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Objective: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy., Methods: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed., Results: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified., Conclusion: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS)., Methods: We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially‑platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC≥3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS., Results: The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001)., Conclusion: Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC≥3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control., Competing Interests: Conflict of interest statement FR acknowledges travel grant from Pfizer. Y-CL acknowledges institutional research grant from Beigene, honoraria from Astra Zeneca for educational event and received honoraria from GSK for participation in advisory board. MF acknowledges institutional grants from Astra Zeneca, Beigene, Novartis; received honoraria from Astra Zeneca, GSK, MSD; consulting fees from Astra Zeneca, Novartis, GSK, Incyclix. JL acknowledges grants from Astra Zeneca, MSD/Merck; advisory board for Astra Zeneca, Clovis Oncology, GSK, Artios Pharma, MSD/Merck, VBL Therapeutics, BMS, Nuvation, Ellipses, Immagene, Incyte, Immunogen; educational events for Astra Zeneca, MSD/Merck, GSK, Eisai, Neopharm, and data safety monitoring board for Mersana. AO acknowledges data safety monitoring board for Morphosys, Astra Zeneca, BMS, and uncompensated leadership role for Ozmosis Research where he is CEO and Board member. FH acknowledges grants from GSK, Astra Zeneca, MSD, PharmaMar, Immunogen, consulting fees from Immunogen, MSD, Astra Zeneca; honoraria from GSK, Astra Zeneca, MSD, Pharma Mar; and has been on data safety monitoring boards for MSD, GSK and Astra Zeneca. JB acknowledges grants from Tesaro, Eisai, Immunogen, Karyopharm. MS acknowledges institutional grants from Astellas, Amgen, Astra Zeneca, Bionomics, BMS, Celgene, Medivation, Merck, Sharp and Dohme, Pfizer, Roche and Sanofi. MK, RO, EA-L, FJ, M-CK, YY, DB and AL declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We present the rare case of a 21 year old woman with small cell carcinoma of the right ovary of the hypercalcemic type with dramatic response to checkpoint inhibitor., Methods: Case report., Results and Conclusions: Our patient, a 22-year old woman with small cell carcinoma of the hypercalcemic type with hepatic metastases, is currently 43 months under treatment with pembrolizumab. Last MRI revealed no viable liver metastases nor other signs of recurrence. This is the longest survival of a patient with small cell carcinoma of the ovary under therapy with checkpoint inhibitors reported in the literature so far. With this report we emphasize the importance of immunohistological testing for PD-L 1. Treating clinicians should keep off-label use of immune checkpoint blockade in mind when treating this highly aggressive tumor if all other treatment options fail., 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 Elsevier Inc. All rights reserved.)

Objective: This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment-associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study., Methods: Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell-inflamed gene expression profile [Tcell inf GEP] and 10 non-Tcell inf GEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for Tcell inf GEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-Tcell inf GEP signatures; all but Tcell inf GEP and TMB were adjusted for multiplicity., Results: No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and Tcell inf GEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c + and CD11c + /MHCII - /CD163 - /CD68 - in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively)., Conclusions: This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c + and CD11c + /MHCII - /CD163 - /CD68 - phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC., Clinical Trial Registration: ClinicalTrials.gov, NCT02674061., Competing Interests: Declaration of Competing Interest J.A. Ledermann reports receiving research grants from AstraZeneca and Merck/MSD; lecture fees from Clovis Oncology, AstraZeneca, Neopharm, GSK and MSD/Merck; and advisory board fees from AstraZeneca, GSK, Artios Pharma, Clovis Oncology, ImmunoGen, Mersana, Bristol Myers Squibb, Nuvation, Ellipses