UNIVERSITY OF MEDICINE AND PHARMACY OF CRAIOVA FACULTY OF GENERAL MEDICINE DOCTORAL THESIS SUMMARY

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1 UNIVERSITY OF MEDICINE AND PHARMACY OF CRAIOVA FACULTY OF GENERAL MEDICINE DOCTORAL THESIS SUMMARY CLINICAL AND PARACLINICAL CORRESPONDENCES IN EPITHELIAL TUMORS OF THE OVARY Thesis Coordinator, Prof. Univ. Dr. NICOLAE RÂCĂ Doctoral Student, LORENA DIJMĂRESCU CRAIOVA

2 TABLE OF CONTENTS PART I. STATE OF KNOWLEDGE CHAPTER 1. OVARY - BETWEEN NORMALITY AND PATHOLOGY 1.1. INTRODUCTION EPIDEMIOLOGY ETIOLOGY AND RISK FACTORS ETIOLOGICAL MECHANISMS OF OVARIAN CARCINOGENESIS CELLULAR MECHANISMS OF CARCINOGENESIS... 9 CHAPTER 2. STRUCTURE AND INFRASTRUCTURE OF NON TUMORAL AND TUMORAL OVARIAN LESIONS 2.1. Histological classification of ovarian tumors Stromal and follicular non - tumoral modifications Tumoral lesions CHAPTER 3. POSITIVE DIAGNOSIS OF OVARIAN TUMORS 3.1. Anamnesis and clinical diagnosis Paraclinical diagnosis Imagistic examination Immunological diagnosis Histopathology and immunohistochemistry of ovarian tumors CHAPTER 4. MALIGNANCY SCORES APPLIED TO OVARIAN PATHOLOGY 4.1. OCSI - Ovarian Cancer Symptom Index RMI Risk malignancy index OVA ROMA (Risk of Ovarian Malignancy Algorithm)... 42

3 II. SPECIAL PART CHAPTER 5. PREREQUISITES, OBJECTIVES AND HYPOTHESIS OF THE DOCTORAL THESIS 5.1. SCOPE AND OBJECTIVES OF THE STUDY MATERIAL AND METHOD Clinical and ultrasound evaluation Immunology study Classification of patients per risk groups through the calculation of malignancy scores Histological and immunohistochemistry study Statistical processing of data CHAPTER 6. CLINICAL STUDY. STATISTICAL ANALYSIS 6.1. General data of the study groups General features of the group to be studied Clinical study on the ovarian pathology CHAPTER 7. ULTRASOUND STUDY IN THE DIAGNOSIS OF OVARIAN LESIONS 7.1. Clinical ultrasound study Ultrasound and histopathological correlations Statistical analysis Results of the statistical analysis for the Sassone ultrasound score Results of the statistical analysis for the value of velocimetry indices Evolution of ovarian lesions upon menopause CHAPTER 8. IMMUNOLOGY STUDY IN THE DIAGNOSIS OF OVARIAN LESIONS 8.1. Use of tumoral biomarkers Use of CA125 and HE4 in pre-surgery evaluation of the adnexal tumor masses Correlations of the CA125 and HE4 levels with the type of histopathological lesion Statistical analysis Results of the statistical analysis for CA Results of the statistical analysis for HE

4 8.3. Serological analysis of the intracystic fluid CHAPTER 9. HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY DIAGNOSIS OF OVARIAN LESIONS 9.1. Histopathological study of ovarian tumors Immunohistochemistry diagnosis of ovarian tumors CHAPTER 10. ULTRASOUND, SEROLOGICAL AND HISTOPATHOLOGICAL CORRELATIONS IN THE DIAGNOSIS OF OVARIAN LESIONS Classification of patients in a group of risk by using the RMI score Use of RMI in pre-surgery evaluation of an ovarian tumoral mass RMI diagnosis correlations with the type of histopathological lesion Results of the statistical analysis for the RMI Score Study on the diagnosis correlation between the HE4 serum marker and the ROMA Algorithm with ovarian lesions Use of the ROMA Algorithm in pre-surgery evaluation of ovarian tumoral masses Correlations of values obtained through the ROMA Algorithm with results of the histopathological examination Results of the statistical analysis for the ROMA Algorithm DISCUSSIONS CONCLUSIONS BIBLIOGRAPHY

