u00e1lez, G.M., Slack, R., Millikan, R.E., Araujo, J.C., Gallick, G.E., Logothetis, C.J., and Corn, P.G. (2016). The combination of serum insulin, osteopontin, and hepatocyte growth factor predicts time to castration-resistant progression in androgen dependent metastatic prostate cancer- an exploratory study. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2723-1"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/CMR.0000000000000269","article-title":"Serum levels of hepatocyte growth factor as a potential tumor marker in patients with malignant melanoma","volume":"26","author":"Muendlein","year":"2016","journal-title":"Melanoma Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13045-018-0691-4","article-title":"Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial","volume":"12","author":"Saltarella","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/cncr.10732","article-title":"Serum concentrations of human hepatocyte growth factor is a useful indicator for predicting the occurrence of hepatocellular carcinomas in C-viral chronic liver diseases","volume":"95","author":"Yamagamim","year":"2002","journal-title":"Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1007\/s13277-013-1308-8","article-title":"Clinical significance of serum hepatocyte growth factor (HGF) levels in hepatocellular carcinoma","volume":"35","author":"Karabulut","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"439752","DOI":"10.1155\/2011\/439752","article-title":"The confluence of stereotactic ablative radiotherapy and tumor immunology","volume":"2011","author":"Finkelstein","year":"2011","journal-title":"Clin. Dev. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cellsig.2018.02.011","article-title":"Pro-inflammatory cytokine and high doses of ionizing radiation have similar effects on the expression of NF-kappaB-dependent genes","volume":"46","author":"Janus","year":"2018","journal-title":"Cell Signal."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1748-717X-5-22","article-title":"Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis","volume":"5","author":"Ong","year":"2010","journal-title":"Radiat. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"24715","DOI":"10.1038\/srep24715","article-title":"Levels of human platelet-derived soluble CD40 ligand depend on haplotypes of CD40LG-CD40-ITGA2","volume":"6","author":"Aloui","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"107709","DOI":"10.1016\/j.pharmthera.2020.107709","article-title":"Molecular basis and therapeutic implications of CD40\/CD40L immune checkpoint","volume":"219","author":"Tang","year":"2021","journal-title":"Pharm. Ther."},{"key":"ref_69","first-page":"3199","article-title":"The Role of Soluble CD40L Ligand in Human Carcinogenesis","volume":"38","author":"Angelou","year":"2018","journal-title":"Anticancer. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1158\/1078-0432.CCR-0348-03","article-title":"Soluble CD40 ligand plasma levels in lung cancer","volume":"10","author":"Roselli","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rico Montanari, N., Anugwom, M., Boonstra, A., and Debes, J.D. (2021). The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13194876"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13046-019-1518-z","article-title":"Correction to: DNMT3b\/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6\/STAT3 regulation","volume":"39","author":"Lai","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"182","DOI":"10.5114\/ceh.2018.78122","article-title":"Evaluation of serum interleukin-6 levels in hepatocellular carcinoma patients: A systematic review and meta-analysis","volume":"4","author":"Shakiba","year":"2018","journal-title":"Clin. Exp. Hepatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.cyto.2013.07.021","article-title":"Change in inflammatory cytokine profiles after transarterial chemotherapy in patients with hepatocellular carcinoma","volume":"64","author":"Kim","year":"2013","journal-title":"Cytokine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.smim.2014.01.001","article-title":"IL-6 and related cytokines as the critical lynchpins between inflammation and cancer","volume":"26","author":"Taniguchi","year":"2014","journal-title":"Semin. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.ijrobp.2010.06.011","article-title":"Development and validation of a prognostic model using blood biomarker information for prediction of survival of non-small-cell lung cancer patients treated with combined chemotherapy and radiation or radiotherapy alone (NCT00181519, NCT00573040, and NCT00572325)","volume":"81","author":"Aerts","year":"2011","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/1748-717X-8-159","article-title":"The role of IL-6 in the radiation response of prostate cancer","volume":"8","author":"Wu","year":"2013","journal-title":"Radiat. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1002\/cncr.23615","article-title":"Interleukin-6 predicts recurrence and survival among head and neck cancer patients","volume":"113","author":"Duffy","year":"2008","journal-title":"Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1634\/theoncologist.11-4-397","article-title":"TNF-alpha in cancer treatment: Molecular insights, antitumor effects, and clinical utility","volume":"11","author":"Eggermont","year":"2006","journal-title":"Oncologist"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nri1184","article-title":"Signalling pathways of the TNF superfamily: A double-edged sword","volume":"3","author":"Aggarwal","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"026","DOI":"10.1055\/s-0038-1676806","article-title":"Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets","volume":"39","author":"Yang","year":"2019","journal-title":"Semin. Liver Dis."