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Secreto G.,Fondazione Istituto Nazionale Dei Tumori | Meneghini E.,Descriptive Studies and Health Planning Unit | Venturelli E.,Fondazione Istituto Nazionale Dei Tumori | Cogliati P.,Fondazione Istituto Nazionale Dei Tumori | And 8 more authors.
International Journal of Biological Markers | Year: 2011

Background: To further investigate the role of sex hormones in breast cancer, we assessed the relations of circulating estradiol and testosterone to tumor size and estrogen receptor (ER) status. Method: This was a cross-sectional study including 492 postmenopausal breast cancer patients. The relation of circulating hormones to patient and tumor characteristics was assessed using the Fisher or Cuzick tests. Multivariable logistic regression was used to estimate the odds ratios (ORs) of having tumors ≥2 cm (vs <2 cm) and having ER-positive tumors (vs ER-negative) with increasing quartiles of estradiol and testosterone. Results: Mean estradiol and testosterone levels increased significantly with increasing tumor size. The ORs of tumors ≥2 cm increased significantly with increasing quartiles of estradiol (P trend<0.001) and testosterone (P trend=0.005). When adjusted for estradiol, the association between testosterone and tumor size was no longer significant. Mean testosterone levels were higher in ER-positive than ER-negative patients (p<0.001), while mean estradiol levels did not differ significantly between the two ER categories (p=0.192). The ORs of having an ER-positive tumor increased significantly with increasing quartiles of testosterone (P trend=0.002), whereas the increase with increasing estradiol quartiles was not significant (P trend=0.07). Conclusion: The association of both hormones with tumor size implies that both are involved in tumor growth, testosterone mainly by conversion to estradiol. The strong association of testosterone with ER contrasts with the weak association of estradiol with ER and confirms testosterone as a marker of hormone-dependent tumors. These findings suggest that testosterone evaluation might be useful to better identify patients with hormone-dependent disease. © 2011 Wichtig Editore.


Piovano E.,University of Turin | Attamante L.,University of Turin | Macchi C.,University of Turin | Cavallero C.,University of Turin | And 7 more authors.
International Journal of Gynecological Cancer | Year: 2014

Objective: The aim of this review was to analyze the state of the art about HE4 and follow-up in patients treated for ovarian cancer. Methods: A literature search was conducted in the MEDLINE database using the key words "HE4" and "ovarian cancer" and "recurrence" or "relapse" or "follow up." Results: Seven of 28 clinical studies were selected. Four studies were prospective, and all of them were based on a small number of patients (8Y73 women). A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis, thus suggesting the need of a closer follow-up. Moreover, HE4 showed better sensibility and specificity in the diagnosis of ovarian cancer recurrence with respect to CA-125, being also an earlier indicator of the relapse with a lead time of 5 to 8 months. HE4 showed a better performance in this setting if performed in association with other markers (CA-125, CA-72.4). HE4 seems to be an independent predictive factor for the surgical outcome at secondary cytoreductive surgery and to maintain its prognostic role even after the recurrence. Conclusions: These preliminary data start to suggest a superiority of HE4 over CA-125 in the detection of ovarian cancer recurrence. Moreover, the prognostic role of HE4 could help clinicians to personalize the follow-up program, whereas its predictive role could be useful to plan the treatment of the relapse. The role of HE4 in ovarian cancer follow-up deserves to be further investigated in prospective randomized multicentric studies. Copyright © 2014 by IGCS and ESGO.


Bandiera E.,University of Brescia | Zanotti L.,University of Brescia | Fabricio A.S.C.,Regional Center for Biomarkers | Bucca E.,Regional Center for Biomarkers | And 12 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2013

Background: Human epididymis protein 4 (HE4), kallikrein 6 (KLK6), osteopontin (OPN) and soluble mesothelin- related peptide (SMRP) are new promising biomarkers that could integrate CA125 in epithelial ovarian cancer (EOC) diagnosis. The autoantibody response to tumor antigens is a potential tool for improving the diagnostic performances of biomarkers. The aim of this study was to assess the diagnostic potential of these biomarkers in the form of free markers and immunocomplexed with immunoglobulin M (IgM). Moreover, we analyzed the association between these markers and clinico-pathological characteristics of EOC patients. Methods: Serum and plasma samples of 60 healthy controls, 60 ovarian benign cysts, 60 endometriosis and 60 EOCs, collected before any treatment, were tested for CICs and free antigens by immunoassays. Results: Immunocomplexes were characterized by poor sensitivity and specificity, since they allowed the detection only of a small number of EOC patients and were increased in patients with benign gynecological pathologies. However, the markers in the form of free antigens showed good diagnostic performances. Of note, CA125 and HE4 showed high sensitivity in the detection of the malignancy and HE4 emerged as a useful biomarker in differential diagnosis between EOC and endometriosis. Finally, elevated KLK6 and OPN, were associated with advanced FIGO stage, high grade disease, suboptimally debulked tumor and ascites. Conclusions: This study confirms the diagnostic role of CA125, HE4, KLK6, OPN and SMRP, and for the first time showed that CA125, HE4, KLK6, OPN and SMRP immunocomplexed with IgM are not a potential tool for EOC diagnosis.