5 KEYWORDS Ovarian lesions, progressive ovarian lesions, ovarian cancer, early diagnosis, ultrasound score, MRI, HE4, ROMA Algorithm INTRODUCTION Found on the border between disciplines, disputed by endocrinologists, anatomic-pathologists, and gynaecologists, the part that represents, in the happiest event, only 0.01% of the weight of a woman, is still a great unknown, despite the expansion of biomedical science and technique. Screening for ovarian cancer is a challenge for clinicians, it is an insufficiently explored subject on national level, and internationally, although there have been set a number of criteria, results are still quite controversial and incompletely studied. An early pre-surgery diagnosis, by non-invasive methods of the benign/malignant nature of the adnexial masses, that would facilitate the choice of an optimal therapeutic stance, which includes also the conservative attitude, is necessary as a very important aspect is the incidence of these formations during the reproductive period. Pathogenesis of the ovarian carcinoma is not known due to the lack of a progression model of the tumor. Based on a review of the most recent clinical-pathological and molecular studies, surface epithelial neoplasia is divided into two broad categories: type I and type II, which correspond to the two main tumorigenesis paths. Tumors of the type I include lower-grade malignant tumors, occurring in a progressive manner from boundary tumors, and tumors of type II, which include high-grade malignant tumors and for which the precursor morphological lesions have not been identified, the so-called "de novo" development tumors [17,18,34]. In Romania, ovarian cancer is the third cause of death by malignant pathology, holding the fifth position, after the incidence of breast cancer, cervical, colorectal and lung cancers. The worldwide incidence of ovarian cancer is 2%, and in Romania it reaches 4.6% [153]. Alarming results for our country are probably due both to non-existent or inoperative screening programs and to the lack of management on the prevention of these diseases and their early detection. The polymorphism of ovarian tumors has an embryo-genetic, histological, clinical and progressive substrate, fact that explains the difficulties of classification, lack of consensus. From the embryology perspective, the ovary is a mosaic of differentiated tissues (wrapp ing epithelium, ovarian stroma, conjunctive tissue, vessels, nerves, lymphatic) and non-differentiated (cells and vestiges of the Wol ff channels, cells with phase antigen derived from the three embryonic foils/ectoderm, endoderm, mesoderm). Ovarian cancer symptoms are related to the presence of an adnexial part and are often vague and non-specific. The main diagnosis objective of assessing such a formation is to determine whether it is benign or malignant. It is estimated that 5-10% of women go for a surgical procedure for a suspicion of ovarian cancer, which is confirmed in % of the cases. Considering that the majority of adnexial

6 formations are benign, it is very important to be able to determine before the surgery if a patient shows an increased risk of ovarian cancer, in order to approach an appropriate therapeutic stance. Owing to the desire and the need to identify a possible resolution of the problems posed by the complex appearance of the tumoral ovary, the incidence of which is increased during the reproductive and post-menopause period, I considered necessary to deepen the clinical-therapeutic inter-relations and physiological, pathophysiological, histopathology and immunohistochemistry aspects through the preparation of the paper herein, with the title Clinical and paraclinical correspondences in epithelial tumors of the ovary. The complexity and importance of the themes explored guided me in my intention to carry out a detailed study in this direction, because the diagnosis overvaluation is frequent, and the impact of noslogical classification as well as the inter-relation with the quality of life of women (post-surgery status and loss of the reproductive potential) represent a major concept that must be heeded. The scope pursued was to specify the correlation between early diagnosis of ovarian cancer, postsurgery, according to morphological and histological appearance, but also pre-surgery, with malignancy scores through the use of tumoral markers with a high level of sensitivity and specificity. The objectives proposed to be achieved are as follows: Pathophysiological implications and practical implications of the risk factors and nontumoral ovarian lesions The correlation between the degree of the ovarian lesion and the early diagnosis, highlighted by the use of malignancy scores (symptomatic, ultrasound and serum) Correlation between different ultrasound parameters with an early diagnosis and standardization of an ultrasound examination Correlation between cutt-of values of the tumoral markers with the histopathological appearance of the ovarian lesion. MATERIAL AND METHOD In addressing this task, I performed a study carried out on a group 329 patients with adnexial tumor formations, examined and treated in the period from January 2005 to March The study was carried out at the Obstetrics-Gynaecology Clinic of the Filantropia Clinical Municipal Hospital and the Emergency Clinical County Hospital of Craiova, the patients being evaluated by ultrasound and serologically, and classified in a group of risk which led to the establishment of the therapeutic protocol with or without surgery, completed with obtaining the histopathological data. There were selected patients with ages between 19 and 71 years who showed adnexial tumor formations, diagnosed by clinical and ultrasound means in the Gynaecology service, but also other specializations (gastroenterology and internal medicine) by non-specific abdominal symptoms. Ultrasound aspects of inclusion in the group were represented by the appearance of suspicious ultrasound images. A

