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Objective: To investigate the role of BRCA1/2 mutations in early ovarian cancer (eOC) (International Federation of Gynecology and Obstetrics FIGO 2014 stage I-II), and its impact on prognosis after relapse., Methods: In this multicenter retrospective study, clinical and survival data from high-grade serous (HGS)-eOC patients at presentation and recurrence were compared according to BRCA status: BRCA-mutated (BRCAmut) vs. BRCA wild-type (BRCAwt)., Results: Among 191 HGS-eOC patients, 89 were BRCAmut and 102 BRCAwt. There was no significant difference according to the BRCA status in terms of Progression-Free Survival (PFS). A longer Overall Survival (OS) was found in BRCAmut patients. Stage I patients had significantly improved PFS vs stage II, regardless of BRCA status. At multivariate analysis, stage at diagnosis was the only variable with a significant effect on PFS. No factors were significantly relevant on OS, albeit younger age and BRCA mutation showed a slight impact. Post-Recurrence Survival (PRS) in the BRCAmut population was significantly improved compared with BRCAwt. At multivariate analysis, Secondary Cytoreductive Surgery was the strongest predictor for longer PRS, followed by PARPi maintenance at recurrence., Conclusions: BRCA-status is not a prognostic factor in early ovarian cancer regarding PFS. However, our data suggest a better prognosis after relapse in BRCAm population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging., Methods: Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1-2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses., Results: 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5-52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06-0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07-0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively)., Conclusion: Staging lymphadenectomy in grade 2 endometrioid ovarian carcinoma patients was associated with improved DFS and OS. Grade 1 and grade 2 might be considered as two different entities, which could benefit from different approach in terms of surgical staging. Prospective studies, including molecular profiles are needed to confirm the survival drivers in this rare setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Bowel dysfunction is frequently reported in patients with ovarian carcinoma (OC). Our aim was to evaluate the incidence of low anterior resection syndrome (LARS) like symptoms in patients with primary OC and its impact on quality of life (QoL)., Methods: A prospective longitudinal observational cohort study was performed, including patients with newly diagnosed OC treated by primary or interval surgery with residual tumor <1 cm, from 2018 until 2021. Patients with a stoma or recurrence of disease were excluded. Intestinal dysfunction was assessed using the validated LARS score questionnaire pre- and postoperatively. There are 3 subgroups based on the results: no, minor, or major LARS. The impact on QoL was evaluated by an additional question to demonstrate the severity of patient's life impairment., Results: The questionnaire was answered by 78 patients pre- and post-operatively. LARS like symptoms were reported preoperatively in 34.6% (24.4% minor/10.2% major) and significantly increased postoperatively to 47.4% (28.2% minor/19.2% major; p = 0.011). Moderate to severe impairment of QoL correlated with LARS scores pre- (80%) and post-operatively (90%). Patients with two bowel anastomoses (mean score 18.6 pre- and 24.9 post-operatively, p = 0.041) showed a significant increase of the questionnaire score., Conclusions: Major LARS like symptoms appear in 10% of OC patients preoperatively and significantly increase to almost two-fold postoperatively. Multiple bowel anastomoses had a significant risk for higher postoperative LARS score. QoL impairment correlates linearly with LARS positive scoring, independent on the timing of the complaints., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Advanced ovarian cancer is managed by extensive surgery, which could be associated with high morbidity. A personalized pre-habilitation strategy combined with an 'enhanced recovery after surgery' (ERAS) pathway may decrease post-operative morbidity., Primary Objective: To analyze the effects of a combined multi-modal pre-habilitation and ERAS strategy on severe post-operative morbidity for patients with ovarian cancer (primary diagnosis or first recurrence) undergoing cytoreductive surgery., Study Hypothesis: A personalized multi-modal pre-habilitation algorithm entailing a physical fitness intervention, nutritional and psycho-oncological support, completed by an ERAS pathway, reduces post-operative morbidity., Trial Design: This is a prospective, controlled, non-randomized, open, interventional two-center clinical study. Endpoints will be compared with a three-fold control: (a) historic control group (data from institutional ovarian cancer databases); (b) prospective control group (assessed before implementing the intervention); and (c) matched health insurance controls., Inclusion Criteria: Patients with ovarian, fallopian, or primary peritoneal cancer undergoing primary surgical treatment (primary ovarian cancer or first recurrence) can be included. The intervention group receives an additional multi-level study treatment: (1) standardized frailty assessment followed by (2) a personalized tri-modal pre-habilitation program and (3) peri-operative care according to an ERAS pathway., Exclusion Criteria: Inoperable disease or neoadjuvant chemotherapy, simultaneous diagnosis of simultaneous primary tumors, in case of interference with the overall prognosis (except for breast cancer); dementia or other conditions that impair compliance or prognosis., Primary Endpoint: Reduction of severe post-operative complications (according to Clavien- Dindo Classification (CDC) III-V) within 30 days after surgery., Sample Size: Intervention group (n=414, of which approximately 20% insure with the participating health insurance); historic control group (n=198); prospective control group (n=50), health insurance controls (for those intervention patients who are members of the participating health insurance)., Estimated Dates for Completing Accrual and Presenting Results: The intervention phase started in December 2021 and will continue until June 2023. As of March 2023, 280 patients have been enrolled in the intervention group. The expected completion of the entire study is September 2024., Trial Registration: NCT05256576., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Adult granulosa cell tumors represent less than 5% of all ovarian malignancies. The aim of this study was to analyze the clinicopathological parameters and their impact on progression-free and overall survival., Methods: Patients with primary adult granulosa cell tumors treated in three international referral centers between July 1999 and December 2018 were included. The following data were anonymously exported from the prospective database: age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, adjuvant therapy, surgical procedures, progression-free survival, and overall survival. Descriptive statistical analysis regarding tumor and treatment characteristics was performed. Survival analyses included Kaplan-Meier functions and Cox proportional hazard ratios (HR)., Results: A total of 168 patients with primary adult granulosa cell tumors were included. Median age was 50 years (range 13-82). With regard to stage distribution, 54.2% (n=91) of patients were FIGO stage IA, 1.2% (n=2) were stage IB, 26.8% (n=45) were stage IC, and 17.9% (n=30) were FIGO stage II-IV. 66.7% (n=112) of patients underwent surgical restaging, of whom 17.9% (n=20) were moved to a higher stage. In addition, 36 (21.4%) patients underwent fertility-sparing surgery. After a median follow-up of 61 months (range 0-209), 10.7% of patients (n=18) had recurrent disease and 4.8% (n=8) died of disease. Five-year progression-free survival was 86.1% and estimated overall survival was 95.7%. Five-year progression-free survival was worse for patients