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Purpose Sphingosine-kinase-1 (SPHK1) is a key enzyme of sphingolipid metabolism which is involved in ovarian cancer pathogenesis, progression and mechanisms of drug resistance. It is overexpressed in a variety of cancer subtypes. We investigated SPHK1 expression as a prognostic factor in epithelial ovarian cancer patients. Methods Expression analysis of SPHK1 was performed on formalin-fixed paraffin-embedded tissue from 1005 ovarian cancer patients with different histological subtypes using immunohistochemistry. Staining intensity of positive tumor cells was assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. Results In our ovarian cancer collective, high levels of SPHK1 expression correlated significantly with complete surgical tumor resection (p = 0.002) and lower FIGO stage (p = 0.04). Progression-free and overall survival were further significantly longer in patients with high-grade serous ovarian cancer and overexpression of SPHK1 (p = 0.002 and p = 0.006, respectively). Conclusion Our data identify high levels of SPHK1 expression as a potential favorable prognostic marker in ovarian cancer patients.

Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883., publishedVersion

Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer. In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅109/L. Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84–1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00–2.14, P = 0.047). The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.

Introduction/Background* According to current guidelines fertility-sparing treatment (FST) in cervical cancer patients should follow the same principles as in patients without fertility preservation. The literature from the last years, however, show a trend towards less-radical procedures. Although oncological outcomes are reported to be equal or better than in non-FST, published groups are small, mostly single institutional, inclusion criteria vary, and treatment is not uniform. The aim of this study was to collect retrospective data from multiple institutions across several countries on oncological and reproductive outcomes after FST. Methodology Included were cervical cancer patients between 18–40 years with stages ≥ IA1+LVSI, who underwent any type of FST and completed follow-up of at least 6 months. Patients were eligible irrespective of neoadjuvant chemotherapy, histotype or tumour grade. Result(s)* Altogether 733 patients from 44 centers in 13 countries were eligible for analyses. Median follow-up of the whole cohort was 6 years (1.2–14.5). More than half of the cases had stage IB1 (54.2%; 397/733). Mean age of patients was 32 years and two thirds were nulliparous (484/733). Most common surgical procedure was conization (48%). Repeated cervical surgery was performed in 161 patients (21.9%), most frequently re-conization (57.8%). Less than half of the patients (49.2%; 361/733) attempted to conceive after treatment. Out of them, 138 (38.2%) got pregnant and 100 (27.7%) successfully delivered. Pre-cancer recurrence was diagnosed in 22 (3%) patients, 51 (7%) patients had cancer recurrence and 19 (2.6%) died of disease. Three times higher risk of recurrence was observed in tumours ≥ 2 cm in comparison to smaller tumours (19.4% vs. 5.7%; p Conclusion* Data from the real life practice showed that FST in cervical cancer patients is safe in patients with HPV related tumours smaller than 2 cm. In such tumours conization represents sufficient procedure with satisfactory pregnancy outcomes. Surprisingly less than half of patients attempt to conceive after treatment.

Acid ceramidase (ASAH1) is a key player in sphingolipid metabolism and signaling. It has prognostic value for several cancers, but histotype-specific analyses of ovarian cancer are not yet available. We used three retrospective TMA cohorts encompassing a total of 1106 ovarian cancers with follow-up data for immunohistochemical analysis of acid ceramidase (ASAH1) expression. Patients with sub-optimal debulking and persistent residual tumor after surgery introduced bias in the prognostic analysis and were excluded from further studies. Overall, we detected an association of ASAH1 expression with better prognosis in ovarian cancer patients. ASAH1 expression differed between histological ovarian cancer histotypes with most frequent expression in endometrioid and clear cell ovarian cancer, which are both associated with good prognosis. Stratified subgroup analyses within these histotypes did not reveal significant survival differences, but the power of the analysis may be limited by smaller sample sizes. In contrast to breast cancer, we found only a modest concordance between estrogen receptor status and ASAH1 expression within the endometrioid ovarian cancer histotype. In an exploratory analysis of estrogen receptor negative endometrioid ovarian cancer, ASAH1 expression was associated with significantly better overall survival (P = 0.007). Acid ceramidase is most frequently expressed in endometrioid and clear cell histotypes and could add independent prognostic value to estrogen receptor in endometrioid ovarian cancer. Modulating sphingolipid metabolism may lead to novel therapeutic intervention strategies for this disease.

Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.

Aims The primary aim of the present study was to assess the association between levator ani muscle (LAM) integrity and function on the one hand, and the risk of urinary incontinence (UI) on the other. A secondary objective was to assess the association between fundal pressure in the second stage of labor (Kristeller maneuver) and the risk of postpartum UI. Methods In this prospective cohort study, women underwent a clinical and transperineal ultrasound examination at rest, at pelvic floor muscle contraction (PFMC), and at Valsalva maneuver 3-6 months after their first vaginal delivery. LAM avulsion and levator hiatal area (LHA) were evaluated. In addition, women were interviewed about the presence of UI, whether stress (SUI) or urgency (UUI). Results Overall, data of 244 women were analyzed. SUI was reported in 50 (20.5%), while UUI was reported in 19 (7.8%) women. Women who reported SUI had a higher prevalence of LAM avulsion and less proportional reduction in LHA from rest to a maximum contraction in comparison to women with no SUI. Women who reported UUI had a greater LHA at rest, during contraction, and during maximal Valsalva in comparison to women without UUI. No significant association was found between the Kristeller maneuver and the incidence of any UI. Conclusion Levator ani avulsion and less proportional reduction of LHA with PFMC appear to be associated with a higher risk of postpartum urinary stress incontinence.

Objective: To assess the feasibility and reliability of transperineal ultrasound in the assessment of fetal breech descent in the birth canal, by measuring the breech progression angle (BPA). Methods: Women with a singleton pregnancy with the fetus in breech presentation between 34 and 41 weeks' gestation were recruited. Transperineal ultrasound images were acquired in the midsagittal view for each woman, twice by one operator and once by another. Each operator measured the BPA after anonymization of the transperineal ultrasound images. BPA was defined as the angle between a line running along the long axis of the pubic symphysis and another line extending from the most inferior portion of the pubic symphysis tangentially to the lowest recognizable fetal part in the maternal pelvis. Each operator was blinded to all other measurements performed for each woman. Intra- and interobserver reproducibility of BPA measurement was evaluated using the intraclass correlation coefficient (ICC). To investigate the presence of any bias, intra- and interobserver agreement was also analyzed using Bland–Altman analysis. Student's t-test and Levene's W0 test were used to investigate whether a number of different clinical factors had an effect on systematic differences and homogeneity, respectively, between BPA measurements. Results: Overall, 44 women were included in the analysis. BPA was measured successfully by both operators on all images. Both intra- and interobserver agreement analyses showed excellent reproducibility in BPA measurement, with ICCs of 0.88 (95% CI, 0.80–0.93) and 0.83 (95% CI, 0.71–0.90), respectively. The mean difference between measurements was 0.4° (95% CI, −1.4 to 2.2°) for intraobserver repeatability and −0.4° (95% CI, −2.6 to 1.8°) for interobserver repeatability. The upper limits of agreement were 12.0° (95% CI, 8.9–15.1°) and 13.6° (95% CI, 9.9–17.3°) for intra- and interobserver repeatability, respectively. The lower limits of agreement were −11.2° (95% CI, −14.3 to −8.1°) and −14.4° (95% CI, −18.2 to −10.7°) for intra- and interobserver repeatability, respectively. No systematic difference between BPA measurements was found on either intra- or interobserver agreement analysis. None of the clinical factors examined (maternal body mass index, maternal age, gestational age at the ultrasound scan and parity) showed a statistically significant effect on intra- or interobserver reliability. Conclusions: BPA represents a new feasible and highly reproducible measurement for the evaluation of fetal breech descent in the birth canal. Future studies assessing its usefulness in the prediction of successful external cephalic version and breech vaginal delivery are needed. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background:\ud State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.\ud Methods:\ud This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.\ud Findings:\ud Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (

hTFM in primary vulvar cancer is an important prognostic factor. Ideally, a diameter of 8 mm should be achieved after primary surgery. The role of VIN III persistence after primary surgery in vulvar cancer is still unclear. The main objective of the current study was to study the role of residual VIN III re-excision and compare differences in disease-free survival among patients with different hTFM and in primary vulvar cancer.Forty-two patients with residual adjacent VIN III after primary surgery for vulvar cancer which were operated between 2000 and 2016 in our clinic were enrolled in this retrospective study. Re-excision rates for residual adjacent VIN III were calculated. According to the histological margin patients were divided into three group: 3, 3-8 and 8 mm. Univariate and multivariate analyses were conducted using the Kaplan-Meier method and Cox proportional hazards models, respectively.The vast majority of patients had pT1b stage (57.1%), grading G2 (71.4%) and lymph node-negative (45.3%) disease at first diagnosis. The re-excision rate was 57.1%. The 5-year disease-free survival (DFS) rates in patients with 3, 3-8 and 8 mm hTFM were 50.0, 50.0 and 81.0%, respectively (p = 0.032). The 5-year DFS rates in patients with re-excision and without re-excision for VIN III were 77.3 and 52.9%, respectively (p = 0.060). In univariate analysis was solely hTFM 8 mm a prognostic factor for DFS (p = 0.017).hTFM may be a potential prognostic indicator for DFS in vulvar cancer patients. Re-excision for residual adjacent VIN III could not be established as a prognostic factor for DFS after primary surgery in squamous cell cancer of vulva.

HIFU steht fur „high intensity focussed ultrasound“ und ist eine relativ neue Technologie, die als MRT(Magnetresonanztomographie)- oder als ultraschallgesteuertes HIFU angeboten wird. Wahrend der letzten Jahre sind vermehrt Arbeiten erschienen, die mogliche Optionen klarer definieren und den medizinischen Nutzen dieser neuen Methode objektiv nachweisen wollen. Inhalt der vorliegenden Publikation ist eine Darstellung der dominanten Techniken und der existierenden Literatur zum Stand der verfugbaren evidenzbasierten Medizin. Es soll herausgearbeitet werden, inwieweit Behauptungen zu Therapieerfolgen berechtigt sind und welche Entwicklungen in der Zukunft realistischerweise zu erwarten sind. Durchsicht der relevanten Datenbanken (PubMed, Medline, Embase) und der verfugbaren Industrieinformationen. HIFU ist eine komplexe Technologie, hinter der beachtliche technische Leistungen stehen. Der konkrete klinische Nutzen wird aktuell etabliert. Wie bei vielen neuen Technologien in der Fruhphase ist die Zukunft von HIFU weder garantiert noch komplett abzusehen. Aufgrund der einzigartigen Wirkweise konnte es sich um eine hochrelevante Zukunftstechnologie handeln. Bei der Kritik an aktuellen Insuffizienzen wird ubersehen, welche Schwierigkeiten ahnlich revolutionare Neuerungen, wie der diagnostische Ultraschall oder die Laparoskopie, uberwinden mussten, bevor sie aus der taglichen Routine nicht mehr wegzudenken waren. Die Frauenheilkunde sollte gegenuber dieser Zukunftstechnologie offen sein; es ware ein Fehler, ihr hohes innovatives Potenzial in Deutschland nicht weiter zu verfolgen.

Myomas, also known as fibroids, are a specific characteristic of the human species. No other primates develop fibroids. At a cellular level, myomas are benign hyperplastic lesions of uterine smooth muscle cells. There are interesting theoretical concepts that link the development of myomas in humans with the highly specific process of childbirth from an upright position and the resulting need for greatly increased “expulsive” forces during labor. Myomas might be the price our species pays for our bipedal and highly intelligent existence. Myomas affect, with some variability, all ethnic groups and approximately 50% of all women during their lifetime. While some remain asymptomatic, myomas can cause significant and sometimes life-threatening uterine bleeding, pain, infertility, and, in extreme cases, ureteral obstruction and death. Traditionally, over 50% of all hysterectomies were performed for fibroids, leading to a significant healthcare burden. In this article, we review the developments of the past 20 years with regard to multiple new treatment strategies that have evolved during this time.