Pharma, VBL Therapeutics, Eisai, Regeneron, and Immagene, outside of the submitted work. R. Shapira-Frommer reports receiving support with medical writing for the submitted work from MSD; a research grant from MSD; consulting fees paid to her from MSD and Clovis Oncology; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events paid to her from MSD, Bristol Myers Squibb, Roche, AstraZeneca, Sanofi, Medison Pharma, Neopharm, and Novartis; participation on a data safety monitoring board or advisory board for MSD (received personal fee), Novartis (received personal fee), and AstraZeneca (unpaid); and a role in the ENGOT early phase study group (unpaid), outside of the submitted work. A.D. Santin reports grants or contracts paid to his institution from Genentech, Immunomedics, Gilead, Merck, Boehringer Ingelheim, and Tesaro; consulting fees paid to him from Merck, Eisai, and R-Pharm US; and participation on a data safety monitoring board or advisory board for Merck, Eisai, and R-PHARM US, outside of the submitted work. A.S. Lisyanskaya reports no disclosures. S. Pignata reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, GSK, Roche, AstraZeneca, and Clovis Oncology, outside of the submitted work. I. Vergote reports contracted research via KU Leuven to his institution from Oncoinvent AS; corporate-sponsored research to his institution from Amgen and Roche; consulting fees paid to him from Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, Roche, Genmab, GSK, ImmunoGen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis; and travel support to himself from Karyopharm Therapeutics, Genmab, and Novocure, outside of the submitted work. F. Raspagliesi reports receiving grants or contracts from GSK, MSD, and AstraZeneca; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from GSK, MSD, and AstraZeneca; and support for attending meetings and/or travel from GSK, outside of the submitted work. G.S. Sonke reports payments to his institution for inclusion of trial subjects and medical writing support, all from MSD, for the submitted work; institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche, and Seagen; and consulting fees paid to his institution from Biovica, Novartis, and Seagen, outside of the submitted work. M. Birrer reports no disclosures. D.M. Provencher reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca and GSK and participation on a data safety monitoring board or advisory board for GSK, outside of the submitted work. J. Sehouli reports receiving consulting fees from Roche, GSK, Tesaro, Novocure, Clovis Oncology, MSD, Merck, Pfizer, and Astra Zeneca; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, GSK, Tesaro, Novocure, Clovis, MSD, Merck, Pfizer, Astra Zeneca, and Eisai; support for attending meetings and/or travel from Roche, GSK, Tesaro, and AstraZeneca; participation on a data safety monitoring board or advisory board for Roche, GSK, Tesaro, Novocure, Clovis Oncology, MSD, Merck, Pfizer, AstraZeneca, Eisai, and PharmaMar; and roles on/as the council of ESGO), president of NOGGO, president of PARSGO, speaker of the Ovarian Cancer Commission (AGO), and delegate to GCIG, outside of the submitted work. N. Colombo reports receiving medical writing support from MSD for the submitted work; grants or contracts paid to her from MSD, Roche, and GSK; consulting fees paid to her from MSD, Roche, GSK, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to her from AstraZeneca, GSK, Novartis, Clovis Oncology, and MSD; support for attending meetings and/or travel from AstraZeneca, MSD, and GSK; participation on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, OncXerna Therapeutics, Pfizer, Pieris, and Roche; and unpaid roles for ACTO Onlus and ESMO Guidelines Committee, outside of the submitted work. A. González-Martín reports receiving grants or contracts from Roche, GSK, and CCUN; consulting fees paid to him from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, HederaDx, ImmunoGen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Sutro Biopharma, Seagen, and Takeda; consulting fees paid to him from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, HederaDx, ImmunoGen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Sutro Biopharma, Seagen, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events paid to him from GSK, Clovis, AstraZeneca, MSD, Mersana, and Roche; support for attending meetings and/or travel paid to him from AstraZeneca/MSD and GSK; and unpaid roles