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High-grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer, and it is often associated with ascites at presentation. The objective of this study was to evaluate the accuracy of cytopathology to identify immunophenotypic features of HGSC and BRCA1/2 mutations from ascites.The study included 45 patients with histologically confirmed primary HGSC and malignant ascites. Immunocytochemistry (ICC) staining for PAX8, WT1, P53, P16, and Ki-67 was performed on cytospins and cytoblocks prepared from ascites. Next-generation sequencing (NGS) was used to detect germline/somatic BRCA1/2 mutations in the ascites. Both ICC and NGS results were compared with immunohistochemistry (IHC) and NGS results from tissue blocks of primary tumor. Cronbach α and χICC/IHC results for PAX8, WT1, P53, and P16 showed good reliability between cytospins, cytoblocks, and tissue blocks (α 0.75), whereas poor reliability and significant differences were observed for Ki-67 between ascites and tissue blocks (α 0.26; p.001 [Kruskal-Wallis]). For germline BRCA1/2 mutations, 100% concordance was confirmed, but only 14% concordance was confirmed for somatic mutations.These results demonstrate that cytopathology is an accurate method for identifying immunophenotypic features of HGSC and detecting germline BRCA1/2 mutations from ascites. However, further investigation is required for assessing the proliferation activity of HGSC in ascites and for detecting somatic BRCA1/2 mutations.

Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of angiogenic factors (AFs) appears early in the process of carcinogenesis. The detection of AFs in plasma and tissue and a better understanding of the angiogenic properties of EC may contribute not only to earlier but also more specific diagnosis and consequently tailored and individual therapeutic approaches. AFs and their receptors also have high potential as binding sites for targeted cancer therapy. In this review, we discuss angiogenesis in EC and the characteristics of the AFs that most contribute to angiogenesis in EC. We also highlight therapeutic strategies that target angiogenesis as potential EC therapy.

Objective Based on the SUCCOR study database, our primary objective was to identify the independent clinical pathological variables associated with the risk of relapse in patients with stage IB1 cervical cancer who underwent a radical hysterectomy. Our secondary goal was to design and validate a risk predictive index (RPI) for classifying patients depending on the risk of recurrence. Methods Overall, 1116 women were included from January 2013 to December 2014. We randomly divided our sample into two cohorts: discovery and validation cohorts. The test group was used to identify the independent variables associated with relapse, and with these variables, we designed our RPI. The index was applied to calculate a relapse risk score for each participant in the validation group. Results A previous cone biopsy was the most significant independent variable that lowered the rate of relapse (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.17–0.60). Additionally, patients with a tumor diameter >2 cm on preoperative imaging assessment (OR 2.15, 95% CI 1.33–3.5) and operated by the minimally invasive approach (OR 1.61, 95% CI 1.00–2.57) were more likely to have a recurrence. Based on these findings, patients in the validation cohort were classified according to the RPI of low, medium, or high risk of relapse, with rates of 3.4%, 9.8%, and 21.3% observed in each group, respectively. With a median follow-up of 58 months, the 5-year disease-free survival rates were 97.2% for the low-risk group, 88.0% for the medium-risk group, and 80.5% for the high-risk group (p < 0.001). Conclusion Previous conization to radical hysterectomy was the most powerful protective variable of relapse. Our risk predictor index was validated to identify patients at risk of recurrence.

Although aldo-keto reductases (AKRs) have been widely studied in cancer, no study to date has examined the roles of AKR family 1 members B1 (AKR1B1) and B10 (AKR1B10) in a large group of ovarian cancer patients. AKR1B1 and AKR1B10 play a significant role in inflammation and the metabolism of different chemotherapeutics as well as cell differentiation, proliferation, and apoptosis. Due to these functions, we examined the potential of AKR1B1 and AKR1B10 as tissue biomarkers. We assessed the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 99 patients with high-grade serous ovarian cancer (HGSC) and compared these levels with clinicopathological characteristics, survival, and response to chemotherapy. A higher immunohistochemical AKR1B1 expression correlated with a better overall and disease-free survival of HGSC patients whereas AKR1B10 expression did not show any significant differences. A multivariant Cox analysis demonstrated that a high AKR1B1 expression was an important prognostic factor for both overall and disease-free survival. However, AKR1B1 and AKR1B10 were not associated with different responses to chemotherapy. Our data suggest that AKR1B1 is involved in the pathogenesis of HGSC and is a potential prognostic biomarker for this cancer.