with advanced stages (FIGO stage IA/B vs IC: HR 5.09 (95% CI 1.53 to 16.9); FIGO stage IA/B vs II-IV: HR 5.62 (95% CI 1.58 to 19.9)). Nineteen patients receiving adjuvant chemotherapy had lower estimated 5-year progression-free survival compared with patients not receiving chemotherapy (49.7% vs 91.1%, p<0.001; HR 9.15 (95% CI 3.62 to 23.1))., Conclusion: The prognosis of patients with primary adult granulosa cell tumors is mainly determined by FIGO stage. The outcome of patients with FIGO stage IC is comparable to those with advanced stages. Fertility-sparing surgery seems to be a safe procedure in stage IA. Our data do not support the use of adjuvant chemotherapy in early and advanced stages of adult granulosa cell tumors., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC., Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated., Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss., Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: To evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer., Methods: This was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations in BRCA1/2 genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type of BRCA1/2 genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared., Results: Excluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. The BRCA1 gene was affected in 324 (68.4%) cases, while BRCA2 was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer between BRCA1 and BRCA2 patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in the BRCA1 and BRCA2 subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55)., Conclusion: Different types of germline BRCA mutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This international study aimed to investigate the impact of substage, histological type and other prognostic factors on long-term survival for stage I ovarian carcinoma., Methods: Our study was a retrospective multicenter cohort study that included patients with the International Federation of Gynecology and Obstetrics (FIGO) stage I (IA-IC3) ovarian carcinoma treated at four European referral centers in Germany and Italy. Using Kaplan-Meier survival curves we compared overall and disease-free survival between the different stage I groups., Results: A total of 1115 patients were included. Of these, 48.4% (n=540) were in stage IA, 6.6% (n=73) stage IB, and 45% (n=502) stage IC, of the latter substage IC1, 54% (n=271), substage IC2, 31.5% (n=158), and substage IC3, 14.5% (n=73). Five-year overall and disease-free survival rates for the entire cohort were 94% and 86%, respectively, with no difference between stage IA and IB. However, there was a significantly better overall and disease-free survival for stage IA as compared with stage IC (p=0.007 and p<0.001, respectively). Multivariate analysis revealed incomplete/fertility-sparing staging (HR 1.95; 95% CI 1.27 to 2.99, and HR 3.54; 95% CI 1.83 to 6.86, respectively), and stage IC (HR 2.47; 95% CI 1.63 to 3.75) as independent risk factors for inferior disease-free survival, while low-grade endometrioid (HR 0.42; 95% CI 0.25 to 0.72) and low-grade mucinous (HR 0.17; 95% CI 0.06 to 0.44) histology had superior disease-free survival. Considering overall survival, stage IC (HR 2.41; 95% CI 1.45 to 4.01) and older age (HR 2.41; 95% CI 1.46 to 3.95) were independent risk factors., Conclusion: Although stage I ovarian carcinoma exhibited excellent outcomes, the prognosis of patients with stage IA differs significantly compared with stage IC. Sub-optimal staging as an indicator for quality of care, and tumor biology defined by histology (low-grade endometrioid/mucinous) independently impact disease-free survival., Competing Interests: Competing interests: MI wrote the first draft of the manuscript., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration., Patients and Methods: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks., Results: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76)., Conclusions: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected., Competing Interests: Disclosure KEF reports intuitional funding from AstraZeneca (AZ). MF reports institutional funding from AZ, Novartis, and Beigene; consulting fees from AZ, Novartis, GlaxoSimthKline (GSK), Merck Sharp & Dohme (MSD), Takeda, and Lilly; honoraria for lectures from AZ, GSK, and ACT-Genomics; travel support from AZ; and participation in a data advisory role with Australasian Gastro-Intestinal Cancer Trials Group and Independent Data and Safety Monitoring Board. IRC reports personal fees and travel support from AZ, GSK, and Clovis Oncology; and personal fees from Roche, Mersana, Deciphera, Eisai, Amgen, Bristol Myers Squibb, OncXerna, and Aravive. AC reports institutional research funding from AZ; payment from Clovis Oncology for lectures and travel support; and he participates in an advisory role to AZ. RP reports institutional funding from AZ. He participates in an advisory role to AbbVie, AZ, Care4ward (unpaid), Clovis Oncology, Curio Science, Eisai Inc., Genentech, Janssen Oncology (J&J), Merck & Co., Mersana Therapeutics, Inc., NewLink Genetics, Nexus Global Group, Pieris Pharma Inc., Roche, Inc., Sutro Biopharma, Syndax Pharmaceuticals, Tesaro Inc., Vascular Biogenics Ltd. NC reports grants, consulting fees, and personal fees from AZ; consulting fees and personal fees from GSK; and personal fees from Tesaro, Novartis, Clovis, MSD, GSK, EISAI. She participates in an advisory role with Roche, PharmaMar, AZ, Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana, OncXerna, and Eisai. KF reports institutional research funding and honoraria for lectures from AZ. GS reports institutional research funding from AZ, MSD, Novartis, and Roche; and consulting fees paid to the institution from BioViva and Segen. IV reports receiving institutional fees from Oncoinvent AS and Genmab; grant funding from Amgen and Roche; consulting fees from Aksebio, Amgen, GmbH, AZ, Clovis Oncology, Carrick Therapeutics, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Roche, Genmab, GSK, Immunogen Inc., Jazz Pharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AS, Sotio a.s., Verastem Oncology, Zentalis; and travel expenses from Amgen, MSD, Tesaro, AZ, Roche. EPL reports medical writing assistance for the primary SOLO2 publication from AZ; institutional grants from AZ and Merck; personal payments for lectures from AZ and GSK; and participation in an advisory role with Incyte, Roche, and Pfizer. He reports other interests including as an employee of ARCAGY GINECO research group. CKL reports institutional payments from Roche, AZ, and Merck KGA; and personal payments for lectures, presentations or travel support from AZ, Amgen, Takeda, Boehringer Ingelheim, Pfizer, Yuhan, Merck KGA, Roche, and MSD. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Hereditary factor (F) XIII-deficiency is a known risk factor for postoperative complications, but data of acquired FXIII-deficiency in malignancies are limited. Therefore, we evaluated the role of acquired FXIII-deficiency in surgery for advanced epithelial ovarian cancer (EOC)., Materials and Methods: We performed a retrospective analysis of patients with known serum FXIII status and treatment between 2011 and 2018 at our center. We defined cohorts according to FXIII with values > 75% as normal (group A), 55-75% as reduced (group B) and < 55% as low (group C). Complications were classified according to the Clavien-Dindo Classification, class III-V complications were defined as severe., Results: 347 patients with EOC were identified. 