7 postulate of ultrasound examination for ovaries is noted, namely that the ovary which is not visible from the ultrasound perspective is considered to be normal. During the period mentioned, patients under study, by filling out the selection file and signing of an informed consent, have undergone an investigative protocol establishing the set of quantifiable parameters, specific to cases tracking. There was considered the clinical and serological evaluation, the management adjusted to each case being prepared subsequently. The personal study is emphasized on the following subchapters: Clinical and ultrasound evaluation Immunological study Classification of patients within risk groups, by calculating the malignant risk index MRI ROMA Histology and immunohistochemistry study Statistical processing of data RESULTS Following the clinical study performed, the breakdown by age group reveals a higher incidence in the age group of years, 121 cases (36.7%) and years, 76 cases (23.1%), namely during the fertile period of women. The higher rate of occurrence correlates in the age periods with both a more detailed investigation into the breeding programmes, but also with a more frequent infections pathology, by early start of the sexual life, sexual transmission diseases, multiple partners. Per the study performed, I noticed that these epidemiological associations, due to low sensitivity and weak positive predictive value, cannot be implemented with a screening value, for the purpose of early diagnosis of ovarian cancer, as there cannot be outlined a phenotype of the patient with ovarian pathology. Following the histopathology and immunohistochemistry study I found that, out of all 122 cases with the clinical diagnosis of ovarian tumor, pseudotumors represented only 19,67% of the cases, the casuistic being dominated by proper ovarian tumors which accounted for over 80% of the cases. With pseudotumors, there were diagnosed histological lesions of type: follicular, lutein cysts, ovarian fibromatosis and the policystic ovary syndrome, the most widely represented being the follicular and lutein cysts (66.66% of pseudotumors). In regards to the pre-surgery diagnosis of ovarian tumors, following the ultrasound study, a percentage of 15.5% of cases with the ovary of more than 10 cm in size was diagnosed by ultrasound and correlated with the histopathological examination of malignant lesion. For tumoral masses of less than 10 cm, the percentage of correct diagnosis of malignant lesion was of about 5%, which reveals that even though it is the most reliable ultrasound feature, it is also the least specific one. In the literature, it is considered that an ovarian volume under 20 cm3, in women at pre-menopause, and under 10cm3 in women at post-menopause is associated with a decreased risk of malignancy [26, 61].

