Anita Chudecka-Głaz

Premature Menopause in Patients with BRCA1 Gene Mutation

This study was undertaken with regard to the gonadotropin theory of ovarian cancer advocated in the literature and was designed to disclose specific features of ovarian morphology in carriers of the BRCA1 gene mutation. We enrolled 171 patients and divided them into two groups: A (n=90)—operated for breast cancer (30 patients with and 60 without the BRCA1 mutation); B (n=81)—with the BRCA1 mutation qualified for preventive adnexectomy. According to the authors’ classification described herein, some patients without the BRCA1 mutation retained “signs of estrogenization” in menopausal ovaries, revealing the role of estrogens as a factor promoting mammary carcinogenesis in these patients. A tendency to premature menopause was observed in BRCA1 mutation carriers of groups A and B as evidenced by the final menorrhea appearing at a younger age and almost total absence of “signs of estrogenization” in menopausal ovaries. It is concluded from these findings that earlier menopause in carriers of the BRCA1 mutation is associated with hypergonadotropic activity and may predispose to ovarian cancer at younger age.

ROMA, an algorithm for ovarian cancer

Improvement of survival in ovarian cancer may be achieved through early diagnosis and modification of treatment. Although abnormalities in the adnexal region are frequently observed in transvaginal ultrasound, interpretation may be equivocal in some cases. If neoplastic tumor is suspected, a wide range of tests and algorithms may be applied. Risk of Malignancy Algorithm (ROMA), as first described by Moore in 2009, is one of the most popular approaches. The clinical utility of this regression model has been demonstrated in both pre- (75.6% sensitivity and 74.8% specificity) and post-menopausal (92.3% sensitivity and 74.7% specificity) women. These findings have been independently confirmed in a number of publications. The sensitivity and specificity of ROMA may, however, be improved with inclusion of supplemental data, such as age and ultrasound findings. Because of its simplicity, ROMA is a reliable tool characterized by high accuracy and reproducibility to stratify patients into a high or a low ovarian cancer risk.

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

Importance Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Vascular endothelial growth factor (VEGF) levels and mutation of the BRCA1 gene in breast cancer patients.

The aim of the study was to compare VEGF serum levels in breast cancer patients with and without BRCA1 gene mutation. We enrolled 80 patients, 22 premenopausal and 58 postmenopausal. We found statistically significant lower levels of VEGF in patients with BRCA1 gene mutation as compared with breast cancer patients without this mutation.

Assessment of selected cytokines, proteins, and growth factors in the peritoneal fluid of patients with ovarian cancer and benign gynecological conditions

Objectives The ovarian tumor microenvironment, ie, the peritoneal fluid, is an intriguing research subject. The goal of this study was to assess the behavior of selected cytokines and growth factors within the peritoneal fluid in pathologies associated with ascites and to assess the relationship between the levels of these substances and select prognostic factors of ovarian cancer. Methods A total of 74 patients were enrolled in the study, including 36 patients with ovarian cancer and 38 patients with benign gynecological conditions. Peritoneal fluid collected during surgical procedures was used to assess the levels of interleukin (IL)-6, IL-8, stem cell factor (SCF), dickkopf-1, growth differentiation factor-15 (GDF-15), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), osteoprotegerin (OPG), osteopontin, osteonectin, and human epididymis protein 4. The median levels of these factors were compared between the two groups, and the levels of selected factors were assessed in the ovarian cancer group with regard to the clinical stage of cancer, tumor differentiation, presence of peritoneal spread and positive peritoneal fluid cytology results. The diagnostic value of the analyzed proteins within the peritoneal fluid was also assessed. Results Differences were observed between the patients with ovarian cancer and the patients with benign gynecological conditions associated with ascites with regard to the levels of IL-6, IL-8, GDF-15, SCF, osteopontin, osteonectin, and OPG. There were no differences in dickkopf-1, TRAIL, and human epididymis protein 4 levels between the two study groups. Cancer stage affected only the mean SCF and OPG levels, with lower SCF values and higher OPG values in advanced cancers compared to less-advanced cancers. Tumor differentiation was associated with significantly lower SCF values in the group of poorly differentiated tumors. A significant reduction in SCF values and a significant increase in OPG and IL-6 values were also observed within cancer cell-positive peritoneal fluid. Peritoneal spread was associated with higher levels of TRAIL, osteonectin, and IL-6 in ovarian cancer patients. Conclusion On the basis of the conducted studies, it appears that of the studied factors, GDF-15, SCF, and OPG deserve special attention in the context of future research on the tumor microenvironment. With regard to diagnostics, attention should be given primarily to GDF-15, IL-6, and osteonectin.