180 patients (51.2%) were in group A, 82 patients (23.6%) in group B, and 85 patients (24.4%) in group C. Lower levels of FXIII were associated with higher amount of ascites, FIGO IV, high grade serous histology, low albumin, and higher CA-125 levels. Regarding intraoperative variables, low FXIII was associated with longer duration of surgery, higher blood loss, higher surgical complexity score/number of bowel anastomosis and a higher probability for macroscopic residual disease. The risk of severe complications in group A was 12.2%, 24.4% in group B, and 31.8% in group C. In a multivariate model, low FXIII (OR 2.8), > 1 bowel anastomosis (OR 2.7), age-adjusted Charlson comorbidity index ≥ 4 (OR 3.6) and a longer duration of surgery (> 285 min.) were significant predictive factors for severe complications., Conclusion: FXIII is associated with tumor and treatment burden. A low level of FXIII is associated with postoperative complications. The knowledge about the presurgical serum FXIII-level might be helpful to plan the treatment strategy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest., Methods: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed., Results: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR] ≥65 0.43, 95%-confidence interval [CI] 0.24-0.81) as compared with younger patients (N = 155, HR <65 0.31 (95%-CI 0.22-0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05)., Conclusions: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS., Competing Interests: Declaration of Competing Interest Dr. Trillsch reports grants and personal fees from AstraZeneca, Clovis, Eisai, Medac, MSD, PharmaMar, Roche, and Tesaro/GSK, outside the submitted work. Dr. Mahner reports grants and personal fees from AstraZeneca, Clovis, Medac, Novartis, Olympus Europe, PharmaMar, Pfizer, Roche, Sensor Kinesis, Tesaro/GSK, and Teva, outside the submitted work. Dr. Ataseven, Dr. Asher, Dr. Aryal, Dr. Dubot have nothing to disclose. Dr. Clamp reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZenca, Clovis Oncology, outside the submitted work. Dr. Penson reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from AbbVie, Array BioPharma Inc., AstraZenca, Cancer Panels, Care4ward, Eisai, Genetech, Merck & Co., Roche Pharma, Sutro Biopharma, GSK Inc., Vascular Biogenics Ltd., WebMD, outside the submitted work. Dr. Oza, Dr. Dr. Amit, and Dr. Huzarski have nothing to disclose. Dr. Casado reports grants and personal fees from AstraZenca, Eisai, Lilly, MSD, PharmaMar, Roche, Tesaro, outside the submitted work. Dr. Scambia has nothing to disclose. Dr. Friedlander reports grants and personal fees from AbbVie, AstraZenca, Beigene, MSD, GSK, Takeda, Novartis, Lilly, outside the submitted work. Dr. Colombo reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZeneca, BIOCAD, Clovis Oncology, Eisai, GlaxoSmithKline, Immonogen, Mersana, MSD, Novartis, Oncxerna, Pfizer, PharmaMar, Roche, Tesaro, outside the submitted work. Dr. Fujiwara reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from MSD, Daiichi Sankyo, Takeda, Genmab, Nano Carrier, Regenerone, Seagen, Zeria, outside the submitted work. Dr. Sonke reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from Biovica, Merck, Novartis, Roche, Seagen, outside the submitted work. Dr. Denys reports grants and personal fees from Pfizer, Roche, PharmaMar, AstraZeneca, Eli Lilly, Novartis, Amgen, Tesaro, GSK, Teva, outside the submitted work. Dr. Lowe reports other from AstraZeneca (full time employee), outside the submitted work. Dr. Lee reports grants from AstraZeneca, during the conduct of the study. Dr. Pujade-Lauraine reports grants and personal fees from AstraZeneca, Merck, GSK, Roche, Incyte, ARCAGY Research, outside the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Predictive models based on radiomics features are novel, highly promising approaches for gynaecological oncology. Here, we wish to assess the prognostic value of the newly discovered Radiomic Prognostic Vector (RPV) in an independent cohort of high-grade serous ovarian cancer (HGSOC) patients, treated within a Centre of Excellence, thus avoiding any bias in treatment quality., Methods: RPV was calculated using standardised algorithms following segmentation of routine preoperative imaging of patients (n = 323) who underwent upfront debulking surgery (01/2011-07/2018). RPV was correlated with operability, survival and adjusted for well-established prognostic factors (age, postoperative residual disease, stage), and compared to previous validation models., Results: The distribution of low, medium and high RPV scores was 54.2% (n = 175), 33.4% (n = 108) and 12.4% (n = 40) across the cohort, respectively. High RPV scores independently associated with significantly worse progression-free survival (PFS) (HR = 1.69; 95% CI:1.06-2.71; P = 0.038), even after adjusting for stage, age, performance status and residual disease. Moreover, lower RPV was significantly associated with total macroscopic tumour clearance (OR = 2.02; 95% CI:1.56-2.62; P = 0.00647)., Conclusions: RPV was validated to independently identify those HGSOC patients who will not be operated tumour-free in an optimal setting, and those who will relapse early despite complete tumour clearance upfront. Further prospective, multicentre trials with a translational aspect are warranted for the incorporation of this radiomics approach into clinical routine., (© 2021. The Author(s).)

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The present prospective study aimed at determining the impact of cell-free tumor DNA (ct-DNA), CA125 and HE4 from blood and ascites for quantification of tumor burden in patients with advanced high-grade serous epithelial ovarian cancer (EOC)., Methods: Genomic DNA was extracted from tumor FFPE and ct-DNA from plasma before surgery and on subsequent post-surgical days. Extracted DNA was subjected to hybrid-capture based next generation sequencing. Blood and ascites were sampled before surgery and on subsequent post-surgical days. 20 patients (10 undergoing complete resection (TR0), 10 undergoing incomplete resection (TR>0)) were included., Results: The minor allele frequency (MAF) of TP53 mutations in ct-DNA of all patients with TR0 decreased significantly, compared to only one patient with TR>0. It was not possible to distinguish between patients with TR0 and patients with TR>0, using CA125 and HE4 from blood and ascites., Conclusions: Based upon the present findings, ct-DNA assessment in patients with high-grade serous EOC might help to better determine disease burden compared to standard tumor markers. Further studies should prospectively evaluate whether this enhancement of accuracy can help to optimize management of patients with EOC., Competing Interests: FH: Travel grants: AstraZeneca, Tesaro, Roche; Honoraria: Roche, AstraZeneca; Clovis, Advisory: Roche; SL: personal fees from NEO New Oncology GmbH, personal fees from BioNTech Diagnostics, personal fees from Definiens GmbH; PH: Honoraria: Roche, AstraZeneca, Tesaro; Advisory: Roche, AstraZeneca, Tesaro, PharmaMar, Lilly; SH: none; JS: HONORARIA: Astra Zeneca, Eisai, Clovis, Olympus, Johnsons and Johnson, PharmaMar, Pfizer, TEVA, TESARO, MSD; CONSULTING OR ADVISORY ROLE: Astra Zeneca, Clovis, Lilly, PharmaMar, Pfizer, Roche, TESARO, MSD; RESEARCH FUNDING: Astra Zeneca, Clovis, Merck, Bayer, PharmaMar, Pfizer, TESARO, MSD; TRAVEL, ACCOMODATIONS, EXPENSES: Astra Zeneca, Clovis, PharmaMar, Roche, Pfizer, TESARO, MSD; JT: employed at New Oncology; RM: employed at New Oncology; BA: reports receiving honoraria from Roche, Tesaro, Clovis, AstraZeneca, and Celgene for lectures, and is an unpaid consultant/advisory board member for Roche and Amgen; MB employed at New Oncology; SS: none; EM: employed at New Oncology; MB: Travel support from prIME Oncology; JNM: employed at New Oncology; SP: none; FL: employed at New Oncology; AH: none; CG: employed at New Oncology; EIB: reports receiving honoraria for advisory board and educational activities from AstraZeneca, Clovis, Tesaro, GSK, Roche Pharma, Incyte, Eisai, MSD, Abbvie; reports receiving travel costs from Clovis, Tesaro, Roche Pharma; LCH: employed at New Oncology; AdB: reports honorary for advisory board and educational activities for Roche, Astra Zeneca, Tesaro, Clovis, Biocad, and Genmab; JMH: employed at New Oncology. That the competing interests does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: We evaluated the clinical impact of germline (g)BRCA1/2-mutation on initial disease presentation, surgical implications, surgical morbidity and survival in patients with advanced epithelial ovarian cancer (EOC) undergoing debulking surgery (DS)., Methods: Data of all consecutive EOC