Certainty-Based Marking (CBM) involves asking students not only the answer to an objective question, but also how certain they are that their answer is correct. In a mixed method design employing an embedded approach with a quasi-experimental design, we have examined the use of CBM during a 5-week Gynaecology and Obstetrics course. The study was conducted as a non-mandatory revision exam with two additional questionnaires on Moodle. Majority of students perceive CBM as fair (78%) and useful (94%). Most students would immediately want CBM to be used for revision exams, but more practice would be needed for CBM to be used in graded exams. The lowest self-evaluation of knowledge was mostly seen by worst (less than 70% Accuracy) and best achievers (more than 90% Accuracy); the worst achievers probably have knowledge gaps, and the best achievers probably correctly guessed at least one question. Our findings conclude that CBM does not discriminate any learner type (p = 0.932) and does not change the general distribution of the exam scores, since there is no significant differences between Certainty-Based Score (M = 80.4%, SD = 10.4%) and Accuracy (M = 79.8%, SD = 11.1%); t(176) = 0.8327, p = 0.4061. These findings are widely applicable, as learner type study models are used extensively in education. In the future, larger samples should be studied and the implementation of CBM on question types other than MCQ should be investigated.

Introduction/Background* Endometrial cancer is the most common gynecological cancer diagnosis in developed countries. Personalized treatments for these cancers depend on identification of prognostic and predictive biomarkers that allow stratification of patients. The aldo-keto reductase (AKR) superfamily is getting attention in cancer research, because of AKR’s involvements in important biochemical processes. The enzyme AKR1C3 has many functions, which include production of prostaglandins, androgens, estrogens, and metabolism of different chemotherapeutics. AKR1C3 is thus implicated in the pathophysiology of different cancers. Methodology In our study, we evaluated the immunohistochemical (IHC) staining of AKR1C3 in 123 paraffin-embedded samples of endometrial cancer and statistically examined possible correlations between expression of AKR1C3 and clinicopathological data (survival, stage of disease, lymphovascular invasion, menopausal status, parous status, smoking, use of hormone replacement therapy). Result(s)* In endometrioid endometrial carcinoma, high AKR1C3 IHC expression correlated with better overall survival (p = 0.008) and with disease-free survival (p = 0.027). Significantly higher percentages of positive epithelial cells were seen for adjacent nonneoplastic endometrium compared to endometrioid endometrial cancer (p = 1 × 10−4). Conclusion* These results demonstrate the potential use of AKR1C3 as an independent prognostic biomarker in endometrioid endometrial cancer. Clinically, this might mean that levels of AKR1C3 in endometrioid endometrial cancer could be determined preoperatively on diagnostic tissue samples to allow prediction of the cancer behavior and stratification of the patients for more personalized treatments. Disclosures Conflicts of Interest The authors declare no conflict of interest. Study was supported by the grants J3-2535 to T.L.R. from the Slovenian Research Agency. Ethical Issues The study was approved by the National Medical Ethics Committee of the Republic of Slovenia (0120-701/2017-6).

Introduction/Background* Endometrial cancer is the second most common carcinoma of the female genital tract globally, and its incidence is still increasing. Optimal treatment of EC depends on early diagnostics and pre-operative stratification to appropriately select the extent of surgery and to plan further therapeutic approach. Current diagnosis and treatment of EC patients is guided by histopathological and surgical findings since there are no accurate non-invasive diagnostic or prognostic methods available. The lack of non-invasive diagnostic and prognostic biomarkers of EC is addressed in the current clinical study titled ‘Biomarkers for Diagnosis and Prognosis of Endometrial Carcinoma’ (NCT03553589). Methodology Patient recruitment takes place at six medical centers (University Medical Centre Ljubljana, Slovenia; University Medical Centre Maribor, Slovenia; Maastricht University Medical Centre, The Netherlands; Lublin Medical University, Poland; University Hospital Brno, Czech Republic, University of Genoa, Italy). Plasma samples from women with diagnosed EC and controls will be examined using non-targeted and targeted metabolomics and targeted proteomics approaches. Combined blood metabolome (>850 metabolites), proteome (>900 proteins), clinical and epidemiological data will be analyzed in order to construct diagnostic/prognostic algorithms for early diagnosis of EC and to identify patients with low/high risk for cancer progression and recurrence. BioEndoCar consortium has defined inclusion/exclusion criteria and a strict standard operating procedure for sample collection, processing and storage that is followed in all medical centers. Result(s)* Since the beginning of the project we recruited more than 440 patients. Discovery proteomics and discovery metabolomics phase have been concluded. Targeted proteomics and targeted metabolomics analysis are currently in progress and we are awaiting the results. Conclusion* Within the project we expect to find different metabolic and protein profiles in patients with early stages of EC as compared to controls and in patients with poor prognosis and high risk of disease progression and recurrence as compared to those with favorable prognosis. Great effort was put into informing the lay and expert public about the importance of the translational studies in EC. We have established an official website (https://bioendocar.eu/), Twitter profile and Facebook page (https://www.facebook.com/bioendocar) where we post all news concerning the project. Funded by ERA-NET Transcan2 and MIZS. Nothing to disclose.