as president of GEICO and ENGOT, outside of the submitted work. A. Oaknin reports grants or contracts paid to her institution from AbbVie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis Oncology Inc., Eisai, Roche, ImmunoGen, MSD de España S.A., Millennium Pharmaceuticals, PharmaMar SA, Regeneron Pharmaceuticals, and Tesaro; consulting fees paid to her from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, Roche, Genmab, GSK, ImmunoGen, Itheos, MSD de España, S.A., Mersana Therapeutics, Novocure, PharmaMar, prIME Oncology, Roche, Sattucklabs, Seagen, Sutro Biopharma, and Tesaro; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ESMO, Edizioni Minerva Medica SpA, and Doctaforum Servicios S.L; support for attending meetings and/or travel paid to her from AstraZeneca, PharmaMar, and Roche; and payment to her for participation on a data safety monitoring board or advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, Roche, Genmab, GSK, ImmunoGen, Itheos, MSD de España S.A., Mersana Therapeutics, Novocure, PharmaMar, prIME Oncology, Roche, Sattucklabs, Seagen, Sutro Biopharma, and Tesaro, outside of the submitted work. P. B. Ottevanger reports receiving support for manuscript writing and provision of study patients from MSD for the submitted work. V. Rudaitis reports no disclosures. J. Kobie is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. M. Nebozhyn is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA, and reports a pending patent (WO 2020/167619) related to the application of angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists. M. Edmondson is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Y. Sun is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and has stock in Merck & Co., Inc., Rahway, NJ, USA. R. Cristescu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and has stock in Merck & Co., Inc., Rahway, NJ, USA; and reports a pending patent (WO 2020/167619) related to the application of Angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists. P. Jelinic is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. S.M. Keefe is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. U.A. Matulonis reports consulting fees paid to her from Merck, GSK, and AstraZeneca; payment made to her from Med Learning Group for her role on the committee on endometrial cancer, which involved creation of the entire lecture and slides; payment made to her for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Research to Practice; payments made to her for participation on the advisory board for Allarity, NextCure, Trillium, Agenus, ImmunoGen, Novartis, Boehringer Ingelheim, Rivkin Foundation, Ovarian Cancer Research Alliance, Clearity Foundation, MorphoSys, and CureLab; and payments for participation on a data safety monitoring board for Alkermes and Symphogen, outside of the submitted work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer., Methods: The placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30)., Results: After 38 months' median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66-1.06; p = 0.13); median OS was not estimable with atezolizumab versus 49.2 months with placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78-1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed ≥10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother., Conclusions: Incorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients., Clinicaltrials: gov registration: NCT03038100., Competing Interests: Declaration of Competing Interest Sandro Pignata: Personal fees (Roche, AstraZeneca, MSD, PharmaMar, GSK, Clovis, Incyte); Research funding to institution (Roche, MSD, AstraZeneca, Clovis, GSK). Michael Bookman: Administrative and per-capita funding for conduct of the clinical trial paid to institution; Consultation fees paid to institution for ad hoc advisory boards (Merck Sharp & Dohme, AstraZeneca, Genentech/Roche, Clovis Oncology, Seattle Genetics, Aravive, AbbVie) and Data Monitoring Committee (Immunogen). Jalid Sehouli: Research funding (Roche Pharma, AstraZeneca, Bayer, Clovis Oncology, GSK, Lilly, Tesaro); Honoraria (Tesaro, GSK, PharmaMar, AstraZeneca, Clovis Oncology, Bayer, Roche, PharmaMar, Vifor Pharma, Hexal AG, Novartis Pharma); Consulting (Tesaro, Merck/Pfizer, PharmaMar, Clovis Oncology, AstraZeneca, Roche Pharma, GSK, MSD, Eisai, Novocure, Oncoinvent). Richard T. Penson: Institutional research funding as principal investigator (Array BioPharma