patients with stage III/IV, high-grade serous disease and known gBRCA1/2 status (gBRCA; non-gBRCA), who underwent DS at our department between 01/2011 and 06/2019 were analyzed. Associations between gBRCA-status and severe postoperative complications and survival were analyzed., Results: gBRCA-status was determined in 50.1% (612/1221) of all patients. gBRCA was present in 21.9% (134/612). Significant differences were observed in terms of median age (p = 0.001) and histology (high-grade serous histology gBRCA: 98.5%, non-gBRCA 76.2%; p < 0.001). gBRCA-status had no impact on intraoperative disease presentation, surgical complexity or complete resection rate (gBRCA: 74.4%, non-gBRCA: 69.0%; p = 0.274). gBRCA-status was not predictive for severe postoperative complication (gBRCA: 12.0%, non-gBRCA: 19.1%; p = 0.082). Median PFS and OS was 31/22 and 71/53 months in patients with/without gBRCA-mutation, respectively. gBRCA was a significant prognostic factor for PFS (HR 0.57 p < 0.001) and for OS (HR 0.64, p = 0.048) after adjusting for established prognostic factors., Conclusions: gBRCA-status had no impact on initial disease presentation, surgical results or postoperative complications. gBRCA patients have a significantly longer PFS but the impact on the long term prognosis is unclear. Complete resection remains the most important prognostic factor in patients with EOC independent of gBRCA-status., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: AB reports personal fees from Roche; grants, personal fees, and non-financial support from Astra Zeneca; personal fees and non-financial support from Clovis; personal fees and non-financial support from Tesaro/GSK; personal fees from Pfizer; personal fees from Genmab; personal fees from Biocad, outside the submitted work. PH reports grants and personal fees from Astra Zeneca; grants and personal fees from Roche; personal fees from Sotio; grants and personal fees from Tesaro; personal fees from Stryker; personal fees from Zai Lab; personal fees from MSD; grants from public funding (DKH, DFG, EU); personal fees from Clovis; personal fees from Immunogen; grants and personal fees from GSK; grants from Boehringer Ingelheim; grants from Medac; grants from Genmab, outside the submitted work. BA reports personal fees and non-financial support from Roche; personal fees from Amgen; personal fees from AstraZeneca; personal fees and non-financial support from Tesaro/GSK; personal fees from Clovis; personal fees from Celgene; non-financial support from PharmaMar; personal fees and non-financial support from MSD; personal fees from Novartis, outside the submitted work.

Purpose: The chemotherapy response score (CRS) is a histopathological tool to evaluate response to neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (OC). We critically evaluated the clinical value of CRS and compared its predictive power to standard serological (CA125) and radiological response., Methods: A retrospective analysis of 277 OC patients, who received primary chemotherapy, was performed. CRS, serological, and radiological findings were correlated with progression-free (PFS) and overall survival (OS)., Results: CRS could be determined in 172 of 277 patients (62.1%). In patients with CRS3, a longer median PFS and OS was observed compared with CRS1/2 patients (31.2 vs. 18.9, P < 0.001; 55.0 vs. 36.1 months, P = 0.050). CA125 and radiological response evaluation were also predictive for PFS and OS. Patients with serological and radiological complete response showed longer PFS (23.0 vs. 14.4, P = 0.011; 21.4 vs. 9.6 months, P < 0.001) and OS (49.5 vs. 29.0, P = 0.003; 45.0 vs. 12.9 months, P < 0.001). Patients with pathological complete response (pCR) had the best median PFS (52.8 months), even compared with non-pCR CRS3 (27.8 months). In the total study cohort, serological, and radiological complete response was better at predicting PFS (hazard ratio 2.23 and 2.77)., Conclusion: In this study, evaluation of response to chemotherapy by CRS was not superior to conventional methods (CA125 or radiology). Independent of the evaluation method, response to NACT was predictive of PFS and OS. We observed no added value for CRS as a prognostic marker. The clinical relevance of CRS should be discussed, as no therapeutic consequences result from CRS evaluation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: The therapeutic role of pelvic and para-aortic lymphadenectomy in surgical staging of apparent early-stage epithelial ovarian cancer (eEOC) is still under debate. The aim of this study was to evaluate the potential therapeutic role of systematic lymphadenectomy in patients with eEOC., Methods: Multi-center retrospective cohort study, comparing women with apparent eEOC who underwent comprehensive bilateral pelvic and para-aortic lymphadenectomy (defined as ≥20 lymph nodes) versus patients receiving no lymphadenectomy or lymph node sampling, from 05/1985 to 12/2016. Patients with bulky nodes at CT-scan and those without complete intra-peritoneal surgical staging were excluded. Only patients who received at least 3 cycles of platinum-based adjuvant chemotherapy were included., Results: Out of 2559 patients with FIGO stage IA-IIIA1 ovarian cancer, 639 (25.0%) met inclusion criteria. 360 (56.3%) underwent comprehensive lymphadenectomy, 150 (23.5%) lymph node sampling and 129 (20.2%) no lymphadenectomy. Patients who underwent comprehensive lymphadenectomy were younger (p < 0.001), experienced a higher number of severe post-operative complications (p = 0.008) and had a longer time to start chemotherapy (p = 0.034). There was no difference in intra-operative complications. Median follow-up was 63 months (range, 5-342). The 5-year disease-free survival (DFS) was 79.7% vs. 76.5% vs. 68.3% (p = 0.006), and 5-year overall survival (OS) was 92.3% vs. 94.5% vs. 89.8% (p = 0.165) in women who received comprehensive lymphadenectomy vs. lymph node sampling vs. no lymphadenectomy, respectively. Lymphadenectomy represented an independent factor for DFS improvement, HR 0.52 (95%CI 0.37-0.73) (p < 0.001)., Conclusion: Pelvic and para-aortic lymphadenectomy in surgical staging of eEOC improves DFS for the price of increasing post-operative complications and time to chemotherapy but does not affect OS. Better understanding of tumor biology may help to identify those patients in whom lymphadenectomy should still play a role., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Due to advances in anticancer treatment and supportive care, patients increasingly complained about nonphysical side effects of chemotherapy and targeted therapy in recent years. Therefore, continuous assessment of side effects and patients' perceptions is important. The aim of this study was to evaluate the identification and severity of side effects perceived by ovarian cancer (OC) and breast cancer (BC) patients undergoing contemporary anticancer therapy., Methods: Between 2015 and 2017, consecutive chemo-naïve OC and BC patients were enrolled in this prospective cohort study. Interviews were performed 12 ± 3 weeks after start of anticancer therapy, and patients were asked to select and rank, according to severity, 72 physical or nonphysical symptoms potentially related to their treatment. Data were analyzed with descriptive statistics., Results: Forty-five OC patients and 98 BC patients completed the interview. Sleeping difficulties were ranked as the most troublesome symptom, followed by concerns about family or partner, and loss of hair. Alopecia was the most predominant side effect for BC patients, whereas OC patients were highly afflicted by numbness in limbs. Chemotherapy alone or in combination with targeted therapy caused pronounced sleep disturbances. Prolonged taxane treatment led to shortness of breath and numbness in limbs. Vomiting was ranked by one and nausea by eight women among the five most bothersome symptoms., Conclusions: Sleep disturbances have lately emerged as the most severe problem in women with OC or BC receiving anticancer therapy. Concerns about family and partner were ranked second in the current study and first in previous investigations.