Background/Aim: Totally implanted venous access devices (TIVAD) are increasingly used in the treatment of cancer patients. The aim of this study was to assess the incidence of early and late complications resulting from subcutaneous TIVADs in patients with breast cancer. Materials and Methods: Between 2004 and 2009, we reviewed patients with breast cancer who had a TIVAD placed. Early and late complications, as well as risk factors for TIVAD-associated thrombosis were retrospectively assessed. Results: A total of 281 patients were included. Complications occurred in 26% of patients, the majority of which were late complications (21.4%.) The development of TIVAD associated thrombosis was the most frequent late complication (16.4%). In the univariate analysis followed by a multivariate model, risk factors for TIVAD associated thrombosis were not identified. Only within the subgroup of metastatic breast cancer patients an increased risk of TIVAD-associated thrombosis of left compared to right venous access was detected (p=0.015). Conclusion: TIVAD implantation done in a gynecological outpatient setting is feasible and safe.

Dargestellt wird die aktuelle Datenlage bezuglich epidemiologischer Beobachtungen und atiologischer Faktoren fur die unterschiedlichen Vulvamalignome. Das Wissen um die Epidemiologie, die Pathogenese und die atiologischen Faktoren des Vulvakarzinoms ist nicht nur relevant fur Praventionsstrategien, Fruherkennungsmasnahmen, die Implementierung von Screnningprogrammen und fur therapeutische Entscheidungen, sondern auch fur das postoperative Management im Sinne der Risikostratifizierung. Skizziert wird auch das beginnende Verstandnis der molekularbiologischen Pathways. Die weitere Forschung kann kunftig eine dezidiert neue Systematisierung der nosologischen Subentitaten initiieren, ferner moglicherweise auch innovative therapeutische Ansatze und Strategien ermoglichen.

BACKGROUND/AIM Borderline ovarian tumors (BOTs) have a less aggressive behavior than invasive epithelial ovarian tumors. Still some patients relapse or succumb to disease. Molecular markers that reliably predict prognosis are lacking. Insulin-like growth factor II mRNA-binding protein (IMP3) has been suggested as a prognostic marker in colorectal, hepatocellular, and ovarian clear-cell carcinomas. MATERIALS AND METHODS We analyzed the expression of IMP3 by immunohistochemistry in a cohort of 140 BOT and its association with histopathological features. RESULTS We found no association of IMP3 expression with patients' age, FIGO stage, microinvasion, and presence of implants. In contrast, IMP3 expression correlated to mucinous subtype of BOTs (42.2% vs. 9.5% among other subtypes) (p

