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Provatopoulou X.,Hellenic Anticancer Institute | Georgiadou D.,George Gennimatas General Hospital | Sergentanis T.N.,Hellenic Anticancer Institute | Kalogera E.,Hellenic Anticancer Institute | And 3 more authors.
Inflammation Research | Year: 2014

Background: Thyroid disorders, including thyroid cancer and autoimmune thyroid diseases, have been closely associated with inflammation. Objective: This study aims to investigate the role of inflammation in thyroid disease by assessing serum cytokine levels in patients with malignant and benign thyroid conditions. Methods: Serum levels of ten interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 and IL-13) were quantitatively determined in 20 patients with thyroid cancer, 38 patients with benign thyroid disease and 50 healthy controls by multiplex technology. Results: Serum IL-1β, IL-2, IL-4, IL-5 and IL-6 levels were strongly associated with each other. IL-10 and IL-12 correlated with IL-1β, IL-5, IL-6, and with each other. Age was inversely correlated with serum levels of IL-2, IL-4 and IL-13. A positive correlation between T3 and IL-13 levels was also observed. Significantly higher levels of IL-6, IL-7, IL-10 and IL-13, as well as significantly lower levels of IL-8 were observed in patients with benign and malignant thyroid disease compared to controls. The combination of IL-13 and IL-8 in a two-marker panel was highly efficient in discriminating thyroid disorders (AUC 0.90). Conclusions: Malignant and benign thyroid conditions are associated with altered expression levels of interleukins, supporting the association between thyroid disease and underlying inflammatory processes. © 2014 Springer.


Kechagioglou P.,Aristotle University of Thessaloniki | Papi R.M.,Aristotle University of Thessaloniki | Provatopoulou X.,Hellenic Anticancer Institute | Kalogera E.,Hellenic Anticancer Institute | And 6 more authors.
Anticancer Research | Year: 2014

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is one of the most frequently mutated human tumor suppressor genes, implicated in cell growth and survival and suppressing tumor formation. Loss of PTEN activity, either at the protein or genomic level, has been related to many primary and metastatic malignancies including breast cancer. The present study investigates the heterozygosity, mutation spectrum and protein expression of PTEN in 43 patients with breast cancer or precursor lesions of the breast and 10 healthy individuals. Microsatellite analysis at the PTEN locus using D10S215, D10S541 and D10S579 markers indicated that the observed heterozygosity (Ho) is lower than the expected heterozygosity (Hs) in benign and malignant breast disease. Mutational analysis in exons 1, 5, 7 and 9 of the PTEN gene revealed several mutations, most of which cause truncation of the PTEN protein and consequently loss of activity. Increased circulating levels of PTEN and phosphorylated PTEN protein were also observed by immunostaining in patients with breast cancer and precursor breast lesions. In support, increased PTEN protein expression was detected in corresponding tissue specimens. Our data suggest an association between breast cancer and PTEN mutations, resulting in the production of truncated forms of the corresponding protein, thus indicating that breast carcinogenesis is potentially related to PTEN loss of activity rather than loss of expression. Peripheral blood sampling may provide an advantageous application for the determination of PTEN gene mutations and its protein expression in human cancer.


Zagouri F.,National and Kapodistrian University of Athens | Sergentanis T.N.,National and Kapodistrian University of Athens | Kalogera E.,Hellenic Anticancer Institute | Provatopoulou X.,Hellenic Anticancer Institute | And 7 more authors.
Clinica Chimica Acta | Year: 2011