Background: Borderline ovarian tumors (BOT) are considered a biological category with increased epithelial proliferation and cellular atypia in the absence of invasive growth. Since BOT occur often in young patients fertility sparing surgery (FSS) is an important issue. With this study we aimed to evaluate risk factors for relapses and fertility of patients after FSS., Methods: Patients diagnosed with BOT and treated between 2000 and 2018 were included. External pathological review was done in all patients. FSS was performed after individual discussion and a complete surgical staging according to FIGO, without lymphadenectomy and with a waiver for preservation of uterus and one ovary., Results: Among 352 Patients 80.2% had FIGO I and 63.9% had a serous BOT. Eighteen patients (5.1%) relapsed and 4 cases of malignant transformation were reported (1.1%). One patient of the latter died, all others have no evidence of disease. The overall recurrence-rate was 1.1% in FIGO-Stage I and 25.5% in FIGO III-IV (HR = 27; 95%-CI 7.7-95; p ≤.001). 95 patients underwent FSS. Thirteen (13.7%) of these patients relapsed, all as BOT. In multivariate analysis FIGO stages II-IV (HR = 27; 95%-CI: 8.1-102; p ≤.001) and FSS (HR = 12; 95%-CI: 2.9-47; p = .001) remained significant risk factors for recurrent disease. Pregnancy rate among forty-one patients attempting to conceive was 82.9%. 29 patients experienced at least one life-birth, in total 38 life-births were reported., Conclusion: FSS in stage I is a safe procedure and life-birth-rates after FSS are high. More advanced FIGO stages have to be discussed individually and relapse rates have to be weighed against FSS. A central review of pathology, as we performed routinely, is mandatory and may have contributed to our low rate of invasive relapses., Competing Interests: Declaration of competing interest H. Plett: nothing to disclose; P.Harter: Honoraria: Astra Zeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab, MSD; Advisory Board: Astra Zeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, MSD/Merck; Research funding (Inst): Astra Zeneca, Roche, GSK, Boehringer Ingelheim, Medac, DFG, European Union, DKH, Tesaro, Genmab; F. Heitz: Honoraria: AstraZeneca, Roche, Tesaro, Clovis; Advisory Board: Astra Zeneca, Roche, Tesaro, Clovis; A. du Bois: personal fees from Roche, personal fees from Astra Zeneca, personal fees from Tesaro, personal fees from Clovis, personal fees from Pfizer, personal fees from Genmab, personal fees from Pharmar, personal fees from Biocad, outside the submitted work; B. Ataseven: Roche Advisory board, lecture, travel/accommodation expenses Tesaro Advisory board, travel/accommodation expenses Amgen Advisory board Celgene lecture PharmaMar travel/accommodation expenses Clovis lecture Astra Zeneca lecture; S. Schneider: Roche: lecture Tesaro: Advisory board,lecture, travel/accommodation expenses Clovis: lecture Astra: Zeneca lecture A. Traut, S. Prader, S. Lax, A. Staebler, F. Kommoss and S. Heikaus: nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: This review provides an overview of the current clinical standard in low-grade serous ovarian cancer (LGSOC). The available evidence for surgery and standard treatments is elaborated. In addition, we discuss recent findings and novel treatments for LGSOC., Recent Findings: Two large multicenter trials studying MEK inhibitors in LGSOC have been presented in the last year. Binimetinib demonstrated an activity in LGSOC, especially in KRAS-mutated disease. Trametinib was associated with an improved progression-free survival in relapsed LGSOC. Based on the current results, MEK inhibitors could be an alternative treatment for LGSOC. Surgery is an important step in the treatment of LGSOC. Hormonal therapy and bevacizumab can be beneficial, next to chemotherapy. Targeted treatments, such as the MEK-inhibitor trametinib, seem to be efficient and should be introduced into clinical practice.

Purpose: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome., Experimental Design: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status., Results: A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent de novo signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology., Conclusions: Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker. See related commentary by Handley and Sood, p. 9 ., (©2019 American Association for Cancer Research.)

The indication for staging lymphadenectomy in patients with ovarian cancer (both early- and late-stage disease) has been a major topic of debate in the last decades. Because the Lymphadenectomy in Ovarian Neoplasms (LION) study has recently demonstrated that systematic lymphadenectomy is not beneficial to patients with advanced ovarian cancer, the discussion has become more complex for patients with early-stage ovarian cancer. Further factors, such as differences in the lymph node metastasis rates of different histologic subtypes, which were not known in the past, need to be taken into account. This review is focused on the available evidence concerning lymphadenectomy in patients with newly diagnosed ovarian cancer., (© 2019 American Cancer Society.)

Objective: To evaluate the prevalence of low anterior resection syndrome (LARS) in patients with debulking surgery for primary advanced epithelial ovarian cancer and to identify potential risk factors for development of LARS., Methods: We reviewed data on 552 consecutive patients with primary epithelial ovarian cancer (EOC), who underwent upfront or interval cytoreductive surgery including low anterior resection at two different academic institutions (Kliniken-Essen-Mitte, Germany, and Medical University of Vienna, Austria). Intestinal dysfunction was assessed by the validated LARS-questionnaire via telephone call. We performed descriptive statistics and a binary logistic regression model to evaluate risk factors for LARS., Results: In total, 341 patients were eligible and 206 (60.4%) were successfully contacted and provided complete information. Major LARS was observed in 78 (37.9%) patients, minor LARS in 44 (21.4%) patients, and no LARS in 84 (40.8%) patients. The prevalence rate of major LARS was not influenced by time interval between surgery and LARS assessment, type of cytoreductive surgery, and recurrent disease at the time of assessment. In multivariate analyses, number of anastomosis was independently associated with an increased risk for presence of major LARS (OR 3.76 [1.95-7.24]). In the present cohort, 25.2% patients had more than one bowel anastomosis., Conclusions: LARS in general and major LARS in particular seem to be a frequent long-term complication after debulking surgery including low anterior resection in primary advanced EOC patients. Particularly EOC patients with more than one bowel anastomosis during surgery seem to be at an increased risk for major LARS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The detection of deleterious germline mutations in BRCA1 and BRCA2 considerably influences the clinical management of healthy and diseased carriers. Therefore, the identification of persons at risk who could uptake genetic counseling and testing is pivotal. We developed a checklist with validated criteria to improve the identification, and prospectively evaluate the incidence, of familial cancer history in 5091 breast cancer patients. The rate of 30.4% of patients at high genetic risk underpins the demand for care in risk identification and counseling. The easy-to-use instrument promotes the implementation and dissemination of risk counseling by physicians., (© 2019 Wiley Periodicals, Inc.)