Introduction/Background In the Phase III SOLO1 first-line trial, maintenance therapy with the PARP inhibitor olaparib provided a substantial progression-free survival (PFS) benefit to advanced ovarian cancer (OC) patients who have a BRCA1/2 mutation (BRCAm) and are in complete or partial response to first-line chemotherapy (Moore K et al. N Engl J Med 2018). VEGF inhibitor may increase PARP sensitivity, particularly in some OC patients with BRCA wild type (Liu JF et al. Lancet Oncol 2014). PAOLA-1/ENGOT-ov25 (NCT02477644) is the first Phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bevacizumab as first-line maintenance therapy, and in patients regardless of BRCAm status. Methodology PAOLA-1 is a randomized, double-blind, international Phase III trial. Eligible patients had newly diagnosed, advanced (FIGO stage IIIA-IV) high-grade serous or endometrioid ovarian, fallopian tube or peritoneal cancer. Patients had no evidence of disease or were in partial response following first-line platinum-based chemotherapy plus bevacizumab. Bevacizumab was to be given for up to 15 months, including the initial combination with chemotherapy. 806 patients were randomized (2:1) in maintenance therapy to olaparib (300 mg bid) or placebo plus bevacizumab (15 mg/kg, d1, q3w), stratified by first-line treatment outcome and tumour BRCAm status. The primary endpoint is investigator-assessed PFS (modified RECIST v1.1). The 458 PFS events required for the primary analysis to show significance at the two-sided 5% level with an estimated >80% power have been reached in March 2019. Database lock was in July and analyses are ongoing. Results The LBA will report: investigator-assessed PFS, PFS by BRCAm/HRD status, health- related quality of life, and safety and tolerability results. Conclusion PAOLA-1 will demonstrate whether addition of olaparib to bevacizumab maintenance therapy following first-line platinum-based chemotherapy plus bevacizumab provides a clinically meaningful benefit to OC patients. Disclosure P Harter declares honoraria from AstraZeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab and MSD; and consultancy/advisory board fees from AstraZeneca, Roche, Tesaro, Lilly, Clovis, Immunogen and MSD/Merck. Marie Ange Mouret-Reynier declares no conflicts of interest. S Pignata declares honoraria from Roche, AstraZeneca, MSD, Pfizer, Incyte, Novartis, PharmaMar, Clovis and Tesaro; and travel expenses from Roche, AstraZeneca and MSD. Claire Cropet declares no conflicts of interest. A Gonzalez-Martin declares consulting/advisory board fees from Roche, AstraZeneca, Tesaro, Clovis, Pfizer, ImmunoGen, PharmaMar, MSD, Genmad and Novartis; and speaker bureau/expert testimony fees from Roche, AstraZeneca, MSD Tesaro and PharmaMar. Gerhard Bogner declares consulting/advisory board fees from AstraZeneca Tesaro and Roche; and travel expenses from GSK, Roche, Pharmamar, AstraZeneca and Tesaro. K Fujiwara declares honoraria from AstraZeneca, Chugai Roche, Zeria, Taiho, Nihon Kayaku, Kyowahakko Kirin, Janssen and Daiichi Sankyo; consulting/advisory board fees from Pfizer, MSD and Eisai; research funding from AstraZeneca, MSD, Chugai Roche, Eisai and Kaken; and travel expenses from Pfizer. I Vergote declares consulting/advisory board fees from Advaxis, BIOCAD, Eisai, MSD, Roche, Genmab, Roche, PharmaMar, Millenium Pharmaceuticals, Clovis, AstraZeneca, Tesaro, Oncoinvent, ImmunoGen and Sotio; contracted research with Oncoinvent and Genmab; research funding from Amgen, Roche and Stichting tegen Kanker; and Takeda Oncology, PharmaMar, Genmab, Roche, AstraZeneca, Tesaro, Clovis and Immunogen. N Colombo declares honoraria from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD and Takeda; consulting/advisory board fees from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD, Takeda; and travel expenses from PharmaMar, Tesaro and Roche. J Maenpaa declares honoraria from Roche, AstraZeneca and Tesaro; consultancy/advisory board fees from AstraZeneca, Tesaro, Clovis and MSD; and travel expenses from Roche. Anne Floquet declares consultancy/advisory board fees from GSK, AstraZeneca and Clovis; and travel expenses from Roche, GSK and AstraZeneca. Ahmed El-Balat declares honoraria from AstraZeneca, Roche, Pharmamar, MSD, Tesaro, Clovis; and consultancy/advisory board fees from AstraZeneca and Roche. D Lorusso declares honoraria from Merck; consultancy/advisory board fees from Merck, AstraZeneca, Tesaro, Clovis, Immunogen, PharmaMar and Roche; research funding from Clovis, PharmaMar, Merck and Roche; and travel expenses from Tesaro, Roche and PharmaMar. EM Guerra Alia declares consultancy/advisory board fees from Roche, Clovis and AstraZeneca; and travel expenses from Roche and Baxter. Michel Fabro declares honoraria from Tesaro and AstraZeneca; and consultancy/advisory board fees from Tesaro and AstraZeneca. Barbara Schmalfeldt declares honoraria from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MSD; consultancy/advisory fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; speaker bureau/expert testimony fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; research grant funding from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS and travel expenses from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS. Anne Claire Hardy Blessard declares honoraria from AstraZeneca, Lilly, Novartis, Pfizer, Roche and Tesaro. Ingo Runnebaum declares honoraria from AstraZeneca. I Ray-Coquard declares honoraria from AstraZeneca, Clovis, Tesaro and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, PharmaMar, MSD and Pfizer; research funding from MSD; and travel expenses from AstraZeneca and Roche; consulting/advisory board fees from Roche; and travel expenses from Roche, MSD, Tesaro and AstraZeneca. E Pujade-Lauraine declares honoraria from AstraZeneca and Tesaro; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, Incyte, MSD and Pfizer; research funding from AstraZeneca, Roche and Tesaro; and travel expenses from AstraZeneca, Roche and Tesaro.