Clinical importance of serum HE4 and MMP2 levels in endometrial cancer patients

Introduction Endometrial cancer is the one of the most common cancers of the genital organ. HE4 and MMP2 are both proteins whose serum levels increase in endometrial cancer. Aim To explore the diagnostic potential of the serum levels of HE4 and MMP2 in patients with endometrial cancer and benign endometrial diseases. To assess the relationship between the serum levels of HE4 and MMP2 and the typical prognostic factors in patients with endometrial cancer. Materials and methods Included in the study was a group of 112 patients presenting with bleeding abnormalities at the Pomeranian Medical University in years 2012–2016. Serum HE4 concentrations were measured using the Elecsys Electrochemiluminescence Immunoassay (ECLIA). MMP2 concentrations were quantified in the serum using multiplex immunoassays. Results We observed statistically significant differences in mean serum levels of HE4 and MMP2 between the group of endometrial cancer patients and the group of patients with no changes in the endometrium (P=0.002/0.003). The diagnostic potential of HE4 and MMP2 in differentiation of high (International Federation of Gynecology and Obstetrics [FIGO] III and IV) vs low (FIGO I and II) clinical stage of tumor and prediction of cellular differentiation grade (G1 vs G3) on the basis of the analysis of the area under the curve is, respectively, 0.86 and 0.82 for HE4 and 0.82 and 0.74 for MMP2. The HE4 marker was significantly more specific than MMP2 in every study group and amounted to 93% vs 86% in all patients included in the analysis, 94% vs 84% in pre-menopausal patients and 84% vs 79% in post-menopausal patients. Conclusion HE4 and MMP2 are characterized by high specificity and may be useful as biomarkers in the diagnostics of endometrial cancer. When determined preoperatively, HE4 is correlated with the prognostic factors of endometrial cancer and may be helpful in the planning of individual treatment of endometrial cancer patients.

Clinical Relevance of NGAL/MMP-9 Pathway in Patients with Endometrial Cancer

The objectives of the study were to assess the relationship between the serum levels of MMP-9 and NGAL and the clinical staging and histopathological grade of the tumor. Lipocalin-2/NGAL and MMP-9 concentrations were quantified in serum by multiplex fluorescent bead-based immunoassays (Luminex Corporation, Austin, TX, USA). The AUC values for NGAL and MMP-9 were 0.9 and 0.78, respectively. The diagnostic potential of NGAL and MMP-9 in differentiating high-stage (FIGO III and IV) and low-stage (FIGO I and II) cancer and predicting the cell differentiation grade (G1 versus G3) on the basis of the analyses of AUC values was determined to be 0.91 and 0.79 for NGAL and 0.82 and 0.84 for MMP-9, respectively. Multifactorial logistic regression analysis in the final method revealed that NGAL and MMP-9 variables were independent of the endometrial cancer risk. OR values for NGAL and MMP-9 were 1.23 (95% CI 1.421–3.27; p = 0.034) and 1.09 (95% CI: 1.38–4.12; p = 0.026), respectively. The NGAL/MMP-9 complex may be useful in the assessment of tumor stage before surgical treatment.