Inc., AstraZeneca., Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, Vascular Biogenics Ltd); Royalties (BMJ Publishing, UptoDate, Elsevier Ltd., Wolters Kluwer Health, Wiley Blackwell); Consulting fees for advisory boards (AstraZeneca, Eisai, GSK Inc., ImmunoGen Inc., Merck & Co., Mersana, Novacure, Roche Pharma, Sutro Biopharma, Vascular Biogenics Ltd); serves on Data and Safety Monitoring Boards (AstraZeneca, EQRx, Roche Pharma). Sakari Hietanen: Consultancy fees (AstraZeneca, Eisai, MSD, GSK); Speaker bureau (AstraZeneca, GSK). Radoslaw Madry: Licences/payments (AstraZeneca); Consulting fees (Roche, MSD, AstraZeneca); Honoraria (GSK, AstraZeneca, Roche); Support for attending meetings and/or travel (AstraZeneca, Roche); Participation on Data Safety Monitoring or Advisory Boards (GlaxoSmithKline, AstraZeneca); Receipt of equipment, materials, drugs, medical writing, gifts, or other services (AstraZeneca). Lyndsay Willmott: Honoraria for speaker bureau (AstraZeneca, Clovis, Eisai, Immunogen, GSK, Merck, Seagen); Honoraria for advisory bureau (Genentech); Participation on advisory boards (AstraZeneca, Clovis, Eisai, Genentech, GSK, Immunogen, Seagen). Tashanna Myers: Personal honorarium for lecture (Immunogen); Honorarium to institution for advisory board (Immunogen). Alain Lortholary: Personal honoraria (AstraZeneca, Clovis Oncology, Tesaro/GSK, Roche, MSD, Novartis). Jessica Thomes-Pepin: Consulting fees for advisory board (Immunogen). Carol Aghajanian: Clinical trial funding to institution (AbbVie, AstraZeneca, Clovis, Genentech/Roche); Consulting fees for advisory boards (AbbVie, Roche/Genentech, Eisai/Merck, AstraZeneca/Merck, Repare Therapeutics); Participation on an advisory board (Blueprint medicine [unrecompensed]); Membership of the Board of Directors (GOG-F [travel cost reimbursement for attending meetings], NRG Oncology [unpaid]). Carolyn McCourt: Royalties (UpToDate). Ashley Stuckey: Royalties (UpToDate). Xiaohua Wu: Honorarium for advisory board (Roche). Larry J. Copeland: DMC membership (Corcept Therapeutics, Inc.); Personal fees for advisory boards (Celsion Corporation, Corcept Therapeutics, Inc., Elevar Therapeutics, GSK Inc., Immunogen, Myriad Genetics, Inc., Rubius Therapeutics, Sorrento Therapeutics, Toray Industries, Inc., VBL Therapeutics, Inc., OncoNova, Inc., Inx Med); Research funding to institution (AbbVie, Advaxis, Agenus, Ajinomoto, Array BioPharm, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono Inc., ERGOMED Clinical Research, Exelixis, Genentech/Roche, Genmab, GSK, Inc., Hoffmann-La Roche, Immunogen, Incyte Corporation, Iovance Biotherapeutics, InVentive Health Clinical, Jansen R&D, Leap Therapetuics, Ludwig Institute for Pharmaceuticals, Merck, Mersana Therapeutics, Inc., Novocure, Novartis Pharmaceuticals, OncoQuest, PRA International, Regeneron Pharmaceuticals, Seattle Genetics, Serono, Sutro Biopharm, Tesaro (GSK), Arcus Biosciences, Inc., Sumitomo Dainippon Pharma Oncology, Cerulean Pharma, Karyopharm, BeiGene USA, Inc., Ovagene, Pfizer Inc., PharmaMar USA Inc.,Precision Therapeutics, Inc., Sanofi, Stemcentrx, Inc., TRACON Pharm, Verastem, Inc.). Yvette He: Employee contracted to provide statistical support to Roche (Parexel). Luciana Molinero, Sheetal Patel, and Victor K. Khor: Employees (Roche/Genentech); Share holders (Roche). Yvonne G. Lin: Employee (Roche/Genentech); Participation on Advisory Board (Intervenn Biosciences, unpaid); Leadership position/committee member (SGO Membership Committee); Share holder (Roche). Kathleen N. Moore: Research funding to institution (PTC Therapeutics, Lilly, Clovis, Genentech, GSK, Verastem), Personal royalties (UptoDate), Personal consulting fees for advisory boards (Aadi, Alkemeres, Aravive, AstraZeneca, Blueprint pharma, Caris, Clovis, Eisai, Genentech/Roche, GSK, Hengrui, Immunogen, Inxmed, IMab, Iovance, Lilly, Merck, Mereo, Mersana, Myriad, Novartis, Novocure, Onconova, OncXerna, Pannavance, Tarveda, VBL Therapeutics, Verastem); Personal honoraria for lectures/presentations/speaker bureau (AstraZeneca, GSK, Immunogen, PRIME, RTP, Medscape, Great Debates and Updates); Support for attending meetings and/or travel (AstraZeneca); Leadership role (GOG Partners Associate director). All authors: Medical writing and article processing charges (F. Hoffmann-La Roche)., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer., Methods: Double-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, β = 80%, one sided., Results: 