Introduction/Background Olaparib (50 mg hard capsules, HC) was the 1st PARPi approved in the EU in 12/2014 as monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. In addition, film-coated tablets (FT, 100/150 mg) were approved in 05/2018 regardless of BRCA status. Here, we report for the first time data on real-world olaparib treatment from patients who switched from HC to FT. Methodology The German prospective non-interventional study C-PATROL (NCT02503436) collects routine clinical and patient-reported outcome data in BRCAm PSR-OC patients treated according to label with olaparib with the recommended total daily dose of 800 mg (HC) or 600 mg (FT). The 3rd interim analysis (cut-off: 01APR2019) for patients treated with olaparib (HC/FT) reflects data on patient characteristics and safety by using descriptive statistics focussing on ‘switcher’ (here patients can be treated with FT since 08/2018). Results 252 olaparib-treated patients were analysed; 177 (70.2%) were treated with HC, 47 (18.7%) switched from HC to FT, and 28 (11.1%) were newly initiated with FT. Median therapy durations for the three subgroups were 9.0 months (HC), 17.4 months (switcher; 13.4 months before [HC] and 4.4 months after [FT] switch) and 9.2 months (FT). 44 switcher (93.6%) had adverse events (AEs); 41 (87.2%) before and 26 (55.3%) after switching. Treatment modifications due to AEs were more frequent prior to switching (i.e. during HC treatment). In total, 30 switcher had therapy modifications; 25 (83.3%) before and 11 (36.7%) after switching. Conclusion The 3rd interim analysis indicates that under routine conditions, olaparib is well tolerated in patients who switched from HC to FT. In fact, fewer AEs occurred after switching. The toxicity profile observed so far is in line with the results of the clinical trial program for olaparib in PSR-OC and 1st-line maintenance. Funding AstraZeneca. Disclosure F. Marme: honoraria received for speaker, consultancy or advisory role, travel, from AstraZeneca, Tesaro, Roche, Novartis, Pfizer, PharmaMar, GenomicHealth, CureVac, Amgen, Eisai, MSD,Celgene, Clovis. F. Hilpert: membership on advisory boards for AstraZeneca, Roche, Tesaro, Clovis, MSD, PharmaMar, receipt of honoraria from Astra Zeneca, Clovis, Roche, Tesaro, MSD, PharmaMar, Pfizer, Novartis. M. Welslau: No conflict of interest, nothing to disclose. J. P. Grabowski: Advisory, consultancy and speakers activities for AstraZeneca, Tesaro, Clovis, Riemser, honoraria from AstraZeneca, Tesaro, Roche, Clovis, Pfizer, Riemser. J. Seitz: no conflict of interest, nothing to disclose. A. El-Balat: membership on advisory councils, speaker’s activities for AstraZeneca, Roche, PharmaMar, Olympus. A. D. Hartkopf has received honoraria (speakers bureau and consulting fees) from AstraZeneca, Eisai, GenomicHealth, Lilly, MSD, Novartis, Pfizer, Roche, Tesaro, Teva. R. Glowik: employee of AstraZeneca. J. Sehouli: Advisory and expert activities for PharmaMar, Clovis, Tesaro, Roche, Roche Diagnostics, Astra Zeneca,Merck, Bayer,Eisei, Johnson and Johnson, MSD, Novocure, Amgen, Lilly; Receipt of professional fees from PharmaMar, Clovis, Tesaro, Roche, Astra Zeneca, receipt of research grant support (institution) from PharmaMar, Clovis, Tesaro, Roche, Astra Zeneca, Medimmune, Bristol Myers, Lilly.

e18061 Background: Risk factors for invasive recurrence of borderline tumours (BOT) of the ovary are needed. The actin-bundling protein Fascin-1 (FSCN1) is involved in alteration of adhesion and cell motility and has been associated with invasion and metastasis in different cancers. Methods: We studied a retrospective cohort of 124 bordeline tumors of the ovary (BOT) with validated diagnosis by an independent pathologist for expression of FSCN1 as potential prognostic biomarker. Results: We found strong expression of the actin-bundling protein FSCN1 in 62 of these tumors. FSCN1 positive patients were slightly younger (46.9±2.2 vs. 53.3±2.3 years, P = 0.049). Expression of FSCN1 was more frequently detected in BOT with serous compared to mucinous histotype (58/78 [74.4%] vs. 3/41 [7.3%], p < 0.001), and in cases with micropapillary pattern (25/28 [89.3%] vs. 38/98 [38.8%], P < 0.001). In addition, a non significant trend was observed for more frequent expression of FSCN1 among cases with implants (8/10 [80.0%] vs. 55/116 [47.4%], P = 0.095). When we compared progression free survival of the patients we found numerical lower but not statistically significant PFS rates of 90.5±6.4% vs. 94.4±5.4% for 10 years, and 81.4±10.3% vs. 94.4±5.4% for 15 years, in BOT with FSCN1 expression compared to those tumors negative for FSCN1, respectively. Conclusions: Our analysis suggests an association of FSCN1 expression in BOT with micropapillary pattern and implants, which have been linked to inferior prognosis. Cases with FSCN1 expression in our cohort displayed numerical lower PFS rates prompting further studies of this marker.

