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Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future.

Background: The prognostic relevance of blood markers in cerebral stroke is still a matter of controversial debate., Patients and Methods: In sera of 63 patients, nucleosomes, neuronspecific enolase (NSE), S100 protein, and C-reactive protein (CRP) were determined daily during the first week after cerebral stroke. Infarction volume was quantified by CT or MRI and the clinical status by Barthel Index (BI) at admission, discharge, and after 12 months (prognosis). All markers were evaluated by univariate and multivariate analysis on their prognostic relevance., Results: During observation time (12 months), three patients died and 33 reached complete recovery. Infarction volume, nucleosomes, NSE, S100, and CRP correlated significantly with clinical status at admission. The same markers except CRP and initial BI correlated with recovery after 12 months. Almost all patients with initial BI double dagger 50 reached complete recovery. In patients with initially severe defects (BI < 50), nucleosomes and S100, both at day 3, were found to be prognostically relevant. At 100%-specificity for non-recovery, only nucleosomes maintained their prognostic power (sensitivity 52.6%; p = 0.014), whereas S100 did not (sensitivity 16.7%; p = 0.25). In multivariate analysis, nucleosomes and BI at admission showed independent prognostic relevance (p = 0.039)., Conclusion: Circulating nucleosomes and clinical scores provide independent prognostic information concerning the later outcome in patients with initially severe defects after stroke.

Facing an era of promising new antitumor therapies, predictors of therapy response are needed for the individual management of treatment. In sera collected prospectively from 311 patients with advanced non-small cell lung cancer receiving first-line chemotherapy, changes in nucleosomal DNA fragments, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. In univariate analysis, high levels, slower and incomplete decline in nucleosomal DNA, CYFRA 21-1, and CEA predicted poor outcome. DNA concentrations at day 8 of the first therapeutic cycle and CYFRA 21-1 before start of the second cycle were identified as best predictive variables. In multivariate analysis, they predicted progression with a specificity of 100% in 29% of the cases earlier than imaging techniques. Thus, nucleosomal DNA and CYFRA 21-1 specifically identify a subgroup of patients with insufficient therapy response at the early treatment phase and showed to be valuable for disease management.

Background: Nucleosomes are cell death products that are elevated in serum of patients with diseases that are associated with massive cell destruction. We investigated the kinetics of circulating nucleosomes after cerebral stroke and their correlation with the clinical status., Methods: In total, we analyzed nucleosomes by ELISA in sera of 63 patients with early stroke daily during the first week after onset. For correlation with the clinical pathology, patients were grouped into those with medium to slight functional impairment (Barthel Index BI >or=50) and those with severe functional impairment (BI<50)., Results: Patients with BI >or=50 showed a continuous increase in nucleosomes until day 5 (median: 523 arbitrary units, AU) followed by a slow decline. In contrast, patients with BI<50 showed a steeper initial increase reaching a maximum already on day 3 (869 AU). Both, days after stroke (p < 0.001) and BI (p < 0.001), had a significant influence on nucleosome concentrations, respectively. Consistently, patients with BI<50 had a significantly larger area under the curve (AUC/day) of nucleosome values during the first week after stroke (800 AU) than patients with BI >or=50 (497 AU; p=0.031). Concerning the infarction volume, nucleosomes showed significant correlations for the concentrations on day 3 (r=0.43; p=0.001) and for the area under the curve (r=0.34; p=0.016)., Conclusion: Even if nucleosomes are nonspecific cell death markers, their release into serum after cerebral stroke correlates with the gross functional status as well as with the infarction volume and can be considered as biochemical correlative to the severity of stroke., (Copyright (c) 2006 S. Karger AG, Basel.)