8 Making the ROC curve for the Doppler ultrasound score showed a sensitivity of and specificity of for this prediction score, with a limit of 0.4 to PI, this limit being useful in the prognostic usage of the score value for the probability of malignancy. Following the immunological study regarding CA 125 I found that it has made a major contribution in the management of patients with benign or malignant adnexial tumors. The use of the CA 125 serum level in the pre-surgery evaluation of adnexial tumor masses cannot be used as a single tool for the prediction of malignancy. It can be used as an indicator of sensitivity for the progression and recurrence of the neoplasic disease, when its serum levels correlate with an ultrasound diagnostic, which increases the ability to distinguish between benign and malignant ovarian pathology. The positive predictive value of CA 125 was 94% for women in post-menopause, with a negative predictive value of 80%, with no statistical differences in correlation with other studies. For patients in pre-menopause, CA 125 had a sensitivity of 85%, with specificity of 88% and a positive predictive value of 83%. However, considering that the sub-evaluation was 0%, we can say that, normal levels of the serum marker represent a definite prediction factor for ovarian non-malignant lesions. Through making the ROC curve, I have also established the sensitivity and specificity, when the MRI score takes on different values, noticing a sensitivity of and specificity of 0.859, as useful prognostic limits the use of the MRI score for the probability of malignancy. HE4 levels are increased in more than 50.0% of the cases where CA125 is not expressed; results of the combined test have a sensitivity and specificity greater than the CA125 as a single marker; correlation with histopathological findings show that CA125 and HE4 or HE4 alone has a higher sensitivity to patients with ovarian cancer; as a single marker HE4 was more sensitive than CA125; the combination of HE4 and CA125 was more sensitive than a single marker. I found that HE4 and ROMA have displayed the best diagnostic performance. HE4 in statistical analysis has shown a sensitivity and specificity of 0.950, respectively, as useful limits in the prognostic usage of the HE4 value for the probability of malignancy. CONCLUSIONS 1. The early diagnosis of ovarian cancer is still a challenge to modern medicine. Evaluation of adnexial masses constitutes a continuous progressive problem worldwide, with a multidisciplinary approach: gynaecological, oncological, immunological, histopathological, imaging, as structured in the international scientific specialized events. 2. In recent years, there has been an explosion of important progresses in biomedical engineering, but at the moment, there is no biomarker with a 100% sensitivity and specificity for the precise detection of early stage epithelial ovarian cancer.

9 3. CA-125: Is not an ideal serum biomarker for the presence of ovarian cancer. CA-125 does not have a sufficient sensitivity or a high specificity to justify its use as a unique screening marker for ovarian cancer. 4. Single biomarker for detection testing: mission impossible? The discovery of specific markers is very difficult. The three major obstacles are molecular heterogeneity between tumors, prevalence of noncancerous diseases that reduces the specificity of the biomarker and production and its low concentration especially for the early stage of the disease where cancerous lesions are minimal. 5. Patients diagnosed with an ovarian disease, enrolled in the original study (329) have been carefully assessed after completing specific screening sheets and guided towards conservative or surgical therapy ( %). Rigorous selection of the patients undergoing ovarian exeresis was confirmed by follow-up of these cases: over the five years of personal research, resulting in no patient of the group under study presented signs of potentially evolutionary ovarian pathology. 6. The study of the selection files outlines the idea that ovarian tumor pathology is more common in the population segment with ages overlapping with the reproductive period, especially in urban areas, while the malignant pathology is the preserve of the 5th or 6th decade of life. Before the serological and sonographic diagnosis, it is necessary to establish particular features, related to the various variables: age, origin, menstrual status, pregnancy status, diet habits, smoking, infectious pathology, which can include the patient in a risk group. 7. The personal study defines the endocrine-social profile of the patients that may develop an ovarian lesion with surgical indication, during a certain stage of life and which, in particular, should be subject to supported gynaecological examinations: patient in the reproductive period with menstrual disorders, with ovarian volume increased, CA125 increased. 8. Ovarian disorders clinic. For the age group of years, lack of pelvi-abdominal pains and symptomatology predominate, in relation to the inflammatory phenomena. Irregular bleeding appears especially in the age group of years, i.e. pre-menopause, being perhaps associated with preclimax menometroragy which have necessitated a closer investigation. Urinary and digestive disorders are mostly the preserve of menopause. 9. From the histopathological point of view, ovarian lesions constellation was dominated by benign lesions (%). The maximum incidence of tumors in the surface epithelium of the 5th decade for benign forms, and in the 6th decade for malignant forms suggests the possible transition from benign to malignant. In addition, the presence within the same tumor of borderline and malignant or benign aspects, argues this evolutionary possibility from benign to malignant, passing through the borderline state. 10. Immunohistochemistry. For a proper diagnosis, some poorly differentiated malignant serum tumors require complementary immunohistochemistry investigations with the help of a panel of antibodies including CK7, CK 20, CA125, CEA, estrogen and progesteron receptors and oncoprotein p53.