Introduction/Background* Endometrial cancer (EC) is the most common gynecological malignancy in more developed countries. At present, endometrial histology is needed for diagnosis, as there are no valid, accurate noninvasive diagnostic methods. Screening of patients’ plasma biomarkers might enable a more precise diagnosis of EC and a tailored treatment approach. The aim of our prospective case-control pilot study was to quantify 37 different angiogenic factors to evalute their potential diagnostic and/or prognostic value. Methodology 76 postmenopausal women (38 patients with endometrioid EC and 38 control patients with prolapsed uterus or chronic pelvic pain) that underwent surgical treatment at the University Medical Centre Ljubljana were included in this prospective case-control pilot study. Plasma samples were evaluated using commercially available kit that enables simultaneous determination of 37 different proteins with the Luminex xMAP™ multiplexing technology. Result(s)* The case group comprised 38 patients with endometrioid EC, with mean age 65.9 ± 8.2 years and mean body mass index (BMI) of 31.8 ± 6.1 kg/m2. Lymphovascular invasion (LVI) was present in five patients while deep myometrial invasion (DMI) was present in 12 patients. The control group included 38 patients with mean age 66.8 ± 8.3 years and mean BMI of 27.6 ± 3.9 kg/m2. There was a significant difference in the BMI distribution between the case and control group (p Conclusion* The results of our study indicate that the plasma levels of different AFs might be involved in the growth of endometrioid EC. The plasma levels of G-CSF, Tie-2, and leptin significantly differ between EC and control patients. The plasma concentrations of these AFs could represent an important additional diagnostic tool for the early detection and characterization of EC and could guide the decision-making regarding the extent of surgery. Further validation studies with larger patient numbers are currently ongoing.

Background The COVID-19 pandemic threatens the impact of cervical cancer screening and global cervical cancer elimination goals. As cervical cancer screening programmes were adjusting to the new situation, we evaluated the intensity, quality, and outcomes of cervical cancer screening in Slovenia in the first seven months of the pandemic. Methods Historical observational study on data from a population-based cervical cancer screening registry. Number of cervical cytopathology (screening and follow-up), histopathology (diagnostic procedures, invasive procedures and number of newly diagnosed CIN2+ cases) and HPV test results from the entire Slovenian women population between January 1st and September 30th 2020 were compared to a three-year average of the years 2017–19. Findings A two-month screening lock-down between March 12th and May 8th 2020 resulted in an epidemic deficit of screening (-92%), follow-up (-70%), and HPV triage tests (-68%), as well as invasive diagnostic (-47%) and treatment (-15%) of cervical lesions. Time to diagnosis and treatment did not increase; times to laboratory results fluctuated but stayed within standards. Slovenia has entered the second epidemic intending to add as little as possible to the pandemic deficit of screening smears (-23%) and yearly CIN2+ cases (-10%). Women aged 30–39 were most affected, with the highest pandemic deficit of screening smears (-26%) and yearly CIN2+ cases (-19%). Interpretation The pandemic has deeply affected all levels of our lives. New vulnerable groups and inequalities have emerged that require recognition and action. To prevent long-term increases in the cervical cancer burden due to the COVID-19 pandemic, it is crucial that organised screening is maintained and monitored in settings where it can be safely and comprehensively provided. Funding None.