120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms., Conclusion: The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed., Competing Interests: Declaration of Competing Interest Vergote I. as corresponding author declares consulting fees from Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis; Contracted research (via KULeuven) from Oncoinvent AS; Corporate sponsored research from Amgen and Roche and accommodations and travel expenses from Karyopharm, Genmab and Novocure. Van Nieuwenhuysen E. declares consulting/advisory board fees from AstraZeneca, Regeneron; research support from Eli Lilly and travel expenses from Roche and PharmaMar. Casado A. declares consulting or advisory role from Roche Spain, PharmaMar, Eisai, Merck Sharp & Dohme, Eisai (all personal); research funding from PharmaMar (institutional); travel and accommodation support from PharmaMar, Roche, Lilly Spain (all personal); other relationship with Lilly (institutional). Laenen A. declares no conflicts. Lorusso D. declares consultant honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis and PharmaMar; invited member of advisory board from Oncoinvest, Corcept, Sutro; invited speaker and member of advisory boards from AstraZeneca, Immunogen, GSK, Seagen, Genmab; research institutional funding from Clovis Oncology, GSK, MSD and PharmaMar; grants for traveling: AstraZeneca, Clovis Oncology, GSK. Braicu E.I. received research funding from Bayer, Roche Diagnostics, Tesaro, GSK, and AstraZeneca and received personal fees from AstraZeneca, Clovis, GSK, Tesaro, EISAI, RochePharma, and Roche Diagnostics. Guerra-Alia E. has received advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar, Roche; she has received speaker bureau/expert testimony honorarium from AstraZeneca-MSD, PharmaMar, Roche, GSK-Tesaro, Clovis and she received travel/accommodation/expenses from Roche, GSK-Tesaro and Baxter. Zola P. declares consulting fees from Astrazeneca. Wimberger P. has received research funding from Amgen, AstraZeneca, MSD, GlaxoSmithKline, Novartis, Pfizer, Roche Pharma, Clovis, Lilly, honoraria from Amgen, AstraZeneca, MSD, GlaxoSmithKline, Novartis, Pfizer, Roche Pharma, Clovis, TEVA, Eisai, Lilly, Gilead, Daichii Sankyo. He participates at advisory boards from Amgen, AstraZeneca, MSD, GlaxoSmithKline, Novartis, Pfizer, Roche Pharma, Clovis, TEVA, Eisai, Lilly, Gilead and Daichii Sankyo. Debruyne P.R. received grants from Pfizer (institutional); consulting fees for Advisory Boards from BMS, Merck Pfizer, Ipsen; honoraria for lectures from Bayer; travel support from Janssen; (Substitute) Board Member, Clinical Trials College, Federal Public Service, Kingdom of Belgium; stock or stock options from Alkermes and Biocartis Group NV. Ferrero A declares honoraria from GlaxoSmithKline, Clovis, Astra Zeneca-MSD; invited member of advisory boards from Astra Zeneca-MSD. Muallem MZ received consulting fees from Styker, Intuitive and BD. Garcia-Martinez E. received accommodations and travel expenses from GSK, Roche, MSD and consulting or educational fees from GSK, AstraZeneca, Pharmamar, MSD. Pignata S. has no COI related to this paper. Sehouli J. received consulting fees from Tesaro, Merck/Pfizer, PharmaMar, Clovis Oncology, Eisai, Oncoinvent, AstraZeneca, Roche Pharma, GlaxoSmith, MSD, Novocure; honoraria for lectures from Tesaro, PharmaMar, Clovis, Roche, Vifor Pharma, Novartis Pharma, GlaxoSmith, AstraZeneca, Bayer, PharmaMar, Hexal AG; patents from Roche Pharma, Bayer, GlaxoSmith, Tesaro, AstraZeneca, Clovis and Lilly. Van Gorp T. received grants from Amgen, Roche and AstraZeneca (institutional); consulting fees from AstraZeneca, Eisai Europe, OncXerna Therapeutics, MSD/Merck, GSK, ImmunoGen and Seagen (all institutional); he received travel support from Amgen, Pfizer, Roche, Sanofi-Aventis, Novartis, Roche, Immunogen, MSD, AstraZeneca, PharmaMar and GSK. Gennigens Ch. declares no disclosures for the present manuscript; grants/contracts from AstraZeneca, consulting fees from Ipsen, GSK and MSD; honoraria for lectures etc. from MSD, BMS, Ipsen, Pfizer, Pharmamar, AstraZeneca, GSK; support for meetings and/or travel: Ipsen, Pharmamar, Pfizer, MSD, GSK; participation on data safety monitoring board or Advisory Board: MSD, BMS, Ipsen, AstraZeneca, GSK, Eisai. Rubio MJ. has served on advisory boards for MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar and received support for travel or accommodation from Roche, AstraZeneca, PharmaMar, MSD and