Serum HMGB1 concentrations at 4 weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy

Abstract

Background Biomarkers predicting the response to the anticancer treatment and prognosis in patients with advanced hepatocellular carcinoma (HCC) are required. Recently, high mobility group box 1 (HMGB1) was reported to promote HCC progression and be associated with poor prognosis for patients with HCC. The purpose of this study was to assess serum HMGB1 concentrations before and during sorafenib treatment or hepatic arterial infusion chemotherapy (HAIC) and to explore the ability of serum HMGB1 concentrations to predict prognosis. Methods Serum HMGB1 concentrations were measured in 71 and 72 patients with advanced HCC treated with sorafenib and HAIC, respectively, to assess their usefulness for prediction of the response to the treatment and prognosis. Results Multivariate analysis identified high HMGB1 at 4 weeks (P = 0.001), high a-fetoprotein (AFP) at baseline (P = 0.025), tumor liver occupying rate (P = 0.009) and modified RECIST (mRECIST, P \ 0.0001) as independent Kazuhiko Masuda and Atsushi Ono are the co-first authors.The original version of this article was revised: An article note about co-first authorship was added and the second sentence in the subheading ''Results'' under the ''Abstract'' section was corrected. predictors of poor overall survival in sorafenib treatment. High HMGB1 at 4 weeks (P = 0.025), vascular invasion to the hepatic vein (Vv) (P = 0.009), mRECIST (P \ 0.0001) and Child-Pugh B (P = 0.004) were identified as independent predictors of poor overall survival in HAIC treatment. The concentrations of HMGB1 at baseline and 4 weeks were not correlated with conventional tumor markers and progressive disease assessed by mRECIST at 8 weeks.Conclusions These results suggest that serum HMGB1 at 4 weeks after the start of treatment might be a useful biomarker with added value to the conventional tumor marker and radiologic responses to predict poor overall survival in patients with advanced HCC treated with sorafenib or HAIC.

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

“…However, the response to sorafenib seems to be moderate, as shown in the SHARP and AP trials . Several research groups have tried to identify biomarkers that may predict patients who will be sensitive to sorafenib treatment . However, no optimal biomarkers have been used clinically to predict responses to sorafenib.…”

“…It is suggested that contrast material‐enhanced computed tomographic (CT) images may help predict response of HCC patients to sorafenib . A few studies reveal that patients with vascular endothelial growth factor (VEGF)A amplification in HCC tissues or with high serum high mobility group box 1, angiopoietin‐2 (Ang‐2), or microRNA‐181a‐5p levels have favorable responses to sorafenib treatment . However, an analysis on levels of 10 plasma proteins shows that these plasma proteins, including VEGF and Ang‐2, could not predict sorafenib response .…”

High‐Mobility Group Box‐1 and Liver Disease

“…HMGB1 induces chronic inflammation and extracellular matrix accumulation, creating a prime microenvironment for the development of HHC. In 2008, serum HMGB1 levels were found to be strongly increased in patients with HCC and correlated with clinicopathologic features, such as with α‐fetoprotein levels and tumor size, and Masuda et al established that serum HMGB1 predicted worse clinical prognosis in patients with HCC.…”

“…(12)(13)(14) In this latter role, HMGB1 acts as a proinflammatory cytokine that contributes to multiple injuries, including those from the liver, such as warm and cold ischemia/reperfusion (I/R) injury, (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) sepsis, (23,(28)(29)(30)(31)(32) acetaminophen (APAP) intoxication, (23,(33)(34)(35)(36)(37)(38)(39)(40) alcoholic liver disease (ALD), (41)(42)(43) fibrosis, (44)(45)(46)(47)(48)(49) nonalcoholic steatohepatitis (NASH), (50)(51)(52) and hepatocellular carcinoma (HCC). (53)(54)(55)(56)(57)…”

Current Status Regarding Tumour Progression, Surveillance, Diagnosis, Staging, and Treatment Of HCC: A Literature Review

“…In the ECM, the HMGB1 links to many receptors such as glycation end products (RAGE), (TLR)-2, TLR-4, TLR-9, and activating reninangiotensin system (RAS)-MAP kinase [23] high mobility group box 1 (HMGB1). Forkhead box protein M1(FOXM1) is another protein which is found in HCC and which is encoded by the FOXM1 gene.…”