Background: Cardiophrenic lymph nodes (CPLN) define FIGO stage IVB disease. We evaluate the pattern of CPLN metastases, their prognostic impact and the potential role of CPLN resection in patients with epithelial ovarian cancer (EOC)., Methods: Analysis of 595 consecutive patients with EOC treated in the period 01/2011-05/2016. CT scans were re-reviewed by two radiologists. Positive CPLN were defined as ≥5 mm in the short-axis diameter. The role of CPLN resection was evaluated in a case-control matched-pair analysis., Results: Of 595 patients 458 had FIGO stage IIIB-IV disease. We excluded patients undergoing interval surgery (n = 54), without debulking surgery (n = 32) and without sufficient pre-operative imaging (n = 22), resulting in a study cohort of 350 patients. Of these, 133 (37.9%) had negative CPLN and 217 (62.0%) had radiologically positive CPLN. In patients with postoperative residual tumor, enlarged CPLN had no impact on survival. In patients with complete resection (n = 223), 98 (44.0%) had negative CPLN and a 5-year OS of 69% and a 5-year PFS of 41%; in contrast, in the 125 patients (56.0%) with positive CPLN, 5-year OS was 30% and 5-year PFS was 13%. In 52 patients we resected CPLN. The matched-pair case-control analysis did not demonstrate any significant impact on survival of CPLN resection., Conclusion: CPLN metastases are associated with impaired PFS and OS in patients with macroscopically completely resected tumor. Intraabdominal residual tumor has a greater prognostic impact than positive CPLN. The impact of the resection of CPLN remains unclear., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Tumor stage and distinct histological subtypes in epithelial ovarian cancer (EOC) show different prognostic outcome. The aim of this study is to evaluate whether the frequency of lymph node (LN) metastases in patients with different tumor stages and histological subtypes undergoing systematic pelvic and paraaortic lymphadenectomy is coincidentally divergent., Methods: Patients with EOC treated with upfront staging or debulking surgery between January 2000 and December 2016 were included. Systematic lymphadenectomy was performed in all consecutive patients with optimal debulking and without medical contraindications., Results: Seven hundred sixty-two patients including 27.2% with early-stage EOC were included. The median number of removed LNs was 69, and metastases to LNs were found in 54.7%. No LN metastases were found in patients with low-grade endometrioid carcinoma, independently of tumor stage. LN metastases in early-stage low-grade serous (N = 5), mucinous (N = 31), and clear cell (N = 28) EOC were found in one (20%), zero, and one (3.6%) patient, respectively. LN metastases were detected in more than 10% of patients with all other histological subtypes. On multivariate analyses, overall survival was significantly impaired in patients with LN metastases, as compared with patients without LN metastases (p = 0.001)., Conclusions: The risk of LN metastases in patients with EOC is dependent on stage and histological subtype. Patients with incidental finding of early mucinous or low-grade endometrioid EOC are at very low risk of retroperitoneal lymph node metastases. Reoperation for lymph node staging only should be discussed individually with caution.

Background: We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center., Patients and Methods: Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB-IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0-1), intermediate (2-3), and high (≥4), and postoperative surgical complications were graded according to the Clavien-Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS., Results: Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3-5; odds ratio 3.27, 95% confidence interval 1.97-5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection., Conclusion: The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

Objective: To identify risk factors for anastomotic leakage (AL) in patients undergoing primary advanced ovarian cancer surgery and to evaluate the prognostic implication of AL on overall survival in these patients., Methods: We analyzed our institutional database for primary EOC and included all consecutive patients treated by debulking surgery including any type of full circumferential bowel resection beyond appendectomy between 1999 and 2015. We performed logistic regression models to identify risk factors for AL and log-rank tests and Cox proportional hazards models to evaluate the association between AL and survival., Results: AL occurred in 36/800 (4.5%; 95% confidence interval [3%-6%]) of all patients with advanced ovarian cancer and 36/518 (6.9% [5%-9%]) patients undergoing bowel resection during debulking surgery. One hundred fifty-six (30.1%) patients had multiple bowel resections. In these patients, AL rate per patient was only slightly higher (9.0% [5%-13%]) than in patients with rectosigmoid resection only (6.9% [4%-10%]), despite the higher number of anastomosis. No independent predictive factors for AL were identified. AL was independently associated with shortened overall survival (HR 1.9 [1.2-3.4], p=0.01)., Conclusion: In the present study, no predictive pre- and/or intraoperative risk factors for AL were identified. AL rate was mainly influenced by rectosigmoid resection and only marginally increased by additional bowel resections., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The evolving knowledge of ovarian carcinogenesis sets the stage for our understanding of high-grade serous pelvic carcinoma (HGSC). Findings in prophylactic surgery introduced serous tubal intraepithelial carcinoma (STIC) as potential precursor of HGSC. The present study explores whether STIC instead should already be considered as an early stage of HGSC with a need for comprehensive staging and therapy., Patients and Methods: We identified all consecutive patients with HGSC who received first-line therapy in our referral center for gynecologic oncology from January 2011 to April 2016. All chemo-naive patients with upfront debulking surgery in whom an association of STIC and tumor lesions could be analyzed were included. Patients with previous removal of the adnexa or overgrown of the fallopian tube by the tumor were excluded. Pathological workup of the fallopian tubes according to the SEE-FIM protocol was conducted., Results: We analyzed a series of 231 consecutive patients with HGSC of whom 121 (52.4%) had ovarian cancer, 74 (32.0%) had cancer of the fallopian tubes and 36 patients (15.6%) had primary peritoneal cancer. Serous tubal intraepithelial carcinoma could be identified in 158 (68.4%) of 231 patients; of 22 patients, 28.1% is ovarian cancer, 30.8% cancer of the fallopian tubes, and 9.5% peritoneal cancer. Four patients without any further intra-abdominal disease were identified of whom 2 patients had stage FIGO IA and 2 patients had lymph node metastases only., Conclusions: Our data suggest that STIC should be regarded as a malignant lesion with metastatic potential. Therefore, we recommend a comprehensive surgical staging including lymphadenectomy.