The aldo-keto reductase (AKR) superfamily is gaining attention in cancer research. AKRs are involved in important biochemical processes and have crucial roles in carcinogenesis and chemoresistance. The enzyme AKR1C3 has many functions, which include production of prostaglandins, androgens and estrogens, and metabolism of different chemotherapeutics, AKR1C3 is thus implicated in the pathophysiology of different cancers. Endometrial and ovarian cancers represent the majority of gynecological malignancies in developed countries. Personalized treatments for these cancers depend on identification of prognostic and predictive biomarkers that allow stratification of patients. In this study, we evaluated the immunohistochemical (IHC) staining of AKR1C3 in 123 paraffin-embedded samples of endometrial cancer and 99 samples of ovarian cancer, and examined possible correlations between expression of AKR1C3 and other clinicopathological data. The IHC expression of AKR1C3 was higher in endometrial cancer compared to ovarian cancer. In endometrioid endometrial carcinoma, high AKR1C3 IHC expression correlated with better overall survival (hazard ratio, 0.19, 95% confidence interval, 0.06&minus, 0.65, p = 0.008) and with disease-free survival (hazard ratio, 0.328, 95% confidence interval, 0.12&ndash, 0.88, p = 0.027). In patients with ovarian cancer, there was no correlation between AKR1C3 IHC expression and overall and disease-free survival or response to chemotherapy. These results demonstrate that AKR1C3 is a potential prognostic biomarker for endometrioid endometrial cancer.

Preoperative determination of the extent of endometrial cancer (EC) would avoid the complications associated with radical surgery. Screening of patients’ plasma biomarkers might enable a more precise diagnosis of EC and a tailored treatment approach. This prospective case-control monocentric pilot study included 76 postmenopausal women (38 endometrioid EC patients and 38 control patients with benign gynecological conditions), and 37 angiogenic factors (AFs) were investigated as potential biomarkers for EC. AF concentrations in preoperative plasma samples were measured using Luminex xMAP™ multiplexing technology. The plasma levels of sTie-2 and G-CSF were significantly lower in EC compared to control patients, whereas the plasma levels of leptin were significantly higher in EC patients. Neuropilin-1 plasma levels were significantly higher in patients with type 2 EC (grade 3) compared to patients with lower grade cancer or controls. Follistatin levels were significantly higher in patients with lymphovascular invasion, and IL-8 plasma levels were significantly higher in patients with metastases. If validated, the plasma concentrations of the indicated AFs could represent an important additional diagnostic tool for the early detection and characterization of EC. This could guide the decision-making on the extent of surgery. Further studies with larger patient numbers are currently ongoing.

In endometrial cancer, biomarkers for preoperative identification of patients with low risk for disease progression would enable stratification according to the extent of surgery needed, and would avoid the complications that can be associated with radical surgery. A panel of proteins, amino acids, enzymes, and miRNA has been investigated as potential biomarkers for endometrial cancer. At the time of the manuscript submission targeted metabolomics/lipidomics approaches have not been applied to biomarker research in endometrial cancer. Using electrospray ionization–tandem mass spectrometry we quantified 163 metabolites in 126 plasma samples (61 patients with endometrial cancer, 65 control patients). Three single phosphatidylcholines were identified with significantly decreased levels in patients with endometrial cancer. A diagnostic model was defined as the ratio between acylcarnitine C16 and phosphatidylcholine PCae C40:1, the ratio between proline and tyrosine, and the ratio between the two phosphatidylcholines PCaa C42:0 and PCae C44:5; which provided sensitivity of 85.25%, specificity of 69.23%, and AUC of 0.837. Addition of smoking status further improved the constructed diagnostic model (AUC = 0.855). The presence of the major prognostic factors of deep myometrial invasion and lymphovascular invasion were also associated with altered metabolite concentrations. A prognostic model for deep myometrial invasion included the ratio between two hydroxysphingomyelins SMOH C14:1 and SMOH C24:1, and the ratio between two phosphatidylcholines PCaa C40:2 and PCaa C42:6, which provided sensitivity of 81.25%, specificity of 86.36%, and AUC of 0.857. The model for lymphovascular invasion included the ratio between two phosphatidylcholines PCaa C34:4 and PCae C38:3, and the ratio between acylcarnitine C16:2 and phosphatidylcholine PCaa C38:1, which provided sensitivity of 88.89%, specificity of 84.31%, and AUC of 0.935.

In the last ten years, clinical oncology has been revolutionized by the introduction of oncological immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs) that transformed the standard of care of several advanced solid malignancies. Using ICIs for advanced gynecological cancers has yielded good results, especially for endometrial cancer. In ovarian or cervical cancer, combining ICIs with other established agents has shown some promise. Concurrently with the clinical development of ICIs, biomarkers that predict responses to such therapy have been discovered and used in clinical trials. The translation of these biomarkers to clinical practice was somewhat hampered by lacking assay standardization and non-comprehensive reporting of biomarker status in trials often performed on a small number of gynecological cancer patients. We can expect increased use of ICIs combined with other agents in gynecological cancer in the near future. This will create a need for reliable response prediction tools, which we believe will be based on biomarker, clinical, and tumor characteristics. In this article, we review the basic biology of ICIs and response prediction biomarkers, as well as the latest clinical trials that focus on subgroup effectiveness based on biomarker status in gynecological cancer patients.

Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential of STAR and AKR1B10 as prognostic biomarkers, which calls for further validation at the protein level.

Endometrial cancer is the sixth most common cancer in women worldwide. It is associated with aberrant actions of steroid hormones, estrogens and progesterone, but also with enhanced inflammation and reduced cellular differentiation. Here, we show data on demographic and histopathological characteristics of 51 patients with endometrial cancer, together with data on correlations between the expression of 38 genes involved in estrogen and progesterone actions, inflammation and differentiation, and demographic characteristics. We also show data on changes in gene expression of these 38 genes according to histopathological and clinical characteristics of these patients. This article includes data referenced in the manuscript entitled »STAR and AKR1B10 are down-regulated in high-grade endometrial cancer by Sinreih et al. (in press) [1].

SUCCOR study: an international European cohort observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer FREE http://orcid.org/0000-0002-1908-3251Luis Chiva1, Vanna Zanagnolo2, Denis Querleu3, Nerea Martin- Calvo4, Juan Arévalo-Serrano5, Mihai Emil Căpîlna6, Anna Fagotti7, Ali Kucukmetin8, Constantijne Mom9, Galina Chakalova10, Shamistan Aliyev11, Mario Malzoni12, http://orcid.org/0000- 0001-5809-3535Fabrice Narducci13, Octavio Arencibia14, Francesco Raspagliesi15, Tayfun Toptas16, David Cibula17, Dilyara Kaidarova18, http://orcid.org/0000-0001-6763-9720Mehmet Mutlu Meydanli19, Mariana Tavares20, Dmytro Golub21, http://orcid.org/0000-0003-3140-4772Anna Myriam Perrone22, Robert Poka23, Dimitrios Tsolakidis24, Goran Vujić25, http://orcid.org/0000-0001-8935- 0311Marcin A Jedryka26, Petra L M Zusterzeel27, Jogchum Jan Beltman28, Frederic Goffin29, Dimitrios Haidopoulos30, Herman Haller31, Robert Jach32, Iryna Yezhova33, Igor Berlev34, Margarida Bernardino35, Rasiah Bharathan36, Maximilian Lanner37, Minna M Maenpaa38, http://orcid.org/0000-0002-4403-3707Vladyslav Sukhin39, Jean-Guillaume Feron40, Robert Fruscio41, 42, Kersti Kukk43, Jordi Ponce44, Jose Angel Minguez45, http://orcid.org/0000-0002-9618- 5606Daniel Vázquez-Vicente45, Teresa Castellanos45, Enrique Chacon46 and http://orcid.org/0000-0002-9700-0853Juan Luis Alcazar47 On behalf of the SUCCOR study Group Author affiliations Abstract Background Minimally invasive surgery in cervical cancer has demonstrated in recent publications worse outcomes than open surgery. The primary objective of the SUCCOR study, a European, multicenter, retrospective, observational cohort study was to evaluate disease-free survival in patients with stage IB1 (FIGO 2009) cervical cancer undergoing open vs minimally invasive radical hysterectomy. As a secondary objective, we aimed to investigate the association between protective surgical maneuvers and the risk of relapse. Methods We obtained data from 1272 patients that underwent a radical hysterectomy by open or minimally invasive surgery for stage IB1 cervical cancer (FIGO 2009) from January 2013 to December 2014. After applying all the inclusion-exclusion criteria, we used an inverse probability weighting to construct a weighted cohort of 693 patients to compare outcomes (minimally invasive surgery vs open). The first endpoint compared disease-free survival at 4.5 years in both groups. Secondary endpoints compared overall survival among groups and the impact of the use of a uterine manipulator and protective closure of the colpotomy over the tumor in the minimally invasive surgery group. Results Mean age was 48.3 years (range ; 23–83) while the mean BMI was 25.7 kg/m2 (range ; 15–49). The risk of recurrence for patients who underwent minimally invasive surgery was twice as high as that in the open surgery group (HR, 2.07 ; 95% CI, 1.35 to 3.15 ; P=0.001). Similarly, the risk of death was 2.42-times higher than in the open surgery group (HR, 2.45 ; 95% CI, 1.30 to 4.60, P=0.005). Patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse (HR, 2.76 ; 95% CI, 1.75 to 4.33 ; P