10 11. 3D ultrasound allows complex analysis of the ovarian formations structure, in some cases being able to replace computerized tomography. Values of the vascular parameters 3D-PD seem to be a promising tool for the prediction of ovarian cancer in complex vascularized adnexial masses. 12. The positive predictive value of CA 125 was of 94% for women in post-menopause, with a negative predictive value of 80%, without existing statistical differences in correlation with other studies. For patients in pre-menopause, CA125 detection had a sensitivity of 85%, with specificity of 88% and a positive predictive value of 83%. 13. Making the ROC curve for the Sassone ultrasound score showed us a sensitivity of and specificity of of this prediction score with a limit of 0.4 to PI, this limit being useful in prognostic usage of the score value for the probability of malignancy. 14. MRI. Through making the ROC curve for MRI, I established the sensitivity and specificity; when the MRI score gets various values, there is distinguished a sensitivity of and a specificity as useful prognostic limits of the MRI score values for the probability of malignancy. 15. HE4. ROC curve calculation showed us a sensitivity and specificity of 0.950, respectively, as useful limits in the use of HE4 prognostic value for the probability of malignancy. 16. ROMA is a simple scoring system that gives excellent diagnostics performance for the detection of EOC in post-menopause, but not in pre-menopause. The ROMA - HE4 Algorithm and CA 125 -applied successfully classified 93.8% of the EOC correctly marked as being with high-risk. 17. The combination of increased levels of serum for CA 125 and HE4 correlates with the risk of epithelial ovarian cancer, and an increased level of CA 125, without an increased level of HE4 correlates with a benign condition. An increased level of HE4 and normal CA 125 suggests the presence of another type of cancer (for example, the endometrium type). 18. Transvaginal ultrasound is the most useful in the correct diagnosis of the adnexial masses in post-menopause, viewing the ovaries being difficult for older women, especially if they have a history of hysterectomy or an increased BMI. The presence of ovarian tumors is common in menopause; they have a dynamic evolution, most of them changing the dimensions between 2 successive examinations. 19. Doppler assessment should complement the examination of a tumoral ovary. Sonographic tracking is recommended in the case of simple ovarian cysts, less than 3 cm, surgery being recommended in cases of cysts with large and complex aspect, with modifications of the velocimetry indices. 20. While the sonographic morphological characteristics represent the first criteria for benign/malignant differential diagnostic, the study of the intracystic liquid concerning CA125, E2, P may confirm the diagnosis. The correlation between the serum level and the intracystic level of CA125 with different variations may set accurately the diagnostic. A profile of differential diagnostic of benign/malignant ovarian lesions may be obtained through the combination of these criteria. However, the histopathological confirmation is necessary in most cases.

11 21. The tumoral ovary correctly investigated with the completion of the clinical - paraclinical stages of diagnostic may be subjected to a conservator surveillance protocol in particular for patients who have not completed the family planning. 22. Obtaining new data in terms of quality of life. As a quintessence of these years of study, I have been concerned about the possibilities of improving the quality of life for women with ovarian pathology by explaining the concept of an ovarian lesion, with lowering the impact of notion of ovarian tumor, which is widely used. It is accepted in the literature the term of tumor and non-tumor ovarian lesion. I have also noted the negative impact of the existence of an ovarian tumor during the reproductive period, patients often opting for surgery, before completing the diagnostics platform, even at the risk of not concluding their family planning. 23. The use of a noninvasive means of discrimination among the malignant ovarian masses and the benign lesions is important considering that approximately 20 percent of women will develop an ovarian cyst at some point in their lives. Without adequate means to discern the potential of these malignant tumors, a considerable proportion of these women will be subjected to unnecessary surgery.

12 Curriculum vitae Europass Personal information Surname(s) / First name(s) Address(es) Dijmarescu, Anda Lorena 11, Dezrobirii, Apartment House E 9, Apartment no.3, Craiova, Romania Telephone(s) Cell: Fax(es) (s) lorenadijmarescu@yahoo.com Nationality Romanian Date of birth 10 th of September 1972 Work experience Occupation or position held Main activities and responsibilities Name and address of employer Type of business or sector Dates University Assistant Professor Practical works - normal and pathological obstetrics UNIVERSITY OF MEDICINE AND PHARMACY Faculty of Midwives and Nurses - Craiova. Teaching and research activities: teaching; hours of practical works and seminars; publishing articles in international and specialization magazines and indexed magazines ISI - WEB OF SCIENCE. Dates Occupation or position held Specialist Physician, Obstetrics Gynaecology Main activities and responsibilities Name and address of employer Type of business or sector Education and training Title of qualification awarded Principal subjects/occupational skills covered Name and type of organization providing education and training Level in international classification Title of qualification awarded Clinical practice City Hospital of Strehaia, detached at the University Hospital of Craiova. Clinical practice. Dates Obstetrics Gynaecology Resident Physician Obstetrics Gynaecology University of Medicine and Pharmacy of Craiova Dates DOCTORAL Student in Medicine