AimsExpression of Claudin-1 has been associated with prognosis in several cancers. Here we investigated the expression pattern of Claudin-1 in borderline tumours of the ovary (BOT).MethodsWe analysed a cohort of 114 cases of borderline tumour (BOT). Claudin-1 expression was studied by immunohistochemistry using a polyclonal antibody and was compared with clinical and histopathological characteristics.ResultsStrong Claudin-1 expression was found in 30 cases (26.3%) independent of histological subtype. Expression was significantly less frequent in International Federation of Gynecology and Obstetrics (FIGO) stage I (p= 0.045), while the presence of microinvasion did not correlate with Claudin-1 expression. In contrast, we detected a highly significant association of Claudin-1 expression with the presence of peritoneal implants (p=0.003) and micropapillary pattern (p=0.047), which are features exclusively seen in serous BOT. Moreover, when we restricted our analysis to the subtype of serous BOT, the association of Claudin-1 expression with peritoneal implants (pConclusionsIn conclusion, Claudin-1 expression is associated with the presence of peritoneal implants and micropapillary pattern, which have been shown to be associated with poor prognosis. We speculate that overexpression of Claudin-1 might be linked to the mitogen-activated protein kinase pathway activation in BOT and suggest further studies to define its prognostic and potential therapeutic value.

Summary Background Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. Methods We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov , number NCT01047891 . Findings Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8–7·6) with sorafenib versus 4·4 months (3·7–5·0) with placebo. The most common grade 3–4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). Interpretation Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. Funding Bayer , Amgen , and GlaxoSmithKline .

Purpose Patients with high-risk early or advanced endometrial cancer (EC) are at high risk for lymph node (LN) metastases. However, both the anatomical pattern of the LN metastases and also the therapeutic value of systematic LN dissection remain a field of discussion and controversy. Methods We performed an exploratory analysis of patients with high-risk or advanced EC who underwent systematic pelvic and para-aortic lymphadenectomy in two tertiary referral centers for gynecological malignancies. Results One hundred and twenty-eight completely surgically staged patients underwent systematic pelvic and paraaortic lymphadenectomy for high-risk or advanced EC. A median of 29 and 21.5 LN was harvested in the pelvis and in the para-aortic region, respectively. Overall, 27 patients (21.1 %) had positive LN: 18 % showed positive pelvic LN and 14.8 % positive para-aortic LN; while 3.1 % showed isolated para-aortic LN metastases. Five-year overall survival was 70 versus 30 % in LN-negative versus LN-positive patients (p\0.01). LN-status was the only factor significantly associated with overall survival [HR: 3.67 (95 % CI 1.48‐9.11); p = 0.01] in a multivariate Cox regression model. Conclusions Patients with high-risk or advanced EC were at a high-risk for LN metastases. Anatomical distribution of positive LN indicates that lymphadenectomy, when performed, should contain both pelvic and para-aortic areas up to the renal vessels for an accurate assessment of all potential positive LN.

Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5%), \(BRCA2\) (5.5%), \(RAD51C\) (2.5%) and \(PALB2\) (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients

e17549Background: The PARP inhibitor olaparib is approved in the EU for maintenance therapy of BRCA-mutated (BRCAm+) platinum-sensitive relapsed ovarian cancer patients, who are in response to thei...

e17537Background: High-grade serous ovarian cancer (HGSOC) (70%) has poor prognosis. Drivers of HGSOC are p53 mutations, homologous recombination deficiencies and CCNE1-amplification. Olaparib chan...