Background: The involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in breast cancer has been documented on palpable lesions. This study aims to assess serum MMP1, MMP-2, TIMP-1, and TIMP-2 in atypical ductal hyperplasia (ADH), lobular neoplasia (LN), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) specifically in non-palpable mammographic breast lesions. Methods: On women with benign (n = 65), precursor [ADH (n = 18) and LN (n = 15)], preinvasive [DCIS (n = 32)] and invasive [IDC (n = 28)] lesions the serum concentrations of MMP-1, MMP-2, TIMP-1, TIMP-2, TPS, and TPA were determined with immunoenzymatic assays. All women had non-palpable mammographic breast lesions of less than 10. mm in diameter, as estimated on the mammographic views. Statistical analysis followed. Results: TIMP-2 serum concentrations were positively associated with the severity of the lesion. On the contrary, MMP-2 levels were marginally negatively associated with severity; as evident, the MMP-2/TIMP-2 ratio significantly decreased along with severity. Regarding TIMP-1, TPS, TPA, and TIMP-1/TIMP-2, no significant associations were demonstrated. MMP-2 and the MMP-2/TIMP-2 ratio were significantly higher in the LN subgroup versus the ADH subgroup. Conclusion: TIMP-2 and MMP-2/TIMP-2 ratio may exhibit meaningful changes along with progression of lesions. Extracellular cell matrix remodeling in ductal and lobular lesions may follow distinct patterns. © 2010 Elsevier B.V.


Kalogera E.,Hellenic Anticancer Institute | Pistos C.,National and Kapodistrian University of Athens | Provatopoulou X.,Hellenic Anticancer Institute | Athanaselis S.,National and Kapodistrian University of Athens | And 2 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2013

Breast and prostate constitute organs of intense steroidogenic activity. Clinical and epidemiologic data provide strong evidence on the influence of androgens and estrogens on the risk of typical hormone-dependent malignancies, like breast and prostate cancer. Recent studies have focused on the role of androgen metabolites in regulating androgen concentrations in hormone-sensitive tissues. Steroid glucuronidation has been suggested to have a prominent role in controlling the levels and the biological activity of unconjugated androgens. It is well-established that serum levels of androgen glucuronides reflect androgen metabolism in androgen-sensitive tissues. Quantitative analysis of androgen metabolites in blood specimens is the only minimally invasive approach permitting an accurate estimate of the total pool of androgens. During the past years, androgen glucuronides analysis most often involved radioimmunoassays (RIA) or direct immunoassays, both methods bearing serious limitations. However, recent impressive technical advances in mass spectrometry, and particularly in high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS), have overcome these drawbacks enabling the simultaneous, quantitative analysis of multiple steroids even at low concentrations. Blood androgen profiling by LC-MS/MS, a robust and reliable technique of high selectivity, sensitivity, specificity, precision and accuracy emerges as a promising new approach in the study of human pathology. The present review offers a contemporary insight in androgen glucuronides profiling through the application of LC-MS/MS, highlighting new perspectives in the study of steroids and their implication in hormone-dependent malignancies. © 2013 Elsevier B.V.


Piperis M.,St Savvas Hospital | Provatopoulou X.,Hellenic Anticancer Institute | Sagkriotis A.,Hellenic Anticancer Institute | Kalogera E.,Hellenic Anticancer Institute | And 4 more authors.
Anticancer Research | Year: 2012

Background: The aim of this study was to investigate the effect of breast cancer adjuvant therapies on the levels of circulating surfactant protein-D (SP-D), C-Reactive protein (CRP) and soluble receptor for advanced glycation end-products (sRAGE), as potential biomarkers of subclinical pulmonary inflammation. Materials and Methods: The soluble molecules were serially determined in 38 patients, prior to the initiation of radiation therapy (RT) and during adjuvant treatment, using immunoassays. Results: Significantly higher levels of all three biomarkers were observed in patients prior to the initiation of RT compared to healthy controls (CRP: p<0.001, SP-D: p<0.05, sRAGE: p<0.05). SP-D levels exhibited a gradual increase after RT and during follow-up (p<0.005). Patients treated with a combination of RT and hormonal therapy presented a significant, but less pronounced, increase in SP-D and a significant decrease in CRP compared to those who did not receive hormonal therapy (p=0.0428 and p=0.0116, respectively). Patients treated with a combination of RT and trastuzumab presented a significant increase in SP-D levels (p=0.0310). Conclusion: The average rate of change in the levels of circulating SP-D and CRP during postoperative irradiation and adjuvant hormonal therapy suggests that the combined therapeutic regiment may potentially exert important anti-inflammatory effects on the lung. On the contrary, combined administration of RT and trastuzumab is likely to induce or provoke pulmonary inflammation.


