Terlikowski S

Circulating free DNA, p53 antibody and mutations of KRAS gene in endometrial cancer

This study was conducted to evaluate the significance of circulating free DNA (CFDNA), p53 antibody (p53‐Ab) and mutations of KRAS gene in the development of endometrial cancer (EC). A total of 109 patients with EC (87 patients with Type I and 22 patients with Type II) took part in this study. KRAS mutations and CFDNA were detected by means of the PCR‐RFLP and enriched by the PCR‐RFPL method. ELISA was used to analyze plasma p53‐Ab. Tissue expression of P53 protein was evaluated immunohistochemically (IHC). The frequency of KRAS mutations was especially high in Grade 2 of Type I EC. CFDNA was frequently detected in patients with early stage of Type II EC at a low level of grade. It is noteworthy that the p53‐Ab positive rate increased in the higher grade of Type I tumors. A significant difference in the number of cases with the p53‐Ab was found in the advanced stage of Type I tumors. The frequency of KRAS and p53‐Ab correlates with tumor stage only in the Type I EC. Plasma CFDNA and p53‐Ab offer a chance to develop a procedure for EC Type II diagnosis. The association between tumor cells related to CFDNA and p53‐Ab with Type II tumor suggests that it might potentially serve as a marker in predicting the prognosis and offers a possibility to individualize treatment regimen.

Potential Application of Curcumin and Its Analogues in the Treatment Strategy of Patients with Primary Epithelial Ovarian Cancer

Recent findings on the molecular basis of ovarian cancer development and progression create new opportunities to develop anticancer medications that would affect specific metabolic pathways and decrease side systemic toxicity of conventional treatment. Among new possibilities for cancer chemoprevention, much attention is paid to curcumin—A broad-spectrum anticancer polyphenolic derivative extracted from the rhizome of Curcuma longa L. According to ClinicalTrials.gov at present there are no running pilot studies, which could assess possible therapeutic benefits from curcumin supplementation to patients with primary epithelial ovarian cancer. Therefore, the goal of this review was to evaluate potential preclinical properties of curcumin and its new analogues on the basis of in vivo and in vitro ovarian cancer studies. Curcumin and its different formulations have been shown to display multifunctional mechanisms of anticancer activity, not only in platinum-resistant primary epithelial ovarian cancer, but also in multidrug resistant cancer cells/xenografts models. Curcumin administered together with platinum-taxane chemotherapeutics have been reported to demonstrate synergistic effects, sensitize resistant cells to drugs, and decrease their biologically effective doses. An accumulating body of evidence suggests that curcumin, due to its long-term safety and an excellent profile of side effects should be considered as a beneficial support in ovarian cancer treatment strategies, especially in patients with platinum-resistant primary epithelial recurrent ovarian cancer or multidrug resistant disease. Although the prospect of curcumin and its formulations as anticancer agents in ovarian cancer treatment strategy appears to be challenging, and at the same time promising, there is a further need to evaluate its effectiveness in clinical studies.

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.

Mutations of the KRAS oncogene in endometrial hyperplasia and carcinoma.

The aim of this study was to examine the prevalence and clinicopathological significance of KRAS point mutation in endometrial hyperplasia and carcinoma. We analysed KRAS in 11 cases of complex atypical hyperplasia and in 49 endometrial carcinomas using polymerase chain reaction associated with restriction fragment length polymorphism (PCR-RFPL). Point mutations at codon 12 of KRAS oncogene were identified in 7 of 49 (14,3%) tumor specimens and in 2 of 11 (18,2%) hyperplasias. No correlation was found between KRAS gene mutation and age at onset, histology, grade of differentiation and clinical stage. We conclude that KRAS mutation is a relatively common event in endometrial carcinogenesis, but with no prognostic value.

Serum levels of VEGF and VEGF-C in patients with endometrial cancer

Endometrial cancer (EC) is the most common type of uterine cancer. A dualistic model of endometrial tumorigenesis serves as a useful way of categorizing these cancers in terms of both etiology and clinical behavior. There are two types of EC: type I and type II. Type I is so-called estrogen-dependent, and appears mostly in pre- and perimenopausal women, it is well differentiated and therefore has a better prognosis. Type II EC is estrogen-independent, diagnosed mostly in postmenopausal women, thin and fertile women, or in women with normal menstrual cycles. It is aggressive and has a worse prognosis than type I. The aim of this study was to evaluate the relationship between the pretreatment serum levels of VEGF and VEGF-C and the outcome of EC patients. A total of 98 patients treated between 1999 and 2003 were included in this study. Circulating VEGF and VEGF-C levels were determined using ELISA kits. VEGF levels among the 76 patients with type I, and the 22 patients with type II EC were significantly higher than those found in the healthy control subjects (p < 0.001). The differences in mean values of VEGF-C were highly significant in both types of tumor examined compared to the control (p < 0.001). The results demonstrate that serum VEGF concentration correlated significantly with advanced FIGO stage in type II EC (p < 0.001). The preoperative VEGF-C level correlated with advancing tumor stages in type I EC (p < 0.05). An elevated preoperative VEGF-C was an independent risk factor for disease-specific survival in patients with type II tumors. Thus, in type II EC patients with high preoperative levels of VEGF-C, pelvic and para-aortic lymphadenectomy should be performed. However, the value of longitudinal measurements of the markers used is yet to be determined.

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.

Biomarkers as prognostic factors in endometrial cancer.

Endometrial cancer is the most common gynecologic malignancy in more developed countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis and endometrioid histology and type II, associated with a poor prognosis and non-endometrioid histology. This review will focus primarily on the molecular biomarkers that have supported the dualistic model of endometrial carcinoma and help determine which patients would benefit from either adjuvant therapy or more aggressive primary treatment.