5538Background: Identification of families at risk for OC including recommendation for prophylactic surgery is the only effective method to reduce OC mortality. In addition, BRCA1/2 mutations are k...

5546 Background: BRCA associated cancers show a distinct pattern of genomic gains and losses that is associated with impaired repair of DNA double-strand breaks via homologous recombination (HR). We investigated whether BRCA1- and BRCA2-like classifiers could predict BRCA1 and BRCA2 mutation status in ovarian cancer. In addition, we explored whether promoter hypermethylation or mutations in other genes involved in DNA repair associate with a BRCA-like profile in ovarian cancer. Methods: The AGO-TR1 cohort study (NCT02222883 ) enrolled 525 consecutive patients with primary (PR) and platinum sensitive relapsed (RE) ovarian cancer to perform paired mutational analysis of germline and tumor tissue. We performed mutation panel sequencing, BRCA1 promoter hypermethylation and low-coverage whole genome sequencing to classify samples as BRCA1-like or BRCA2-like in 298 ovarian cancer samples (PR: n = 159, RE: n = 139). Results: A BRCA-like profile was observed in 58.1% of the samples without germline or somatic mutation in BRCA1/2 (n = 179; BRCA1-like: n = 26, BRCA2-like: n = 23, BRCA1- and 2-like: n = 55). There was no significant difference between PR- and RE-cases (54.5% vs 61.3%). 64 of 70 BRCA1 germline mutation carriers could be identified by the BRCA1-like classifier (sensitivity: 0.91). The BRCA2-like classifier identified BRCA2 germline mutation carrier with a sensitivity of 0.71 (17 of 24). The complementary use of both classifiers led to the detection of 22 of 25 somatic mutations in BRCA1 (16/16) or - 2 (6/9). Remarkably, 12 of 13 tumor samples from germline RAD51C mutation carriers were recognized by the BRCA1-like classifier (sensitivity: 0.92). No correlation of PALB2 mutation status (n = 7) with BRCA-like profile was observed. Of 28 tumor samples with a BRCA1 promoter hypermethylation 26 had a BRCA1-like profile (sensitivity: 0.93). Conclusions: A high number of ovarian cancer cases display a BRCA-like profile. Mutations (germline and somatic) in BRCA1, BRCA2, RAD51C as well as BRCA1 hypermethylation strongly associate with a BRCA-like profile and can explain 146 of 212 cases. Future studies will investigate whether the classifiers identify patients who benefit from HR-deficiency directed approaches beyond the BRCA mutation status. Clinical trial information: NCT02222883.

Background: Malignant transformation of thyroid tissue in struma ovarii and metastasis are uncommon. Benign thyroid tissue may spread to the peritoneal cavity in rare cases, and pathologic examination of the peritoneal implants shows multiple nodules of varying sizes of mature thyroid tissue similar to struma ovarii. This condition is termed “peritoneal strumosis”. It is very rare and therefore, both the criteria for diagnosis and its management are under discussion. The recommended treatment of metastatic struma ovarii should contain, in addition to local resection of the extraovarian tumor, total thyroidectomy in conjunction with radioiodine scanning and radioiodine ablation. Case report: A 38 year-old woman had presented with benign struma ovarii 12 years previously. She was referred to our department because of a right ovarian tumor. After confirming the diagnoses of metastatic recurrent benign struma ovarii, we performed debulking surgery with the aim of resecting all tumor masses. The uterus, left adnexa, and pelvic peritoneum were surgically extracted “en bloc”. No macroscopic tumor was left post-operatively. The first post operative 123 I scintography with15 MBq iodine-123 one month post-operatively showed a small but suspicious focus in the front left perivesical pelvic area. In the ventral visual presentation multiple discrete foci, located in right perivesical, supravesical and in the ventral upper abdomen, were seen. We then referred the patient for thyroidectomy and radioiodine ablation. The following periodic follow-ups of the patient did not show any signs of recurrence or progression of the disease. Conclusion: Patient with benign metastatic struma ovarii (also known as Highly differentiated follicular carcinoma of ovarian origin - HDFCO) may affectively be treated with local resection of the extraovarian tumor and subsequent thyroidectomy followed by radioactive iodine ablation.