Provatopoulou X.,Hellenic Anticancer Institute | Kalogera E.,Hellenic Anticancer Institute | Sagkriotis A.,Hellenic Anticancer Institute | Zagouri F.,National and Kapodistrian University of Athens | And 3 more authors.
Anticancer Research | Year: 2012

Background: Human leukocyte antigen-G (HLA-G) has been closely associated with diagnosis and prognosis in many types of human cancer. The current study aims to investigate soluble (s) HLA-G expression in patients with breast malignancy. Patients and Methods: sHLA-G plasma expression was determined in 120 patients with breast cancer and 40 healthy controls using enzyme-linked immunosorbent assay. Results: Plasma sHLA-G levels were significantly higher in breast cancer patients compared to healthy controls (p<0.001), with an area under the receiver operating characteristic (ROC) curve of 0.735 (95% Confidence interval=0.630-0.841, p<0.001). Significantly increased sHLA-G expression was detected in patients with mixed type of coexisting ductal and lobular breast lesions, compared to patients with pure ductal carcinoma or pure lobular neoplasia (p<0.05). Conclusion: sHLA-G expression is closely associated with the histological type of breast cancer. Our findings support the application of sHLA-G as a potential biomarker in body fluids for preoperative breast cancer detection and diagnosis.


PubMed | Hellenic Anticancer Institute, Naval and Veterans Hospital of Athens and National and Kapodistrian University of Athens
Type: | Journal: BMC cancer | Year: 2015

Irisin is a recently discovered myokine, involved in the browning of white adipose tissue. To date, its function has been mainly associated with energy homeostasis and metabolism, and it has been proposed as a promising therapeutic target for obesity and metabolic diseases. This is the first study investigating the role of irisin in human breast cancer.Participants included one hundred and one (101) female patients with invasive ductal breast cancer and fifty one (51) healthy women. Serum levels of irisin, leptin, adiponectin and resistin were quantified in duplicates by ELISA. Serum levels of CEA, CA 15-3 and Her-2/neu were measured on an immunology analyzer. The association between irisin and breast cancer was examined by logistic regression analysis. The feasibility of serum irisin in discriminating breast cancer patients was assessed by ROC curve analysis. Potential correlations with demographic, anthropometric and clinical parameters, with markers of adiposity and with breast tumor characteristics were also investigated.Serum levels of irisin were significantly lower in breast cancer patients compared to controls (2.47 0.57 and 3.24 0.66 g/ml, respectively, p < 0.001). A significant independent association between irisin and breast cancer was observed by univariate and multivariate analysis (p < 0.001). It was estimated that a 1 unit increase in irisin levels leads to a reduction in the probability of breast cancer by almost 90%. Irisin could effectively discriminate breast cancer patients at a cut-off point of 3.21 g/ml, with 62.7% sensitivity and 91.1% specificity. A positive association with tumor stage and marginal associations with tumor size and lymph node metastasis were observed (p < 0.05, p < 0.01, p < 0.01, respectively).Our novel findings implicate irisin in breast cancer and suggest its potential application as a new diagnostic indicator of the presence of disease.


