Maciej Kinalski

Circulating free DNA and p53 antibodies in plasma of patients with ovarian epithelial cancers

BACKGROUND This study was conducted in order to evaluate the significance of circulating free DNA (CFDNA), blood plasma p53 antibodies (p53-Ab) and mutations of KRAS gene in the prognosis of ovarian epithelial cancers. PATIENTS AND METHODS A total of 126 patients were included in this study. KRAS mutations and CFDNA were detected by means of the PCR-restriction fragment length polymorphism (PCR-RFLP) and enriched by the PCR-RFLP method. Enzyme-linked immunosorbent assay was used to analyze plasma p53-Ab. RESULTS KRAS mutations were detected in 27 (21.4%) of examined tumors. The frequency of KRAS mutations was especially high in mucinous cancers (P < 0.001). CFDNA and p53-Ab were frequently detected in patients with serous cancers in high grade (P < 0.001). The overall survival rate was significantly lower for patients with serous tumors and CFDNA and p53-Ab-positive than negative tumors (P = 0.022 and P < 0.001, respectively). In mucinous ovarian cancer, a worse overall survival was correlated with the KRAS mutations (P = 0.03). CONCLUSIONS The results of the present study suggested that a presence of KRAS mutations in mucinous ovarian cancer and CFDNA and p53-Ab in serous tumors was correlated with the highest risk of cancer progression.

Circulating levels of TNF-α and its soluble receptors in the plasma of patients with epithelial ovarian cancer

The significance of circulating levels of TNF-alpha and its soluble receptors (sTNF-Rs) in the plasma of patients with epithelial ovarian cancer (EOC) has not been fully elucidated. The present study was to investigate the relationship of pretreatment plasma levels of TNF-alpha, sTNFR-1 and sTNFR-2 with outcome in 126 patients with EOC. Concentrations of TNF-alpha and sTNF-Rs were determined by enzyme-linked immunosorbent assay (ELISA). Median TNF-alpha and sTNF-Rs levels were significantly higher in EOC patients than in healthy controls. High plasma levels of TNF-alpha and sTNF-Rs were correlated with tumor stage and with reduced mean survival time (MST). The results of the present study suggested that preoperative plasma TNF-alpha and sTNF-Rs levels in EOC patients correlated with the highest risk of cancer progression. Thus, the clinical value of an activated TNF system in EOC needs to be further investigated.

Serum levels of IL-6, IL-8 and CRP as prognostic factors in epithelial ovarian cancer.

In the present study, associations between pretreatment interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP) serum levels and epithelial ovarian cancer (EOC) were analyzed using commercially available, enzyme-linked immunosorbent assay (ELISA) in 118 patients and 64 control subjects. Values were correlated with clinicopathological characteristics and outcomes. Control variables included age, stage, grade, histological type and residual tumor size. Kaplan-Meier plots and univariate and multivariate Cox proportional hazards models were used to study the associations between IL-6, IL-8 and CRP levels, control variables, overall survival and disease-free survival. The median IL-6, IL-8 and CRP serum levels in EOC were significantly higher than in the normal control group; 11.5 pg/mL (range, 3.4-62.6) versus 2.9 (1.1-12.3) pg/mL (p<0.001) and 21.8 pg/mL (range, 16.4-105.3) versus 9.3 (4.3-32.4) pg/mL (p<0.001) and 9.51 mg/L (range, 0.3-129.2) versus 1.2 (0.1-11.5) mg/L (p = 0.001), respectively. High levels of IL-6, IL-8 and CRP were associated with reduced overall survival (P = 0.003, P = 0.035, P = 0.046) and disease-free survival (P<0.001, P = 0.026, P = 0.043), respectively. Multivariate analyses showed that IL-6, IL-8 and CRP serum levels independently predicted disease-free survival (P = 0.011, P = 0.001 and P = 0.021), and overall survival (P = 0.004, P = 0.014 and P = 0.016), respectively. EOC is associated with extensive changes in the serum cytokine environment, highlighting the importance of further investigations of relative cytokine level changes. Preoperative serum IL-6, IL-8, and CRP levels seem promising for distinguishing EOC patients from healthy controls; however, their clinical value is still to be confirmed. High levels of IL-6, IL-8, and CRP in EOC patients have been suggested to be a poor prognostic factor for OS and DFS.

Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer.