Romagnolo C.,Unit of Gynecology and Obstetrics | Leon A.E.,Regional Center for Biomarkers | Fabricio A.S.C.,Regional Center for Biomarkers | Fabricio A.S.C.,Italian National Cancer Institute | And 14 more authors.
Gynecologic Oncology | Year: 2016

Objective This multicenter study aims to evaluate HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) performance in the differential diagnosis of epithelial ovarian cancer (EOC). Methods A total of 405 patients referred to gynecological oncologist with suspicious pelvic mass requiring a surgery for identification of EOC were consecutively enrolled; 387 patients satisfied inclusion criteria: 290 benign diseases; 15 borderline neoplasia and 82 tumors (73 EOC). Results Good diagnostic performance in discriminating benign from EOC patients was obtained for CA125, HE4 and ROMA when calculating optimal cut-off values: premenopause, specificity (SP) > 86.6, sensitivity (SN) > 82.6, area under the curves (AUC) ≥ 0.894; postmenopause, SP > 93.2, SN > 82, AUC ≥ 0.928. Fixing SP at 98%, performance indicators obtained for benign vs EOC patients were: premenopause, SN:65.2%, positive predictive value (+ PV): 75%, positive likelihood ratio (+ LR): 26.4 for CA125; SN:69.6%, + PV:76.2%, + LR:28.1 for HE4; SN:69.6%, + PV: 80%; + LR:35.1 for ROMA; postmenopause, SN:88%, + PV: 95.7%, + LR:38.7 for CA125; SN:78%, + PV:95.1%, + LR:34.3 for HE4; SN:88%, + PV:97.8%, + LR:77.4 for ROMA. When using routine cut-off thresholds, ROMA showed better well-balanced values of both SP and SN (premenopause, SN:87%, SP:86.1%; postmenopause, SN:90%; SP:94.3%). Conclusions Overall, ROMA showed well balanced diagnostic performance to differentiate EOC from benign diseases. Meaningful differences of + PVs and + LRs between HE4 and CA125 suggest that the two markers may play at least in part different roles in EOC diagnosis, with HE4 seeming to be more efficient than CA125 in ruling in EOC patients in the disease group, also in early stages tumors, both in pre and postmenopause. © 2016 Published by Elsevier Inc.


Gion M.,Regional Center for Biomarkers | Franceschini R.,Regional Center for Biomarkers | Rosin C.,Regional Center for Biomarkers | Trevisiol C.,Istituto Oncologico Veneto | And 3 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2014

Background: Appropriateness of tumor markers (TMs) has been retrospectively studied in limited patients' series, matching the requests to clinical records. Methods to monitor appropriateness suitable for use on a large scale are required. This study aims to establish and validate an innovative model to estimate appropriateness based on the comparison between the number of TMs requested and the expected requests inferred from epidemiological data. Methods: The number of CA15.3, CA19.9 and CA125 requests theoretically expected according to the epidemiology of malignancies in a known geographic area (2 Italian regions) was compared with the number of TMs actually requested - the surveyed requests projected on a regional scale - during a given time span (1 year). The expected number of requests was calculated comparing TMs recommended by guidelines in different clinical scenarios with the prevalence or incidence figures of the examined diseases (carcinomas of breast, pancreas and biliary tract, ovary and endometrium). Results: Suitability of the model was demonstrated with the analysis of 1,891,070 TM requests surveyed in 66 laboratories from Veneto and Tuscany regions. The percentage difference over the total of expected TMs (delta%) ranged from -6.9% for CA15.3 to +1022.6% for CA19.9 in Veneto and from +35.7% for CA15.3 to +1842.6% for CA19.9 in Tuscany. Conclusions: The presented model was effective in demonstrating higher than expected TM request rates, possibly associated with inappropriate use. Moreover, it can be applied on a large scale survey setting since it circumvents the unavailability of clinical information on test orders.

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