},{"key":"ref_82","first-page":"115","article-title":"Cytokine kinetics in an in vitro whole blood model following an endotoxin challenge","volume":"12","author":"Oliver","year":"1993","journal-title":"Lymphokine Cytokine Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.ijrobp.2021.07.1695","article-title":"The Influence of Severe Radiation-Induced Lymphopenia on Overall Survival in Solid Tumors: A Systematic Review and Meta-Analysis","volume":"111","author":"Damen","year":"2021","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.radonc.2020.07.025","article-title":"A tumor-immune interaction model for hepatocellular carcinoma based on measured lymphocyte counts in patients undergoing radiotherapy","volume":"151","author":"Sung","year":"2020","journal-title":"Radiother. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.adro.2018.09.004","article-title":"A Comparison of Grade 4 Lymphopenia with Proton Versus Photon Radiation Therapy for Esophageal Cancer","volume":"4","author":"Routman","year":"2019","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/neuonc\/noaa182","article-title":"Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: Phase II randomized study of protons vs photons","volume":"23","author":"Mohan","year":"2020","journal-title":"Neuro-Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.semradonc.2019.12.003","article-title":"Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy with Immunotherapy","volume":"30","author":"Lambin","year":"2020","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"736330","DOI":"10.3389\/fmolb.2021.736330","article-title":"Clinical Application Value of Circulating Cell-free DNA in Hepatocellular Carcinoma","volume":"8","author":"Zhang","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1056\/NEJMra1706174","article-title":"Application of Cell-free DNA Analysis to Cancer Treatment","volume":"379","author":"Corcoran","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"470","DOI":"10.3349\/ymj.2018.59.4.470","article-title":"Plasma Cell-Free DNA as a Predictive Marker after Radiotherapy for Hepatocellular Carcinoma","volume":"59","author":"Park","year":"2018","journal-title":"Yonsei Med. J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.3748\/wjg.v12.i24.3911","article-title":"Circulating DNA level is negatively associated with the long-term survival of hepatocellular carcinoma patients","volume":"12","author":"Ren","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.radonc.2018.07.016","article-title":"Circulating cell-free DNA: A potential biomarker to differentiate inflammation and infection during radiochemotherapy","volume":"129","author":"Zwirner","year":"2018","journal-title":"Radiother. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1159\/000368010","article-title":"Prognostic values of vascular endothelial growth factor and matrix metalloproteinase-2 in hepatocellular carcinoma after radiotherapy","volume":"32","author":"Suh","year":"2014","journal-title":"Dig. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5458","DOI":"10.1158\/0008-5472.CAN-14-1258","article-title":"Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade","volume":"74","author":"Dovedi","year":"2014","journal-title":"Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"41242","DOI":"10.18632\/oncotarget.17168","article-title":"Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model","volume":"8","author":"Kim","year":"2017","journal-title":"Oncotarget"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"568759","DOI":"10.3389\/fimmu.2020.568759","article-title":"Combinational Immunotherapy for Hepatocellular Carcinoma: Radiotherapy, Immune Checkpoint Blockade and Beyond","volume":"11","author":"Lee","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/s43018-021-00269-7","article-title":"Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial","volume":"2","author":"Parikh","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"102973","DOI":"10.1016\/j.ebiom.2020.102973","article-title":"Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy","volume":"59","author":"Ng","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.radonc.2016.03.014","article-title":"Plasma ceramide, a real-time predictive marker of pulmonary and hepatic metastases response to stereotactic body radiation therapy combined with irinotecan","volume":"119","author":"Dubois","year":"2016","journal-title":"Radiother. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"646","DOI":"10.4143\/crt.2016.550","article-title":"Inter-alpha Inhibitor H4 as a Potential Biomarker Predicting the Treatment Outcomes in Patients with Hepatocellular Carcinoma","volume":"50","author":"Lee","year":"2018","journal-title":"Cancer Res. Treat."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"S202","DOI":"10.1016\/j.ijrobp.2016.06.504","article-title":"MicroRNAs Predict Liver Toxicity in Patients Receiving Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma","volume":"96","author":"Cuneo","year":"2016","journal-title":"Int. J. Rad. Oncol. Biol. Phys."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.radonc.2017.11.027","article-title":"Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy","volume":"129","author":"Kim","year":"2018","journal-title":"Radiother. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/1926\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:16:40Z","timestamp":1760134600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/1926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,9]]},"references-count":102,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23041926"],"URL":"https:\/\/doi.org\/10.3390\/ijms23041926","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,9]]}}}