C. Landolfo

Chromosomal instability in cell-free DNA as a highly specific biomarker for detection of ovarian cancer in women with adnexal masses

Purpose: Chromosomal instability is a hallmark of ovarian cancer. Here, we explore copy-number alteration (CNA) profiling in cell-free DNA as a potential biomarker to detect malignancy in patients presenting with an adnexal mass. Experimental Design: We prospectively enrolled 68 patients with an adnexal mass, of which 57 were diagnosed with invasive or borderline carcinoma and 11 with benign disease. Cell-free DNA was extracted from plasma and analyzed by low-coverage whole-genome sequencing. Results: Patterns of chromosomal instability were detectable in cell-free DNA using 44 healthy individuals as a reference. Profiles were representative of those observed in matching tumor tissue and contained CNAs enriched in two large datasets of high-grade serous ovarian cancer (HGSOC). Quantitative measures of chromosomal instability, referred to as genome-wide z-scores, were significantly higher in patients with ovarian carcinoma than in healthy individuals or patients with benign disease. Cell-free DNA testing improved malignancy detection (AUC 0.89) over serum CA-125 (AUC 0.78) or the risk of malignancy index (RMI, AUC 0.81). AUC values of cell-free DNA testing even further increased for HGSOC patients specifically (AUC 0.94). At a specificity of 99.6%, a theoretical threshold required for ovarian cancer screening, sensitivity of cell-free DNA testing was 2- to 5-fold higher compared with CA-125 and RMI testing. Conclusions: This is the first study evaluating the potential of cell-free DNA for the diagnosis of primary ovarian cancer using chromosomal instability as a read-out. We present a promising method to increase specificity of presurgical prediction of malignancy in patients with adnexal masses. Clin Cancer Res; 23(9); 2223–31. ©2016 AACR.

Validation of the Performance of International Ovarian Tumor Analysis (IOTA) Methods in the Diagnosis of Early Stage Ovarian Cancer in a Non-Screening Population

Background: The aim of this study was to assess and compare the performance of different ultrasound-based International Ovarian Tumor Analysis (IOTA) strategies and subjective assessment for the diagnosis of early stage ovarian malignancy. Methods: This is a secondary analysis of a prospective multicenter cross-sectional diagnostic accuracy study that included 1653 patients recruited at 18 centers from 2009 to 2012. All patients underwent standardized transvaginal ultrasonography by experienced ultrasound investigators. We assessed test performance of the IOTA Simple Rules (SRs), Simple Rules Risk (SRR), the Assessment of Different NEoplasias in the adneXa (ADNEX) model and subjective assessment to discriminate between stage I-II ovarian cancer and benign disease. Reference standard was histology after surgery. Results: 230 (13.9%) patients proved to have stage I–II primary invasive ovarian malignancy, and 1423 (86.1%) had benign disease. Sensitivity and specificity with respect to malignancy (95% confidence intervals) of the original SRs (classifying all inconclusive cases as malignant) were 94.3% (90.6% to 96.7%) and 73.4% (71.0% to 75.6%). Subjective assessment had a sensitivity and specificity of 90.0% (85.4% to 93.2%) and 86.7% (84.9% to 88.4%), respectively. The areas under the receiver operator characteristic curves of SRR and ADNEX were 0.917 (0.902 to 0.933) and 0.905 (0.920 to 0.934), respectively. At a 1% risk cut-off, sensitivity and specificity for SRR were 100% (98.4% to 100%) and 38.0% (35.5% to 40.6%), and for ADNEX were 100% (98.4% to 100%) and 19.4% (17.4% to 21.5%). At a 30% risk cut-off, sensitivity and specificity for SRR were 88.3% (83.5% to 91.8%) and 81.1% (79% to 83%), and for ADNEX were 84.5% (80.5% to 89.6%) and 84.5% (82.6% to 86.3%). Conclusion: This study shows that all three IOTA strategies have good ability to discriminate between stage I-II ovarian malignancy and benign disease.

Differences in ultrasound features of papillations in unilocular‐solid adnexal cysts: a retrospective international multicenter study

To identify ultrasound features of papillations or of the cyst wall that can discriminate between benign and malignant unilocular‐solid cysts with papillations but no other solid components.

Imaging in gynecological disease: clinical and ultrasound characteristics of ovarian clear cell carcinoma

To describe the clinical and ultrasound characteristics of ovarian pure clear cell carcinoma.

OC11.03: Prospective validation of IOTA methods in the differentiation between benign and malignant adnexal masses

