Predictive value of immunogenic cell death biomarkers HMGB1, sRAGE, and DNase in liver cancer patients receiving transarterial chemoembolization therapy.

Transarterial chemoembolization (TACE) therapy is an effective locoregional anticancer treatment for liver cancer patients. Serum biomarkers involved in immunogenic cell death may be valuable for early predicting therapy response and estimating prognosis. Sera of 50 prospectively and consecutively included hepatocellular carcinoma (HCC) patients, undergoing TACE therapy, were taken before and 24 h after TACE application. In these samples, soluble biomarkers involved in immunogenic cell death, and among them, high-mobility group box 1 (HMGB1), soluble receptor of advanced glycation end products (sRAGE), and DNase activity were measured. They were compared with radiological response to therapy. A total of 71 TACE therapies were evaluated, of which 32 were classified as "no progression," and 39, as "progression." While HMGB1 levels increased already 24 h after TACE, there was an early decrease of sRAGE and DNase activity. Pretherapeutic and 24-h values of sRAGE were significantly higher in the no progression group than those in the progression group. There was no difference with respect to treatment response for DNase and HMGB1. Soluble RAGE is a new parameter with predictive relevance in primary liver cancer patients undergoing TACE therapy.

Circulating nucleosomes and biomarkers of immunogenic cell death as predictive and prognostic markers in cancer patients undergoing cytotoxic therapy.

INTRODUCTION: Immunogenic cell death markers are released from apoptotic and necrotic cells upon pathologic or therapeutic causes and stimulate the innate and adaptive immune system. Cell death products such as nucleosomes, damage-associated molecular pattern (DAMP) molecules such as the high-mobility group box 1 protein (HMGB1) and its receptor of advanced glycation end products (sRAGE) are supposed to play an essential role in driving this process. However, this immunogenic activation may have dual effects, either by sensitizing the immune system for more efficient tumor cell removal or by creating a favorable tumor microenvironment that facilitates tumor growth, proliferation and invasiveness. AREAS COVERED: Here, we review recent findings on the relevance of serum nucleosomes, DNAse activity, HMGB1 and sRAGE as biomarkers for the diagnosis, prognosis and therapy prediction in cancer disease. EXPERT OPINION: In comparison with healthy controls, cancer patients demonstrated elevated serum levels of nucleosomes and HMGB1 while sRAGE levels were decreased. During locoregional and systemic cytotoxic therapies, a high release of nucleosomes and HMGB1 as well as low release of sRAGE before and during the initial phase of the treatment was found to be associated with poor response to the therapy and patient survival. Therefore, immunogenic cell death markers are promising tools for the prognosis, therapy prediction and monitoring in cancer patients.

Prognostic relevance of oncological serum biomarkers in liver cancer patients undergoing transarterial chemoembolization therapy.

As transarterial chemoembolization (TACE) therapy is an effective locoregional treatment for patients with advanced liver cancer, prognostic biomarkers are highly needed for pretherapeutic stratification of patients to TACE therapy. Sera of 50 prospectively and consecutively included patients with hepatocellular carcinoma (HCC) undergoing TACE were taken before and 24 h after TACE application. Levels of liver-specific, tumor-related, and cell death biomarkers were analyzed and correlated with overall patient survival. The study was particularly focused on patients treated by TACE with palliative intention (N = 38). Sixteen of 38 patients died within 1 year after TACE, 22 were still alive. In univariate analysis, high levels of cytokeratin 19-fragments (CYFRA 21-1), alpha fetoprotein (AFP), and low choline esterase (CHE) levels measured before and 24 h after TACE were correlated with unfavorable outcome. Further high pretherapeutic lactate dehydrogenase (LDH), aspartate-aminotransferase, and bilirubin levels as well as high 24 h C-reactive protein values were associated with poor survival. In multivariate analysis of clinical and only pretherapeutic biomarkers, AFP, CHE, and LDH showed to be independent prognostic parameters. When additionally 24 h values were included, CHE (24 h) and AFP (24 h) were the strongest independent prognostic biomarkers with a slightly higher prognostic power (Akaike's information criterion 90.3 vs. 92.7). The combination of AFP, CHE, and LDH enables efficient pretherapeutic stratification of HCC patients in advanced tumor stage for TACE therapy.

Relevance of circulating nucleosomes and oncological biomarkers for predicting response to transarterial chemoembolization therapy in liver cancer patients.

BACKGROUND: Transarterial chemoembolization (TACE) therapy is an effective locoregional treatment in hepatocellular cancer (HCC) patients. For early modification of therapy, markers predicting therapy response are urgently required. METHODS: Here, sera of 50 prospectively and consecutively included HCC patients undergoing 71 TACE therapies were taken before and 3 h, 6 h and 24 h after TACE application to analyze concentrations of circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), alpha fetoprotein (AFP), C-reactive protein (CRP) and several liver biomarkers, and to compare these with radiological response to therapy. RESULTS: While nucleosomes, CYFRA 21-1, CRP and some liver biomarkers increased already 24 h after TACE, percental changes of nucleosome concentrations before and 24 h after TACE and pre- and posttherapeutic values of AFP, gamma-glutamyl-transferase (GGT) and alkaline phosphatase (AP) significantly indicated the later therapy response (39 progression versus 32 no progression). In multivariate analysis, nucleosomes (24 h), AP (24 h) and TACE number were independent predictive markers. The risk score of this combination model achieved an AUC of 81.8% in receiver operating characteristic (ROC) curves and a sensitivity for prediction of non-response to therapy of 41% at 97% specificity, and of 72% at 78% specificity. CONCLUSION: Circulating nucleosomes and liver markers are valuable tools for early estimation of the efficacy of TACE therapy in HCC patients.