Apoptotic markers and tumor-associated antigens might be suitable to indicate the response to radiochemotherapy early. We analyzed the courses of nucleosomes, CEA, CA 19-9 and CYFRA 21-1 in 25 colorectal cancer patients during radiochemotherapy (4 postoperative, 13 preoperative, 8 local relapse therapy). Blood was taken before therapy, daily during the first week, once weekly during the following weeks, and at the end of the radiochemotherapy. After a temporary decline 6 h after the first irradiation, nucleosomes rose in most patients rapidly reaching a maximum during the first days which was followed by a subsequent decrease. In patients receiving postoperative therapy after complete resection of tumor, nucleosome levels generally were lower than in patients with preoperative or relapse therapy. Correspondingly, CEA, CA 19-9 and CYFRA 21-1 levels of postoperatively treated patients were the lowest whereas those with tumor relapse had the highest ones. During preoperative therapy, lower nucleosome concentrations were found in patients with response to therapy resulting in a smaller area under the curve of days 1-3 (AUC) than in those with progressive disease (p = 0.028). The other parameters did not indicate the response to therapy at the initial treatment phase. In conclusion, the course of nucleosomes (AUC) might be valuable for the early prediction of therapy response in preoperatively treated colorectal cancer patients., (Copyright (c) 2006 S. Karger AG, Basel.)

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 Elisa plus (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 > or =50% after radiochemotherapy was considered as 'remission'; an increase of > or =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.

Purpose: We investigated the potential of circulating, nucleosomal DNA for the early prediction of the efficacy of chemotherapy in patients with advanced lung cancer., Experimental Design: In serum of 212 patients with newly diagnosed non-small cell lung cancer (stages III and IV) undergoing chemotherapy, nucleosomes (ELISA, Roche) were measured at days 1, 3, 5, and 8 of the first cycle and before each new therapeutic cycle. Additionally, carcinoembryonic antigen and cytokeratin 19 fragments (CYFRA 21-1; Elecsys, Roche) were determined before each cycle. The therapeutic success was classified by computed tomography before start of the third cycle according to the World Health Organization criteria., Results: In univariate analysis, responders (patients with remission) showed significantly (P < 0.05) lower values for the area under the curve of days 1 to 8 (AUC 1-8) of nucleosomes, the pretherapeutic baseline values of cycle 2 (BV2) and cycle 3 (BV3) of nucleosomes, and higher decreases of the baseline values from cycle 1 to 2 (BV1-2) and from cycle 1 to 3 (BV1-3) compared with nonresponders (patients with stable or progressive disease). Additionally, CYFRA 21-1 (BV1, BV2, BV3, BV1-2, BV1-3) and carcinoembryonic antigen (BV1-2) discriminated significantly between both groups. In multivariate analysis including all parameters available until end of the first therapeutic cycle, nucleosomes (AUC 1-8), CYFRA 21-1 (BV1), stage, and age were independent predictors of therapy response with nucleosomes (AUC 1-8) having the strongest impact., Conclusion: Circulating nucleosomes in combination with oncological biomarkers are valuable for the early estimation of the efficacy of chemotherapy in patients with lung cancer.

Apoptotic markers and tumor-associated antigens might be suitable to indicate the response to radiochemotherapy early. We analyzed the courses of nucleosomes, CEA, CA 19-9 and CYFRA 21-1 in 25 colorectal cancer patients during radiochemotherapy (4 postoperative, 13 preoperative, 8 local relapse therapy). Blood was taken before therapy, daily during the first week, once weekly during the following weeks, and at the end of the radiochemotherapy. After a temporary decline 6 h after the first irradiation, nucleosomes rose in most patients rapidly reaching a maximum during the first days which was followed by a subsequent decrease. In patients receiving postoperative therapy after complete resection of tumor, nucleosome levels generally were lower than in patients with preoperative or relapse therapy. Correspondingly, CEA, CA 19-9 and CYFRA 21-1 levels of postoperatively treated patients were the lowest whereas those with tumor relapse had the highest ones. During preoperative therapy, lower nucleosome concentrations were found in patients with response to therapy resulting in a smaller area under the curve of days 1–3 (AUC) than in those with progressive disease (p = 0.028). The other parameters did not indicate the response to therapy at the initial treatment phase. In conclusion, the course of nucleosomes (AUC) might be valuable for the early prediction of therapy response in preoperatively treated colorectal cancer patients. Copyright © 2006 S. Karger AG, Basel [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]