13 Principal subjects/occupational skills covered Name and type of organization providing education and training Level in international classification University education Title of qualification awarded Principal subjects/occupational skills covered Name and type of organization providing education and training Level in international classification Specialization Obstetrics - Gynaecology Competency in Reanimation Of The New Born Competency in Ultrasound for Obstetrics - Gynaecology Competency in Colposcopy Module I Hysteroscopy Psycho Pedagogical Module graduated with the thesis University of Medicine and Pharmacy of Craiova Dates BACHELOR DEGREE IN Medicine General Medicine University of Medicine and Pharmacy of Craiova University education Personal skills and competences Mother tongue(s) Romanian Other language(s) Self evaluation Understanding Speaking Writing European level (*) Listening Reading Participation to a conversation English Speech Writing assertion B2 Independent user B2 Independent user B2 Independent user B2 Independent user B2 Independent user French B1 Beginner B1 Beginner B1 Beginner B1 Beginner B1 Beginner Social skills and competences Team spirit, capacity to adjust and effective communication, reliability, dynamic and sociable spirit acquired through professional activity. Competency Ultrasound in Obstetrics and Gynaecology, Colposcopy, Reanimation of the new born, Psycho - Pedagogy Organizational skills and competences Computer skills and competences The ability to engage in teamwork, ability of synthesis and mobilization, optimal management of time, autonomy, initiative, decision-making skills, creativity, dynamism, efficiency. Microsoft Office: Word, Excel, Internet navigation, use of the Blackboard system - elearning type - for evaluation and teaching.