GSK., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels., Methods: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance., Results: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy., Conclusions: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950)., Competing Interests: Declaration of Competing Interest TH reports medical writing support; consulting fees from Astra Zeneca (AZ), Caris, Clovis, Genentech, Gradalis, Epsilogen, Merck (MSD), Eisai, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, GlaxoSmithKline (GSK); participation on a Data Safety Monitoring Board or Advisory Board from Incyte, Corcept; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as Treasurer GOG Foundation and Associate Director GOG-P. SP reports no conflicts of interest. SG reports payments for clinical trial conduct from Eisai; grants or contracts for clinical trial conduct from GSK, Merck, Mersana, Jounce, AZ, Seagen, Clovis; consulting fees from Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eisai and GSK; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as GOG foundation, GASCO, National Cancer Institute Cervix committee. MR reports no conflicts of interest. KF reports grants and contracts from Eisai; consulting fees from Eisai. CV reports medical writing support from Eisai; consulting fees from Janssen-Cilag, Roche, GSK, Atheneum Partners, Astellas Pharma, MSD, Bristol Myers Squibb (BMS), Leo-Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssens Cilag, Leo Pharma, Bayer; support for attending meetings and/or travel from Roche and Pfizer. DA reports clinical trial support from Eisai. JS reports consulting fees from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck, Clovis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck; payment for expert testimony from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck; support for attending meetings and/or travel from GSK, Roche, AZ; participation on a Data Safety Monitoring Board or Advisory Board from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck, Clovis; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as ESGO council, NOGGO council, AGO Executive Board, GCIG member; RC reports grants or contracts from AZ, Clovis, Genelux, Genmab, Merck, Immunogen Janssen, Roche/Genentech; consulting fees from Agenus, Alkermes, AZ, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Janssen, OncoQuest, Onxeo, Onxerna, Regeneron, Roche/Genentech, Novocure, Merck, Abbvie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, Roche/Genentech, Merck; participation on a Data Safety Monitoring Board or Advisory Board from VBL Therapeutics. HG reports no conflicts of interest. GS reports grants or contracts from MSD Italia; consulting fees from Tesaro Bio Italy srl, Johnson and Johnson; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Clovis Oncology Italy srl. BM reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AZ, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Lovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem, Zentalis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, Eisai, Merck, Myriad, Roche/Genentech, Tesaro/GSK. JA reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Merck, Astellas, Eisai, Ipsen, Pfizer; support for attending meetngs and/or travel from Ipsen. KU reports grants or contracts from Eisai. RH reports grants or contracts from AZ, Clovis, GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, GSK; multiple cases for medicolegal expert witness; participation on a Data Safety Monitoring Board or Advisory Board from AZ, Clovis, GSK. CZ reports grants or contracts from Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Eisai, GSK; support for attending meetings or travel from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Eisai, GSK, ExactSciences, Clovis; participation on a Data Safety Monitoring Board or Advisory Board from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Eisai, GSK, DaichiSankyo. RW reports support for medical writing from Eisai; grants or contracts from OnTarget Labs, Merck, Anixa Bioscience; consulting fees from Novocure, Mersana, AZ, Ovation Diagnostics, Sonnet Biotherapeutics, Shattuck Labs, Clovis, Abbvie, Tesaro/GSK, Seagen, Genentech, Merck, Regeneron, Legend Biotech, Eisai; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ and GSK; support for attending meetngs and/or travel from Sonnet Biotherapeutics and Tapimmune; participation on a Data Safety Monitoring Board or Advisory Board from Tesaro, Seagen; stock