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Neoadjuvant chemotherapy in breast cancer patients aims at preoperative reduction of tumor volume for better resection results and prognosis. As not all patients respond to neoadjuvant therapy, predictive biomarkers are needed for more efficient individual management. In prospectively collected sera of 51 consecutive locally confined breast cancer (LBC) patients receiving preoperative, neoadjuvant chemotherapy, value level kinetics of soluble high mobility group box 1 (HMGB1), soluble receptor for advanced glycation end products (sRAGE) as well as the established breast cancer biomarkers CA 15-3 and carcinoembryonic antigen (CEA) were investigated and correlated with therapy response objectified by pathological staging at surgery. In addition, biomarkers were measured in sera of 30 healthy controls (HC), 13 patients with benign breast diseases, and 28 metastatic breast cancer (MBC) patients. Pretherapeutic levels of soluble HMGB1 were decreased in MBC, while sRAGE was already decreased in LBC. In contrast, CA 15-3 and CEA were strongly elevated in MBC, but not in LBC. Combination of sRAGE and CA 15-3 enabled best discrimination of LBC from HC (AUC 78.2 %; sens 58 % at 95 % spec), while CA15-3 and CEA discriminated best between MBC and all controls (AUC 90.9 %; sens 70 % at 95 % spec). In LBC patients undergoing neoadjuvant chemotherapy, nine patients achieved complete remission (CR), 29 achieved partial remission (PR), while 13 had no change of disease (NC). NC patients tended to have higher HMGB1 and lower sRAGE levels before therapy onset ( p = 0.056 and p = 0.054), while CA 15-3 and CEA did not predict therapeutic outcome. Furthermore, kinetics of HMGB1 during therapy correlated with efficacy of the treatment ( p = 0.053). Markers of immunogenic cell death are valuable for the diagnosis of MBC and early estimation of response to neoadjuvant therapy in LBC patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Expression of ligands of the immunoreceptor NKG2D such as MICA and MICB has been proposed to play an important role in the immunosurveillance of tumors. Proteolytic shedding of NKG2D ligands from cancer cells therefore constitutes an immune escape mechanism impairing anti-tumor reactivity by NKG2D-bearing cytotoxic lymphocytes. Serum levels of sMICA have been shown to be of diagnostic significance in malignant diseases of various origins. Here, we investigated the potential of soluble MICB, the sister molecule of MICA, as a marker in cancer and its correlation with soluble MICA. Analysis of MICB in sera of 512 individuals revealed slightly higher MICB levels in patients with various malignancies ( N = 296; 95th percentile 216 pg/ml; P = 0.069) than in healthy individuals ( N = 62; 95th percentile 51 pg/ml). Patients with benign diseases ( N = 154; 95th percentile 198 pg/ml) exhibited intermediate MICB levels. In cancer patients, elevated MICB levels correlated significantly with cancer stage and metastasis ( P = 0.007 and 0.007, respectively). Between MICB and MICA levels, only a weak correlation was found ( r = 0.24). Combination of both markers resulted only in a slightly higher diagnostic power in the high specificity range. The reduction of MICA and MICB surface expression on cells by shedding and the effects of sMICA and sMICB in serum on host lymphocyte NKG2D expression might play a role in late stages of tumor progression by overcoming the confining effect of NK cells and CD8 T cells. While MICB levels are not suited for the diagnosis of cancer in early stages, they may provide additional information for the staging of cancer disease. [ABSTRACT FROM AUTHOR]

Nucleosomes appear spontaneously in elevated concentrations in the serum of patients with malignant diseases as well as during chemo- and radiotherapy. We analyzed whether their kinetics show typical characteristics during radiochemotherapy and enable an early estimation of therapy efficacy. We used the Cell Death Detection Elisaplus (Roche Diagnostics) and investigated the course of nucleosomes in the serum of 32 patients with a local stage of pancreatic cancer who were treated with radiochemotherapy for several weeks. Ten of them received postsurgical therapy, 21 received primary therapy and 1 received therapy for local relapse. Blood was taken before the beginning of therapy, daily during the first week, once weekly during the following weeks and at the end of radiochemotherapy. The response to therapy was defined according to the kinetics of CA 19-9: a decrease of CA 19-9 ≥50% after radiochemotherapy was considered as ‘remission’; an increase of ≥100% (which was confirmed by two following values) was defined as ‘progression’. Patients with ‘stable disease’ ranged intermediately. Most of the examined patients showed a decrease of the concentration of nucleosomes within 6 h after the first dose of radiation. Afterwards, nucleosome levels increased rapidly, reaching their maximum during the following days. Patients receiving postsurgery, primary or relapse therapies did not show significant differences in nucleosome values during the time of treatment. Single nucleosome values, measured at 6, 24 and 48 h after the application of therapy, could not discriminate significantly between patients with no progression and those with progression of disease. However, the area under the curve of the first 3 days, which integrated all variables of the initial therapeutic phase, showed a significant correlation with the progression-free interval (p = 0.008). Our results indicate that the area under the curve of nucleosomes during the initial phase of radiochemotherapy could be valuable for the early prediction of the progression-free interval. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]