W. Froyman16,17, C. Landolfo16, B. De Cock16, L. Wynants16, A.C. Testa15, E. Domali14, P. Sladkevicius13, L. Savelli12, D. Franchi11, E. Epstein10,18, C. Van Holsbeke9, R. Fruscio19, M. Blanco20, J. Alcázar8, S. Guerriero7, A. Rossi6, A. Czekierdowski5, V. Chiappa4, F. Buonomo21, M.J. Kudla3, T. Bourne2,16, L. Valentin1, J.Y. Verbakel16,22, B. Van Calster16, D. Timmerman16,17 1Department of Obstetrics and Gynecology, Skåne University Hospital Malmö, Lund University, Malmö, Sweden; 2Queen Charlotte’s and Chelsea Hospital, Imperial College, London, United Kingdom; 3Clinical Department of Oncological Gynecology, Medical University of Silesia, Katowice, Poland; 4Department of Gynecological Oncology, National Cancer Institute of Milan, Milan, Italy; 5First Department of Gynecological Oncology and Gynecology, Medical University of Lublin, Lublin, Poland; 6Department of Obstetrics and Gynecology, University of Udine, Udine, Italy; 7Department of Obstetrics and Gynecology, Azienda Ospedaliero Universitaria di Cagliari, Cagliari, Italy; 8Department of Obstetrics and Gynecology, Clinica Universidad de Navarra, School of Medicine, Pamplona, Spain; 9Department of Obstetrics and Gynecology, Ziekenhuis Oost-Limburg, Genk, Belgium; 10Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden; 11Preventive Gynecology Unit, Division of Gynecology, European Institute of Oncology, Milan, Italy; 12Department of Obstetrics and Gynecology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 13Department of Obstetrics and Gynecology, Skåne University Hospital Malmö, Lund University, Malmö, Sweden; 14First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 15Department of Oncology, Catholic University of the Sacred Heart, Rome, Italy; 16Department of Development and Regeneration, KU Leuven, Leuven, Belgium; 17Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; 18Department of Women and Children’s Health, Karolinska Institutet, Stockholm, Sweden; 19Clinic of Obstetrics and Gynecology, University of Milan-Bicocca, San Gerardo Hospital, Monza, Italy; 20Department of Obstetrics and Gynecology, Ospedale Garibaldi, Catania, Italy; 21Institute for Maternal and Child Health – IRCCS ‘‘Burlo Garofolo’’, Trieste, Italy; 22Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom

OC17.04: Intra‐ and interobserver agreement using the MUSA terminology for ultrasonographic features associated with ill‐defined lesions

462 articles were discarded. Full text of 41 articles was reviewed, of which 33 were discarded and 8 articles that met all the inclusion criteria were finally selected for evaluation. A total of 4382 women were included. The prevalence of EC/HEA was 0.03% (72 cases). The relative risk of EC/EHA in the ≥11mm group was 3.1 (95% CI: 1.5–6.4). Moderate heterogeneity was observed between studies (I2: 44.6%, p = 0.08). Conclusions: The risk of EC/HEA in asymptomatic postmenopausal women with endometrial thickness ≥11mm is three times greater than in women with endometrial thickness <11mm. The indication of endometrial biopsy in these cases seems justifiable. OC17.04 Intraand interobserver agreement using the MUSA terminology for ultrasonographic features associated with ill-defined lesions C. Kjaergaard1, T. Van den Bosch6, C. Exacoustos13, G. Manegold-Brauer12, B.R. Benacerraf8, W. Froyman11, C. Landolfo14,15, M. Condorelli7, A.G. Egekvist9, H. Josefsson10, F. Leone2, L. Jokubkiene5, L. Zannoni4, E. Epstein10, A. Installé3, M. Dueholm1 1Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Obstetrics and Gynecology, DSC L Sacco, Milan, Italy; 3KU Leuven Department of Electrical Engineering (ESAT) – STADIUS, KU Leuven, Leuven, Belgium; 4Obstetrics and Gynecology, S Orsola Malpighi Hospital, Bologna, Italy; 5Department of Obstetrics and Gynecology, Skåne University Hospital, Malmö, Sweden; 6Obstetrics and Gynecology, University Hospital Leuven, Leuven, Belgium; 7Erasmus University Hospital, Brussels, Belgium; 8Harvard Medical School, Brookline, MA, USA; 9Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark; 10Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden; 11University Hospital KULeuven, Leuven, Belgium; 12Department of Gynecologic Ultrasound and Prenatal Medicine, Women’s Hospital, University of Basel, Basel, Switzerland; 13Department of Biomedicine and Prevention, Obstetrics and Gynecology Clinic, Università degli Studi di Roma ‘‘Tor Vergata’’, Rome, Italy; 14Department of Development and Regeneration, KU Leuven, Leuven, Belgium; 15Department of Obstetrics and Gynecology, Leuven University Hospital, Leuven, Belgium Objectives: To evaluate intraand interobserver agreement in the reporting of ultrasonographic features associated with ill-defined lesions using the Morphological Uterus Sonographic Assessment (MUSA) terms. Methods: Multicentre clinical study, using three-dimensional (3D) transvaginal ultrasound clips of 30 premenopausal women suffering from abnormal uterine bleeding and/or menstrual pain. All women had transcervical deep resection of the endometrium and inner myometrium (n=25) or hysterectomy (n=5) and histopathological examination for adenomyosis (AM). Twelve women had a confident diagnosis of AM. Thirteen gynecologists with high (n=7) or medium (n=6) experience in TVS evaluated each 3D ultrasound clip in two rounds, with a two months’ interval, blinded to histopathology. The evaluation was managed online with Clinical Data Miner software and the presence of ill-defined lesions and associated features, as defined in MUSA, were recorded. Results are presented as interobserver agreement during the first evaluation and intraobserver agreement between first and second evaluation.