Background and Objective: Some authors have claimed a significant impact of β-blocking agents on outcome in epithelial ovarian cancer (EOC). This study investigated the impact of concurrent medication with selective beta blockers (SBB) in patients undergoing primary treatment for EOC., Methods: The study included all consecutive patients with primary EOC treated in two tertiary gynecological-oncologic units between 1999 and 2014. Medication was retrospectively analyzed by chart review., Results: The study cohort comprised 801 patients, of whom 141 (17.6%) had received SBB. Median age of patients without SBB medication was 56years (range: 19-90years) and 64years (range: 41-84years) in patients taking SBB (p<0.001). The main prognostic factor FIGO stage did not differ between both cohorts. 63.8% of patients taking SBB underwent complete tumor resection compared to 74.2% of patients without SBB (p=0.012). Patients without SBB experienced less severe post-operative complications according to the Clavien-Dindo classification (18.8% vs 29.0%; p=0.003). Between the both groups without and with SBB intake, PFS and OS did not differ significantly (PFS: 27months and 24months, p=0.40; OS: 56months and 44, p=0.15). Multivariate analyses did not yield any association between SBB intake and prognosis but confirmed well-known prognostic factors., Conclusions: Intake of selective β-blockers did not influence the prognosis of patients with EOC., (Published by Elsevier Inc.)

Background: This study was designed to evaluate the prevalence, morbidity, and prognostic impact of port-site metastasis (PSM) in patients with epithelial ovarian cancer (EOC) undergoing laparoscopy before subsequent primary debulking surgery (PDS)., Methods: All consecutive patients treated between 2000 and 2014, who had a laparoscopy followed by PDS, were extracted from our prospectively maintained database. All patients with histological examination of port-sites were included in this unicentric exploratory analysis., Results: A total of 250 (25.5 %) of 982 patients with EOC underwent laparoscopy before PDS. Port-site resection was performed in those 214 (85.6 %) patients in whom a complete or almost complete resection with residuals ≤1 cm was achieved. Median interval between laparoscopy and PDS was 25 days. PSM was detected in 100 of 214 patients (46.7 %). Risk factors for PSM were higher tumor stage (odds ratio [OR] 13.5, 95 % confidence interval [CI] 2.9-62.0, p = 0.04), positive lymph node status (OR 3.0, 95 % CI 1.3-6.7, p = 0.009), and ascites >500 mL (OR 3.9, 95 % CI 1.5-10.0, p = 0.005). Wound healing disorders and postoperative morbidity were significantly higher in patients with PSM (Clavien-Dindo Classification grade 3-5: 41.0 vs. 14.9 %, p < 0.001). However, multivariate Cox-regression models did not identify PSM as independent prognostic factor., Conclusions: The prevalence of PSM after laparoscopy in EOC patients is considerably high. PSM had no impact on survival; however, PSM were associated with more postoperative complications and a higher surgical treatment burden. This should be balanced with the expected benefit when laparoscopy is considered for the management of EOC.

Objective: Epithelial ovarian cancer (EOC) patients with the presence of abdominal wall metastasis (AWM) are categorized as stage International Federation of Gynecology and Obstetrics (FIGO) IVB, irrespective of other biologic factors or preceding invasive intervention before final surgery. We evaluated the impact of AWM on patients' overall survival (OS)., Patients and Methods: In this exploratory study, 634 consecutive patients with advanced EOC treated in our center from 2000 to 2014 were included. Patients were categorized into FIGO IIIC (n = 308), FIGO IVB AWM only (n = 86), and FIGO IV others (metastases other than AWM, n = 240). Clinicopathological parameters and survival data were extracted from our prospectively maintained tumor registry. Survival analyses were calculated using Kaplan-Meier method and Cox regression models., Results: In 75 (87.2%) of 86 cases, AWM was seen after a preceding intervention, and only in 12.7%, the deposits were spontaneously established. The median OS in patients with stage FIGO IIIC, FIGO IVB AWM only, and FIGO IV others was 37, 58, and 25 months (P < 0.001), respectively. Patients with FIGO IVB AWM only had a significantly better OS than patients with FIGO IV others (P < 0.001). The numeric longer OS of patients with FIGO IVB AWM only compared with patients with FIGO IIIC was not statistically significant (P = 0.151). In multivariate analysis considering all confounding factors including residual disease, OS of patients with FIGO IIIC did not differ from patients with FIGO AWM only (hazard ratio, 0.84; 95% confidence interval, 0.56-12.26; P = 0.398)., Conclusions: Most AWM are acquired after preceding intervention (puncture or laparoscopy). Prognosis of patients with AWM as the only site of distant metastasis is superior compared with other stage FIGO IV patients. Therefore, up-staging of patients only because of AWM to FIGO IVB may be questioned. A revision/clarification of the FIGO classification system should be considered to avoid unnecessary stigmatization of patients and to classify these patients more appropriately according to prognosis.

Epithelial ovarian, fallopian tube and peritoneal cancer (EOC) is the seventh most common cancer diagnosis among women worldwide and shows the highest mortality rate of all gynecologic tumors. Different histological and anatomic spread patterns as well as multiple gene-expression based studies have demonstrated that EOC is indeed a heterogeneous disease. The prognostic factors that best predict the survival in this disease include: age, performance status and patient's comorbidities at the time of diagnosis; tumor biology, histological type, amount of residual tumor after surgery and finally tumor stage as surrogate for pre-operative tumor burden and growth pattern. In the majority of patients, the disease is diagnosed in advanced stage, disseminated intra- and/or extra-abdominally. It is unclear whether this is a consequence of distinct tumor biology, absence of anatomic barriers between ovary and the abdominal cavity, delay of diagnosis and/or the lack of sufficient early detection methods. FIGO stage IV disease, defined as tumor spread outside the abdominal cavity (including malignant pleural effusion) and/or visceral metastases, will be present in 12-33% of the patients at initial diagnosis. Overall, median survival for patients with stage IV disease ranges from 15 to 29months, with an estimated 5-year survival of approximately 20%. Unfortunately, over the past decades the overall survival gain compared to stage III remains disappointing. The current review aims to summarize the current data published in the international literature concerning FIGO stage IV EOC and discusses the published evidence for the clinical management of these patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The revised 2014 FIGO staging system for epithelial ovarian cancer (EOC) included many changes of the previous system, particularly dividing FIGO stage IV in two subgroups. We evaluated if classifying patients with EOC in FIGO stage IVA and IVB has any prognostic implication., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Debulking surgery for advanced ovarian cancer does not routinely include opening of the thorax. Even systematic lymphadenectomy does not commonly extend to lymph nodes above the diaphragm. We evaluated the outcome of systematic resection of suspicious cardiophrenic lymph nodes detected on preoperative CT-scan in patients with advanced epithelial ovarian cancer (EOC)., Methods: Single-center, prospective series of 196 consecutive patients with EOC undergoing primary debulking surgery between June 2013 and June 2015. Suspicious cardiophrenic lymph nodes were defined as ≥10mm on the short axis diagnosed in pre-operative CT-scan and were removed if intra-abdominal debulking resulted in complete resection or residual tumor <10mm and the patients' performance status allowed this additional procedure. Removal of suspicious cardiophrenic lymph nodes was performed via a trans-diaphragmatic approach., Results: Thirty (15%) out of 196 EOC patients had radiologically suspicious cardiophrenic lymph nodes ≥10mm and complete resection or residual tumor <10mm. Twenty-seven out of the thirty patients had at least one confirmed metastatic cardiophrenic lymph node. Metastatic cardiophrenic lymph nodes were associated with extensive intra-abdominal tumor spread in the upper abdomen., Conclusions: Patients with suspicious cardiophrenic lymph nodes detected by preoperative CT-scan had histologically confirmed metastasis in 90% of cases. The surgical procedure is feasible without major complications if performed by experienced gyneco-oncologists. The prognostic value of this procedure should be evaluated in larger controlled studies., (Copyright © 2016. Published by Elsevier Inc.)