The aim of the present study was to characterize the expression pattern of tumor necrosis factor (TNF)-alpha and its receptors (TNF-Rs) in the epithelial ovarian cancer (EOC) and compare these results with the outcome of 126 patients. Presence of TNF-alpha, TNFR-1 and TNFR-2 were studied by Western blotting and immunohistochemistry. The proportion of samples positive for TNF-alpha and TNF-R2 was higher in epithelial ovarian cancer patients than in benign ovarian diseases (p<0.001 and p=0.016, respectively). Immunostaining intensity of TNF-R2 were correlated with tumor stage (p<0.001) and with reduced mean survival time (MST) (p=0.002). The results of the present study suggested that tissue expression of TNF-R2 in epithelial ovarian cancer was correlated with the highest risk of cancer progression. Thus, the clinical value of activated TNF system in epithelial ovarian cancer needs to be further investigated.

Pretreatment serum levels of bFGF and VEGF and its clinical significance in endometrial carcinoma

OBJECTIVE In this study, we examined the frequency of serum elevation as well as the prognostic significance of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in endometrial cancer (EC) type I and a biologically aggressive variant of EC type II. MATERIALS AND METHODS Pretreatment serum levels of bFGF and VEGF were evaluated by commercially available enzyme-linked immunosorbent assay (ELISA) for cancer patient samples with type I EC (n=70) and type II EC (n=64) and compared to a cohort of normal individuals (n=64). Values were correlated with clinicopathological characteristics and outcome. RESULTS Median pretreatment VEGF values were 470.4pg/ml (range, 164.3-598.4pg/ml) for type I EC, 608.8pg/ml (range, 354.2-783.6pg/ml) for type II of EC patients and 215.6pg/ml (range, 128.3-332.9pg/ml) for normal healthy subjects (p<0.001). Elevated serum VEGF concentration correlated significantly with advanced FIGO stage in type II EC (p=0.011). Median values of bFGF were 10.7pg/ml (range, 0.5-22.5pg/ml) for type I EC, 21.2 (range, 0.5-62.4pg/ml) for type II EC and 1.1 (range, 0-7.2pg/ml) in controls (p<0.0001). The pretreatment bFGF levels correlated with advancing tumor stages in types I and II EC (p <0.05). Multivariate analysis with Cox proportional hazard regression models revealed that high bFGF serum level correlated with shorter overall survival (OS) in type I EC (HR, 0.39, p<0.001) and in type II EC (HR, 0.47, p=0.01) and disease-free survival (DFS) (HR, 0.53, p=0.03 and HR, 0.51, p=0.02, respectively). CONCLUSION High preoperative bFGF levels predict a poor prognosis in patients with EC, and the prognostic value is independent of established prognostic parameters. These data suggest that bFGF might potentially serve as a marker in prognosis and offer a possibility to individualize treatment regimen.

Utility of HE4 to identify patients with endometrioid endometrial cancer who may require lymphadenectomy

PURPOSE The aim of the study was to establish whether preoperative serum levels of HE4 and CA125 could be a good predictor for lymphadenectomy in the early stage of endometrioid adenocarcinoma of the uterus. MATERIAL AND METHODS Preoperative serum HE4 and CA125 were measured in 78 postmenopausal patients treated surgically. The ROC curves were generated to determine the optimal cutoff values of HE4 and CA125 levels with optimum sensitivity and specificity for the prediction of lymphadenectomy. RESULTS Based on ROC curve, we found that the HE4 value of 78pmol/l is the best cutoff to identify candidates who may require lymphadenectomy with the sensitivity of 86.6% and the specificity of 67.2% (NPV=88.4% and PPV=51.2%). The area under the curve (AUC) equals 0.814 (95% CI=0.721-0.886). The cutoff level of CA125 that shows the prognostic indices is 26U/ml, with the sensitivity of 66.6% and the specificity of 61.2% (NPV=69.4% and PPV=44.3%). For CA125 the AUC amounts to 0.671 (95% CI=0.568-0.764). We also found a statistically significant difference, comparing HE4 and CA125 AUC (0.814 vs. 0.671, respectively, p<0.001). The combination of HE4 and CA125 established in our study as the cutoff point has the sensitivity of 81.2% and the specificity of 65.9% with NPV=83.4% and PPV=47.9%. CONCLUSIONS Our findings indicate that in the early stage of endometrioid endometrial cancer, HE4 can serve as a preoperative tool that can help to identify postmenopausal women who may require lymphadenectomy.