HE4 Serum Levels in Patients with BRCA1 Gene Mutation Undergoing Prophylactic Surgery as well as in Other Benign and Malignant Gynecological Diseases

Objective. We assess the behavior of serum concentrations of HE4 marker in female carriers of BRCA1 and assess the diagnostic usefulness of HE4 in ovarian and endometrial cancer. Methods. A total of 619 women with BRCA1 gene mutation, ovarian, endometrial, metastatic, other gynecological cancers, or benign gynecological diseases were included. Intergroup comparative analyses were carried out, the BRCA1 gene carriers subgroup was subjected to detailed analysis, and ROC curves were determined for the assessment of diagnostic usefulness of HE4 in ovarian and endometrial cancer. Results. Statistically lower serum HE4 and CA 125 levels were observed in BRCA1 gene mutation premenopausal carriers. Occult ovarian/fallopian tube cancer was found 3.6%. Each of those patients was characterized by slightly elevated levels of either CA 125 (63.9 and 39.4 U/mL) or HE4 (79 pmol/L). The ROC-AUC curves were 0.892 and 0.894 for diagnostic usefulness of ovarian cancer and 0.865 for differentiation of endometrial cancer from endometrial polyps. Conclusions. Patients with BRCA1 gene mutations have relatively low serum HE4 levels. Even the slightest elevation in HE4 or CA 125 levels in female BRCA1 carriers undergoing prophylactic surgery should significantly increase oncological alertness. The HE4 marker is valuable in ovarian and uterine cancer diagnosis.

Thrombospondin-I concentrations behavior in plasma of patients with ovarian cancer

PURPOSE To determine whether thrombospondin-1 might be used as a prognostic factor in ovarian cancer patients. METHOD Ninety-six female subjects hospitalized in years 2011-2014 was included in the study. Transvaginal ultrasound examination was performed in all patients. In 39 cases of suspected ovarian cancer, CT scans were also performed. Each patient had been subjected to collection of a 5-mL blood sample before the laparoscopic procedure. Thrombospondin-1 concentrations were quantified in serum by multiplex fluorescent bead-based immunoassays (Luminex) at the Laboratory of the Department of General Pathology. RESULTS Statistical analysis performed using the Kaplan-Meier survival curves and log-rank test revealed no statistically significant correlations between the median, 75th percentile and 95th percentile thrombospondin-1 levels with progression-free survival of patients (p= 0.47). In the univariate OS model, median thrombospondin-1 level was a significant variable. Correlation was demonstrated between baseline thrombospondin-1 levels and overall survival of patients (p= 0.04, HR = 0.99). The higher the baseline TSP1 level, the longer the overall survival of patients. CONCLUSION In our study, we were the first to demonstrate correlation between the levels of thrombospondin-1 and overall survival of patients. Therefore, it appears that thrombospondin-1 may be used as a prognostic factor in ovarian cancer patients.

HE4 tumor marker concentration in neoplastic peritoneal effusion and in peritoneal fluid associated with benign gynecological diseases

BackgroundThe aim of our study was to evaluate the behaviour of the human epididymis protein 4 (HE4) in the peritoneal fluid encountered in various female genital diseases.MethodsWe enrolled 139 patients, 40 with ovarian cancer (group I), 82 with benign diseases (group II), and 17 with other malignant neoplasms (group III). The HE4 tumor marker concentrations were determined in serum, in the peritoneal effusion and ovarian cyst/ tumor fluids, CA125 in the serum only. We compared the groups, examined correlations and determined corresponding ROC curves. We evaluated the relationship between the HE4 marker concentration in the peritoneal effusion in the group I, depending on the selected prognostic parameters.ResultsThe HE4 median value between the study groups did not differ statistically significantly and were as follows: in group I 3322 pmol/L, in the group II 2150 pmol/L and in the group III 627 pmol/L (p = 0.206376 for the groups I and II, p = 0.05929 for the groups I and III and p = 0.0797 for the groups II and III. In group I there were no differences found in the HE4 concentrations in the peritoneal fluid, depending on the stage, grade, the presence of neoplastic cells and the peritoneal dissemination.ConclusionsThe HE4 marker concentrations in the peritoneal fluid are highly irrespective of the pathology observed in the female sexual organ. Therefore, it seems that its determinations in the peritoneal fluid are completely useless in terms of diagnostics. More research is needed on the role of the HE4 marker, especially the place of its formation and possible use in the targeted therapy.