Introduction/Background Endometrial carcinoma (EC) is the most frequent gynecological malignancy in the developed world. Currently there are no valid non-invasive diagnostic or prognostic methods available and therefore, diagnosis and treatment of EC patients is guided by histopathological and surgical findings. The lack of non-invasive diagnostic and prognostic biomarkers of EC is addressed in the current clinical study titled ‘Biomarkers for Diagnosis and Prognosis of Endometrial Carcinoma’ (BioEndoCar). Methodology Prospective observational case - control study. Patient recruitment takes place at three medical centers (University Medical Centre Ljubljana, Slovenia; Maastricht University, The Netherlands; Lublin Medical University, Poland). Plasma samples from women with diagnosed EC and controls will be examined using non-targeted and targeted metabolomics (Helmholtz Zentrum Munchen, Germany) and semi-targeted proteomics approaches (Sciomics GmbH, Heidelberg, Germany). Combined blood metabolome (>850 metabolites), proteome (900 different proteins), clinical and epidemiological data will be analyzed (University of Tartu, Estonia) in order to construct diagnostic/prognostic algorithms for early diagnosis of EC and to identify patients with low/high risk for cancer progression and recurrence. Results BioEndoCar project has defined inclusion/exclusion criteria and a strict standard operating procedure for sample collection, processing and sample storage that is followed by in all three medical centers. Since the beginning of the project (April 1st 2018) we recruited nearly 100 patients in total. Great effort was put into informing the lay and expert public about the importance of the translational studies in EC. We have established an official website (https://bioendocar.eu/) and Facebook page where we post all news concerning the project. Conclusion We expect to find different metabolic and protein profiles in patients with early stages of EC as compared to controls and in patients with poor prognosis with high risk of disease progression and recurrence as compared to those with favorable prognosis. The BioEndoCar project is currently ongoing. Disclosure Nothing to disclose.

Introduction/Background Endometrial cancer (EC) is the most frequent gynecological malignancy in more developed countries. Although the majority of patients are diagnosed at an early stage and cured by hysterectomy, the cancer recurs in about 20% patients with no sign of advanced/metastatic disease with limited response to systemic therapy. Novel biomarkers for EC would be invaluable for preoperative stratification of patients as low/high-risk, detection of primary and recurrent disease and thus enabling personalized therapeutic approaches. Angiogenesis plays an important role in the development and progression of several types of cancer, including EC. This process of is controlled by angiogenic factors (AF). Currently, AF have been studied in some malignancies but their role in EC has not been determined yet. In our study, we analyzed plasma concentration of 20 different AF in patients with the endometrioid type of EC. Methodology Prospective case - control study of women who underwent surgical treatment at the University Medical Centre Ljubljana (38 patients with endometrioid EC, 38 control patients with prolapsed uterus or myoma). Plasma samples were measured using commercially available kit that enables simultaneous determination of 20 different AF with the Luminex xMAP multiplexing technology. Results Plasma levels of sTie-2 (soluble angiopoietin-2) showed significantly decreased levels in patients with EC compared to the control group (p Conclusion Results of our pilot study indicate that plasma levels of different AF might have a diagnostic and/or prognostic value in endometrioid EC. Further statistical evaluation is currently ongoing. Disclosure Nothing to disclose.

A population of small stem cells with diameters of up to 5 &mu, m resembling very small embryonic-like stem cells (VSELs) were sorted from human embryonic stem cell (hESC) cultures using magnetic-activated cell sorting (MACS) based on the expression of a stem-cell-related marker prominin-1 (CD133). These VSEL-like stem cells had nuclei that almost filled the whole cell volume and expressed stem-cell-related markers (CD133, SSEA-4) and markers of germinal lineage (DDX4/VASA, PRDM14). They were comparable to similar populations of small stem cells sorted from cell cultures of normal ovaries and were the predominant cells in ascites of recurrent ovarian cancer. The sorted populations of CD133+ VSEL-like stem cells were quiescent in vitro, except for ascites, and were highly activated after exposure to valproic acid and follicle-stimulating hormone (FSH), indicating a new tool to study these cells in vitro. These VSEL-like stem cells spontaneously formed clusters resembling tumour-like structures or grew into larger, oocyte-like cells and were differentiated in vitro into adipogenic, osteogenic and neural lineages after sorting. We propose the population of VSEL-like stem cells from hESC cultures as potential original embryonic stem cells, which are present in the human embryo, persist in adult human ovaries from the embryonic period of life and are involved in cancer manifestation.