14 ARTICLES PUBLISHED IN MAGAZINES 1. Therapeutic attitude in infertility associated with serum ovary cysts. N. Râcă, Lorena Dijmărescu, Florentina Tănase, OBSTETRICS AND GYNAECOLOGT, SROB - volume 4, no. Supplement, October THE EVOLUTION OF OVARIAN INJURIES IN MENOPAUSE Lorena Dijmarescu*, Carmen Gheta**, Magda Manolea*, Florentina Tanase*, Comanescu A*, Cristina Fota *,Liliana Novac*, CRAIOVA MEDICALĂ 3. DIAGNOSIS CORRELATIONS IN OVARIAN TUMORS Lorena Dijmarescu*, Carmen Gheta**, Florentina Tanase*, Comanescu A*,Magda Manolea*, Liliana Novac*, CRAIOVA MEDICALĂ ARTICLES PUBLISHED IN VOLUMES OF INTERNATIONAL SCIENTIFIC EVENTS RECOGNIZED IN THE FIELD Correlation of the ultrasound appearance of the pseudopolicystic ovary with ureaplasma urealitycum infection, Lorena Dijmărescu, Magda Manolea, S. Cotarcea, D. Plesan, IX International Congress of Medical Sciences, Sofia, Bulgaria,13-16 May 2010 Immunohistochemical variations in case of pregnancy associated with ovarian tumors - case report, L. Dijmarescu, L. Novac, S. Cotarcea, M. Manolea T. Tanase, A. Comanescu, R. Lanoiu,S. Neamtu, S. Cerga X International Congress of Medical Sciences, Sofia, Bulgaria,13-16 May 2010 Study on pre and after surgery diagnosis correlations in ovarian tumors L Dijmarescu, ESGO, Milano, Italia, October 2011 The ovarian medicamentary stimulation Lorena Dijmarescu, N. Raca, Florentina Tanase, V. Gheorman Human Reproduction, Venice, March 10-13, 2005 Study regarding morphological velocimetrical and imunological corelation of ovarian tumor formations, Lorena Dijmarescu, Magda Manolea, Florentina Tanase, Liliana Novac Summary Volume of ESGO, The 15 th International Meeting of the European Society of Gynecological Oncology (ESGO)- Belgrad, Serbia October 2009 Other skills and competences ARTICLES PUBLISHED IN VOLUMES OF NATIONAL SCIENTIFIC EVENTS WITH INTERNATIONAL PARTICIPATION RECOGNIZED Preserving fertility in Oncology N. Râcă, Lorena Dijmărescu, Florentina Tănase- report- the 14 th Congress of Obstetrics and Gynaecology with International Participation Bucharest September 2006 Correlation of the ultrasound appearance of the pseudo-polycystic ovary with the UU infection, Lorena Dijmărescu, Smărăndiţa Cotarcea, Magda Manolea, Raluca Lînoiu, UMF Craiova, Edition XXXX,4-5 June 2010, Craiova Genetic context of the polycystic ovaries syndrome in teenagers, Liliana Novac, Magda Manolea, Lorena Dijmărescu, Lidia Boldeanu, Adela Voican, Smărăndiţa Cotarcea, Raluca Lînoiu, D. Pleşan, 5 th Congress of the Romanian Society of Endocrinological Gynaecology, Sinaia, June 2010 Diagnostics, ultrasound and hormone correlations between SOPC and the micropolycystic ovary, Lorena Dijmărescu, Smărăndiţa Cotarcea, L. Novac, Florentina Tănase, Magda Manolea, Raluca Lînoiu, 15 th National Congress of Obstetrics and Gynaecology, Bucharest, October 2010 Diagnostic correlations in ovarian tumors, Dijmarescu Lorena*, Comanescu A*, Manolea Magda *, Novac Liliana*, Niculescu Mihaela, UMF Craiova, Edition XLI, 3-4 June 2011, Craiova Caesarean surgery - the Misgav Ladach method Dijmărescu Lorena, Voinea B., Roibu Mădălina, Manolea Magda, Novac Liliana, Neaţu Alina, UMF Craiova Edition XXXVIII-a, 6-7 June 2008 Association of bacterial vaginosis with premature birth and the role of screening in vaginal infection for pregnant women Lorena Dijmărescu, T. Grigore, Liliana Novac, Magdalena Manolea, R. Pană, F. Braneţ, Alina Neaţu, Anca Groza, 9 th National Conference of the Romanian Society of Obstetrics-Gynaecology, September 2008 Cluj-Napoca Preliminary study on Hyperemesis gravidarum associated with hypothyroidia before pregnancy L. Dijmărescu, L. Novac, S. Cotarcea, F. Tănase, M. Manolea 6 th Congress of the Romanian Society of Endocrinological Gynaecology with international participation, Sinaia 7-9 Mai 2009 Diagnostics, ultrasound and hormone correlations between SOPC and the micropolycystic ovary, Lorena Dijmărescu, Smărăndiţa Cotarcea, L. Novac, Florentina Tănase, Magda Manolea, Raluca Lînoiu, 15 th National Congress of Obstetrics and Gynaecology, Bucharest, October 2010 Hormonal and ultrasound correlations in early secondary ovarian failure prediction, Lorena Dijmărescu, Smărăndiţa Cotarcea, Magda Manolea, D. Pleşan, Liliana Novac, 5 th Congress of the Romanian Society of Endocrinological Gynaecology, Sinaia, June 2010 Preliminary study on the association of thyroid autoimmune and trombophilia in pregnancies with increased risk, Lorena Dijmărescu, L. Novac, Smărăndiţa Cotarcea, Tănase Florentina, Magda Manolea, D. Pleşan, Medical Days Vasile Dobrovici, Iaşi, Mai 2010 Antenatal factors associated with the syndrome of discordant growth in twins, Lorena Dijmărescu, Novac Liliana, Magdalena Manolea, Voinea B, Pleşan D, UMF Craiova, Edition XXXIX, Craiova, 5-6 June 2009, p.346, verbal presentation, ISSN RESEARCH-DEVELOPMENT-INNOVATION PROJECTS - BASED ON CONTRACT OR GRANT -

15 Annexes PROFESSIONAL AND ACADEMIC SERVICES MEMBERSHIP IN PRESTIGIOUS PROFESSIONAL SOCIETIES IN ROMANIA AND ABROAD Romanian Society of Obstetrics Gynaecology Romanian Society of Endocrinological Gynaecology European society of Gynaecological Oncology SRCMIG