Objective: Describing the pattern of and reasons for post-operative tumor residuals in patients with advanced epithelial ovarian cancer (AOC) operated in a specialized gynecologic cancer center following a strategy of maximum upfront debulking followed by systemic chemotherapy., Methods: All consecutive AOC-patients treated between 2005 and 2015 due to stages FIGO IIIB/IV were included in this single-center analysis., Results: 739 patients were included in this analysis. In 81 (11.0%) patients, chemotherapy had already started before referral. Of the remaining 658 patients, upfront debulking was indicated in 578 patients (87.8%), while 80 patients (12.8%) were classified ineligible for upfront debulking; mostly due to comorbidities. A complete tumor resection was achieved in 66.1% of the 578 patients with upfront surgery, 25.4% had residuals 1-10mm and 8.5% had residuals exceeding 10mm, and 12.5% of patients had multifocal residual disease. Most common localization was small bowel mesentery and serosa (79.8%), porta hepatis/hepatoduodenal ligament (10.1%), liver parenchyma (4.3%), pancreas (8.0%), gastric serosa (3.2%), and tumor surrounding/infiltrating the truncus coeliacus (2.7%); 14.9% of the patients had non-resectable supra diaphragmatic lesions. Size of residual tumor was significantly associated with progression-free and overall survival., Conclusions: Upfront debulking for AOC followed by systemic chemotherapy was our main treatment strategy in almost 90% of all patients. The majority experienced a benefit by this approach; while 11.7% of patients probably did not. Understanding sites and reason for residual disease may help to develop adequate surgical training programs but also to identify patients that would better benefit from alternative treatment strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine the impact of debulking surgery (DS) and residual disease (RD) on outcome in patients with FIGO stage IV epithelial ovarian cancer (EOC)., Patients and Methods: This exploratory study included 326 consecutive patients with FIGO IV EOC treated in our centers from 2000 to 2014. Data were extracted from our prospectively maintained registry., Results: In patients, who underwent DS (n=286; 87.7%), complete macroscopic resection was achieved in 54.9% (RD0; n=157), RD of 1-10mm in 30.8% (RD1-10; n=88), and RD of >10mm in 14.3% (RD>10, n=41). Forty patients without surgery (NoCS; 12.3%) underwent either primary chemotherapy or palliative care only. Median overall survival (OS) in NoCS was 19months compared to 16, 25, and 50months in RD>10, RD1-10, and RD0, respectively (p<0.001). Multivariate analysis confirmed an inferior OS for NoCS (HR 2.51, 95% CI 1.25-3.57; p=0.001), RD>10 (HR 2.17, 95% CI 1.43-3.70; p=0.002), and RD1-10 (HR 1.50, 95% CI 1.01-2.23; p=0.046) when compared with RD0. Additional independent prognostic factors were poor performance status, ascites >500mL, and advanced intraabdominal tumor stage., Conclusion: Our results confirm the prognostic impact of optimal DS in FIGO stage IV disease. Survival benefit was greatest for patients with complete resection. Although not to the same extent patients do benefit from DS with RD≤10mm. Of note, patients with RD>10mm after DS seemed not to profit from surgery showing comparable OS to patients without DS. Selecting patients who benefit from DS is as crucial in stage IV EOC patients as it is in any other patients with advanced EOC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Hypoalbuminemia has been reported as a risk factor for post-operative complications and unfavorable survival in cancer patients. We aimed to evaluate the predictive value of preoperative serum albumin levels on post-operative complication rate and the impact on overall survival (OS) in patients with epithelial ovarian cancer (EOC) undergoing primary cytoreductive surgery., Methods: The present retrospective study included 604 consecutive patients with EOC who underwent primary cytoreductive surgery at two tertiary cancer centers specialized in gynecologic oncology. Hypoalbuminemia was defined as a pre-operative serum albumin level≤35g/L. Post-operative surgical complications were graded according to the Clavien-Dindo-Classification (CDC). Fisher-test was used to investigate the predictive value of hypoalbuminemia on the rate of severe post-operative complications. Survival analyses were calculated using log-rank test and Cox regression models., Results: The incidence of pre-operative hypoalbuminemia in the entire cohort was 16.4%. Hypoalbuminemia was a predictive factor for severe post-operative complications (CDC 3-5) (OR 3.65, (CI95% 1.59--8.39); p=0.002). Furthermore, median overall survival time of patients with hypoalbuminemia was 24 months compared to 83 months in patients with normal albumin (p<0.001), respectively. Hypoalbuminemia was independently associated with shortened overall survival (HR 2.2 (95% CI 1.6-3.0); p<0.001) even after adjusting established prognostic factors such as age, tumor stage, performance status, and post-operative residual disease., Conclusion: Pre-operative hypoalbuminemia can be used as both an independent predictive factor for severe post-operative complications and as prognostic parameter regarding overall survival in EOC patients. Therefore, albumin levels may be incorporated into future clinical trials as stratification factor., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Lymph node status is an established prognostic factor in epithelial ovarian cancer (EOC). Lymph node ratio (number of positive LN/number of resected LN) reflects both qualitative and quantitative lymph node spread as well as surgical effort and extent of disease. We evaluated whether LNR is a more precise prognostic factor than conventional lymph node status in patients with EOC., Methods: The present retrospective study includes 809 patients with EOC, who underwent primary cytoreductive surgery between 2000-2013. Clinico-pathological parameters and survival data were extracted from a prospectively maintained tumor registry database. The optimal cut-off point for LNR was calculated by using Martingale residuals. Survival analyses were calculated using Kaplan-Meier method and Cox regression models., Results: Lymphadenectomy was performed in 693 (85.7%) out of 809 patients. Median number of removed LN was 64 (IQR 25-75%: 39-84). LNR of 0.25 was identified as the optimal prognostic cut-off value. The estimated 5-year-OS rates were 69.3% for patients with node-negative EOC compared to 33.1% for patients with any lymph node metastasis (p<0.001). The estimated 5-year-OS rates were 42.5% for patients with LNR≤0.25, and 18.0% for patients with LNR>0.25 (p<0.001). Additionally in multivariate analysis LNR>0.25 was approved to be an independent prognostic factor for overall survival (adjusted HR 1.44, 95% CI 1.04-2.00; p=0.028)., Conclusion: LNR more precisely predicts overall survival than conventional lymph node status in EOC patients undergoing primary debulking surgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)