B Bock1, D Hasdemir2, F Wandrer1, T Rodt2, M P Manns1, K Schulze-Osthoff3,4, H Bantel1. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 2. Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany. 3. Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany. 4. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) represents an increasing health problem with limited therapeutic options. In patients with intermediate disease stage, transarterial chemoembolisation (TACE) is widely applied. Treatment response is routinely assessed by imaging techniques according to the international response evaluation criteria in solid tumours (RECIST), which consider tumour regression or additionally tumour necrosis (modified RECIST). Evaluation of treatment response, however, by these methods is time- and cost-intensive and usually performed at earliest several months following TACE. AIM: To investigate the suitability of novel non-invasive cell death biomarkers for an earlier prediction of TACE response. METHODS: We analysed activation of pro-apoptotic caspases and the proteolytic cleavage of the caspase substrate CK-18 in liver tissues and sera from HCC patients by immunohistochemistry, a luminometric substrate assay and ELISA. RESULTS: Both caspase activity and caspase-cleaved CK-18 fragments were elevated in HCC patients compared to healthy controls. CK-18 serum levels significantly increased during the first 3 days and peaked at day two following TACE. Interestingly, we found significant differences in CK-18 levels between patients with and without tumour regression. Detection of CK-18 fragments revealed a promising performance for the early prediction of TACE response with an area under the curve value of 0.76. CONCLUSIONS: Caspase-cleaved CK-18 levels mirror liver cancer regression and allow an earlier prediction of TACE response. The concordance with mRECIST suggests that the detection of CK-18 levels immediately after TACE might be used as a short-term decision guide to continue or change HCC therapy.
BACKGROUND:Hepatocellular carcinoma (HCC) represents an increasing health problem with limited therapeutic options. In patients with intermediate disease stage, transarterial chemoembolisation (TACE) is widely applied. Treatment response is routinely assessed by imaging techniques according to the international response evaluation criteria in solid tumours (RECIST), which consider tumour regression or additionally tumour necrosis (modified RECIST). Evaluation of treatment response, however, by these methods is time- and cost-intensive and usually performed at earliest several months following TACE. AIM: To investigate the suitability of novel non-invasive cell death biomarkers for an earlier prediction of TACE response. METHODS: We analysed activation of pro-apoptotic caspases and the proteolytic cleavage of the caspase substrate CK-18 in liver tissues and sera from HCC patients by immunohistochemistry, a luminometric substrate assay and ELISA. RESULTS: Both caspase activity and caspase-cleaved CK-18 fragments were elevated in HCC patients compared to healthy controls. CK-18 serum levels significantly increased during the first 3 days and peaked at day two following TACE. Interestingly, we found significant differences in CK-18 levels between patients with and without tumour regression. Detection of CK-18 fragments revealed a promising performance for the early prediction of TACE response with an area under the curve value of 0.76. CONCLUSIONS: Caspase-cleaved CK-18 levels mirror liver cancer regression and allow an earlier prediction of TACE response. The concordance with mRECIST suggests that the detection of CK-18 levels immediately after TACE might be used as a short-term decision guide to continue or change HCC therapy.
Authors: Franziska Wandrer; Stephanie Liebig; Silke Marhenke; Arndt Vogel; Katharina John; Michael P Manns; Andreas Teufel; Timo Itzel; Thomas Longerich; Olaf Maier; Roman Fischer; Roland E Kontermann; Klaus Pfizenmaier; Klaus Schulze-Osthoff; Heike Bantel Journal: Cell Death Dis Date: 2020-03-31 Impact factor: 8.469