Introduction/Background. Endometrial carcinoma (EC) is the most frequent gynecological malignancy in the developed world. Currently there are no valid non-invasive diagnostic or prognostic methods available and therefore, diagnosis and treatment of EC patients is guided by histopathological and surgical findings. The lack of non-invasive diagnostic and prognostic biomarkers of EC is addressed in the current clinical study titled “Biomarkers for Diagnosis and Prognosis of Endometrial Carcinoma” (BioEndoCar; NCT03553589). Methodology. Prospective observational case - control study. Patient recruitment takes place at six medical centers (University Medical Centre Ljubljana, Slovenia; Maastricht University, The Netherlands; Lublin Medical University, Poland; University Hospital Brno, Czech Republic; IRCCS Ospedale Policlinico San Martino, Genoa, Italy; University Medical Centre Maribor, Slovenia). Plasma samples from women with diagnosed EC and controls will be examined using non-targeted and targeted metabolomic (Helmholtz Zentrum München, Germany) and semi-quantitative immune-based proteomic (Sciomics GmbH, Heidelberg, Germany) approaches. Combined blood metabolome (>850 metabolites), proteome (>900 proteins), clinical and epidemiological data will be analyzed (University of Tartu, Estonia) in order to construct diagnostic/prognostic algorithms for early diagnosis of EC and to identify patients with low/high risk for cancer progression and recurrence. Results. BioEndoCar project has defined inclusion/exclusion criteria and a strict standard operating procedure for sample collection, processing and sample storage that is followed in all medical centers. Recently, the first milestone of the project was achieved: Since the beginning of the project (April 1st, 2018) more than 440 patients were recruited. Currently, proteomic analysis is ongoing: Using a selected cohort (100 patients), the discovery phase will allow to identify and select promising protein biomarker candidates, which will be validated on a separate cohort composed of 300 patients. Great effort was put into informing the lay and expert public about the importance of the translational studies in EC. BioEndoCar project has been presented at the ENITEC meeting and the ESGO congress. We have established an official website (https://bioendocar.eu/) and we are updating the community on the progress of the study using social media (https://twitter.com/car_endo). Conclusions. Within the project, we expect to find different metabolic and protein profiles in patients with early stages of EC as compared to controls and in patients with poor prognosis with high risk of disease progression and recurrence as compared to those with favorable prognosis. Citation Format: Eva Hafner, Špela Smrkolj, Andrea Romano, Henrica MJ Werner, Andrzej Semczuk, Aleksandra Kaminska, Aneta Adamiak-Godlewska, Dmytro Fishman, Jaak Vilo, Camille Lowy, Christoph Schröder, Janina Tokarz, Jerzy Adamski, Vít Weinberger, Markéta Bednaříková, Petra Vinklerova, Simone Ferrero, Fabio Barra, Iztok Takač, Jure Knez, Tea Lanišnik Rižner. BioEndoCar: in search of new Biomarkers for Diagnosis and Prognosis of Endometrial Carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 464.

Onkologija, leto XXII, št. 1, junij 2018, Onkologija, Volume XXII, No. 1, June 2018

ObjectiveThe objectives of this study were to assess cancer stem cell–related marker NANOG expression in ovarian serous tumors and to evaluate its prognostic significance in relation to ovarian serous carcinoma.MethodsNANOG protein expression was immunohistochemically evaluated in the ovarian tissue microarrays of 20 patients with benign ovarian serous tumors, 30 patients with borderline ovarian serous tumors, and 109 patients with ovarian serous carcinomas, from which 106 were of high-grade and 3 of low-grade morphology Immunohistochemical reaction was scored according to signal intensity and the percentage of positive cells in tumor samples. Pursuant to our summation of signal intensity and positive cell occurrence, we divided our samples into 4 groups: NANOG-negative, NANOG–slightly positive, NANOG–moderately positive, and NANOG–strongly positive group. Complete clinical data were obtained for the ovarian serous carcinoma group, and correlation between clinical data and NANOG expression was analyzed.ResultsA specific brown nuclear, or cytoplasmic reaction, was considered a positive NANOG staining. In terms of the ovarian serous carcinoma group, 69.7% were NANOG positive, 22.9% slightly positive, 22.9% moderately positive, and 23.9% strongly positive. All NANOG-positive cases were of high-grade morphology. Benign and borderline tumors and low-grade serous carcinomas were NANOG negative. There was no significant correlation between NANOG expression and clinical parameters in terms of the ovarian serous carcinoma group.ConclusionsPositive NANOG expression is significantly associated with high-grade ovarian serous carcinoma and is absent in benign, borderline, and low-grade serous lesions. In our study, there was no correlation between NANOG expression and clinical parameters, including its use in the prognosis of ovarian serous carcinoma.