PubMed | Hippokratio Hospital, Hellenic Anticancer Institute, 3rd Surgical Clinic of George Gennimatas General Hospital and National and Kapodistrian University of Athens
Type: Journal Article | Journal: Anticancer research | Year: 2015

The objectives of our explorative study were to (i) evaluate the immunohistochemical expression of sex steroid hormone receptors (estrogen receptor a [ER], estrogen receptor [ER], progesterone receptor [PR] and androgen receptor [AR]), angiogenesis factors (vascular endothelial growth factor [VEGF] and inhibitor of differentiation/DNA synthesis 1 [Id-1]) and cell-cycle regulators (cyclin D1, p16 and p27) in intraductal papillary mucinous neoplasms (IPMNs) in comparison to normal adjacent pancreatic tissues and (ii) assess their correlation with the grade and histological sub-type of those lesions.Paraffin-embedded specimens from 12 consecutive patients with IPMNs were immunostained for the studied markers and staining quantification was assessed by an image analysis system.AR H-score and cyclin D1 H-score were significantly higher in the IPMN lesions (0.860.33 vs. 0.570.12 in the normal tissue, p=0.010 and 0.470.23 vs. 0.210.20 in the normal tissue, p=0.019, respectively). No significant differences were noted regarding the expression of ER, ER, PR, p16, p27, VEGF, Id-1 or MVD. Moreover, no significant associations were found between the expression of studied markers and grade or histological subtype.Our study showed higher expression of AR and cyclin D1 in IPMNs compared to normal pancreatic ducts without any association between AR and cyclin D1 expression and IPMNs grade or subtype.


PubMed | Hellenic Anticancer Institute and National and Kapodistrian University of Athens
Type: | Journal: Breast (Edinburgh, Scotland) | Year: 2016

Adipokines have been suggested as potential mediators linking obesity and breast cancer. Resistin is the least-studied adipokine with diverse findings regarding its association with disease development and progression. The present study aimed to determine resistin serum levels in breast cancer in relation to the histological type of disease and to investigate their association with breast cancer risk.The study included 216 women, of which 163 were diagnosed with breast cancer (58 with IDC, 52 with DCIS and 53 with LN) and 53 were healthy. Serum levels of resistin, leptin and adiponectin were quantitatively determined in duplicates by ELISA. Differences in resistin levels among patient groups were evaluated with Kruskal-Wallis and Mann-Whitney tests. The association of resistin with breast cancer risk was evaluated by multiple logistic regression analysis.Resistin levels varied between histological types of breast cancer (p=0.044). Significant differences in serum resistin were observed in IDC patients compared to those with DCIS and to controls (p<0.014 and p<0.03, respectively). Decreased levels of resistin, adiponectin and leptin were observed in premenopausal patients. Resistin was associated with a reduced risk for ductal carcinoma only in premenopausal women (OR: 0.364, 95% CI: 0.154-0.862, p<0.022).Our findings indicate that resistin levels were inversely related to breast cancer risk in premenopausal women, supporting a protective role of resistin for these patients. Further advances in adipokine research may lead to tangible benefits for overweight/obese women at an increased risk for breast cancer.


PubMed | United International University Dhanmondi, Hellenic Anticancer Institute and National and Kapodistrian University of Athens
Type: Journal Article | Journal: Journal of chromatographic science | Year: 2016

The physiological and pathological development of the breast is strongly affected by the hormonal milieu consisting of steroid hormones. Mass spectrometry (MS) technologies of high sensitivity and specificity enable the quantification of androgens and consequently the characterization of the hormonal status. The aim of this study is the assessment of plasma androgens and androgen glucuronides, in the par excellence hormone-sensitive tissue of the breast, through the application of liquid chromatography-mass spectrometry (LC-MS). A simple and efficient fit-for-purpose method for the simultaneous identification and quantification of dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), androsterone glucuronide (ADTG) and androstane-3, 17-diol-17-glucuronide (3-diol-17G) in human plasma was developed and validated. The presented method permits omission of derivatization, requires a single solid-phase extraction procedure and the chromatographic separation can be achieved on a single C18 analytical column, for all four analytes. The validated method was successfully applied for the analysis of 191 human plasma samples from postmenopausal women with benign breast disease (BBD), lobular neoplasia (LN), ductal carcinoma in situ and invasive ductal carcinoma (IDC). DHEAS plasma levels exhibited significant differences between LN, IDC and BBD patients (P < 0.05). Additionally, ADTG levels were significantly higher in patients with LN compared with those with BBD (P < 0.05).

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