Objectives To evaluate the diagnostic and prognostic potential of preoperative serum CA-125 and HE4 levels in patients with endometrial cancer. Methods Prospective case–control study of 133 women who underwent surgical treatment at the University Medical Centre Ljubljana (64 patients with endometrial cancer, 69 control patients with prolapsed uterus or myoma). Serum CA-125 and HE4 levels were determined using electrochemiluminescent assays. Results Serum CA-125 and HE4 levels were significantly higher in patients with endometrial cancer, compared to the controls ( p =2.67×10 −4 , 1.36×10 −7 , respectively). A diagnostic model that combines serum CA-125 and HE4 levels and body mass index separated patients with endometrial cancer from controls, with AUC of 0.804, sensitivity of 66.7%, and specificity of 84.6%. Serum HE4 levels showed good prognostic potential and stratified the patients according to presence/absence of deep myometrial invasion ( p =0.001) or lymphovascular invasion ( p =0.003), with AUCs of 0.78 and 0.81, respectively. In low-risk patients with grade 1 and 2 endometrioid cancer for whom lymphadenectomy can be avoided, HE4 allowed stratification according to deep myometrial invasion ( p =3.39×10 −4 ), with AUC of 0.84. Although median HE4 levels were higher in patients with lymphovascular invasion, this difference did not reach significance ( p =0.06). Conclusions A model based on preoperative serum CA-125 and HE4 levels and body mass index has good diagnostic accuracy for separation of patients with endometrial cancer and control patients. In patients with endometrial cancer, serum HE4 levels allow prediction of deep myometrial and lymphovascular invasion.

Objective : In Slovenia the opportunistic cervical cancer (CC) screening programme has been performed within the regular gynaecological practice since 1960. The incidence rate 28.8/10 5 decreased to 16.1/10 5 in 1982, and increased to 23/10 5 in 1996. To explain the increased CC incidence the patients' screening histories, occurrence of symptoms, and details of preventive measures were studied on the basis of medical records and questionnaire. Errors of cytological screening were analysed by reviewing previous smears. Material : The answers obtained from 324 women, treated for CC in the period 1995–2000, were analysed in relation to age, stage and histology. The mean women's age was 46.76 ± 13.07 (S.D.) years (range 23–85 years). After therapy, 271 patients were followed-up by the end of January 2004, (mean follow-up time 80.3 ± 20 S.D. months, range 29.7–110.3 months). Statistical analysis was performed using Chi-square test. Results : In 208 (80%) cases, CC was detected in stage 1, in 43 (17%) in stages 2A to 3B. Squamous-cell carcinoma (192, 74.1%) was followed by adenocarcinoma (61, 23.5%) and (5, 1.9%) other malignancies. The screening interval ranged from 6 months to 4 years. Statistically significant differences existed between clinical and screening variables. CC was diagnosed in higher stages in women who were ignorant of the Pap test. Re-screened smears ( n = 126) showed 27.8% of false negative results. Conclusions : The reasons for high incidence of CC are poor performance of cytological screening, failures in gynecological examinations and diagnostic procedures, and the patients' negligence of attending regular screening.

Cervical cancer, the second most common cancer in women, develops through well-defined precursor lesions with potential to progress to invasive disease if not properly detected and eradicated. In cervical carcinogenesis, human papillomavirus (HPV) plays an important causal role. Besides the evidental causal role in cervical carcinogenesis, HPV is an important prognostic factor for disease progression as well (Syrjanen, 2000). Early invasive carcinoma is an intermediate state in the development of invasive carcinoma from a cervical intraepithelial neoplasia. According to clinical experience, the early stage of invasion has much better prognosis when compared to an advanced invasive cancer. This warrants the recognition of microinvasive carcinoma (MIC) as a separate entity among cervical cancer that is not visible at inspection, and therefore only diagnosed by histological examination of a biopsy specimen that contains the complete lesion (Wright et al., 1994).