or stock options from Ovation Diagnostics; AG reports grants or contracts from Roche and Tesaro/GSK; consulting fees from AZ, Genmab, MSD, Oncoinvent, PharmaMar, SOTIO, Clovis, Immunogen, Amgen Merck/Pfizer, Roche, GSK/Tesaro; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Tesaro/GSK, Clovis, Immunogen, Pfizer, Amgen, SOTIO, Marcrogenics, AZ, MSD, Genmab, Oncoinvent, EMD Serono, Mersana, SUTRO, PharmaMar; support for attending meetngs and/or travel from Roche, PharmaMar, AZ, Tesaro/GSK; BS reports consulting fees from AZ, Clovis, GSK, Merck, Eisai, Lilly, Novartis, Immunogen, Seagen, Genmab, Genentech; YJ reports employment from Eisai; LR reports employment from Eisai. KT reports support for the manuscript from Eisai; consulting fees from Merck, GSK, Clovis, AZ, Regeneron, Eisai, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, GSK, Clovis, AZ, Regeneron, Eisai, Seagen; participation on a Data Safety Monitoring Board or Advisory Board from Lovance. SW reports employment from Eisai. IV reports grants or contracts from Oncoinvent, AS, Amgen, Roche; consulting fees from Agenus, Akesobio, AZ BMS, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis; support for attending meetngs and/or travel from Karyopharm, Genmab, Novocure., (Copyright © 2023. Published by Elsevier Inc.)

Endometrial cancer incidence and mortality are rising among all ethnic groups. Carboplatin plus paclitaxel is the established frontline treatment for advanced/recurrent disease; however, subsequent treatment with traditional cytotoxic chemotherapy is challenging. The molecular characterization of endometrial cancer has provided important insights into the biological drivers of carcinogenesis, which has allowed for the development of newer precision immunotherapies and targeted therapies, including pembrolizumab, dostarlimab, and lenvatinib. Until recently, platinum rechallenge was often considered at the time of recurrence, given the lack of other available therapeutic options; however, "platinum sensitivity" in endometrial cancer is subjective and largely based on expert opinion and/or practitioner experience. Small retrospective studies have tried to provide guidance on the utility of platinum rechallenge, but they are limited by variable patient characteristics and small sample sizes. The applicability of these retrospective studies to contemporary clinical practice is difficult in the setting of changing patient demographics, a better understanding of endometrial cancer drivers, and the recent approvals of immune checkpoint inhibitors and the combination of lenvatinib plus pembrolizumab in the second-line setting. The primary focus of this review is to distill the available data regarding platinum-doublet chemotherapy rechallenge and highlight recent pivotal developments in endometrial cancer treatment, as well as future directions., Competing Interests: Conflict of interest statement Outside the submitted work, M Rubinstein reports funding from Merck, Zentalis, and AstraZeneca. V Makker reports advisory board participation for Eisai, Merck, Clovis, Faeth, Duality, Morphyes, Karyopharm, Novartis, Lilly, and Immunocore. A Nogueira-Rodrigues is a speaker for AstraZeneca, Merck, Roche, Daiichi Sankyo, Pfizer, Oncologia Brasil, and GSK; and is a consultant for Agenus, AstraZeneca, Eisai, Merck, Roche, and GSK. D Aoki reports consulting fees from Abbie, MSD, AstraZeneca, Takeda, Eisai, and Chugai; and personal fees from MSD, AstraZeneca, Eisai, Genmab, Takeda, Chugai, and Myriad Genetics. S Shen reports payment/honoraria from MJH Life Sciences. J Sehouli reports funding from GSK, Clovis, AstraZeneca, Tesaro, MSD, and Merck; consulting fees from GSK, Clovis, AstraZeneca, Tesaro, MSD, Merck, Roche, Pharmamar, and Eisai; payment/honoraria and advisory board from GSK, Clovis, AstraZeneca, Tesaro, MSD, Merck, Pharmamar, Novocure, and Incyte; payment from GSK, Clovis, AstraZeneca, Tesaro, MSD, Merck, Pharmamar, Novocure, and Eisai; support for meetings/travel from AstraZeneca, Roche, GSK, Tesaro, and Pharmamar; and leadership/fiduciary role for NOGGO, AGO, ENGAGE, and ESGO. DSP Tan reports consultancy fees and honoraria from AstraZeneca, Roche, MSD, Merck Serono, Bayer, Eisai, GSK, Boehringer Ingelheim; institutional research funding from AstraZeneca, Bayer, MSD, Eisai, BMS, Roche and Karyopharm; stock ownership of the Asian Microbiome Library (AMiLi); and support from the Singapore Ministry of Health's National Medical Research Council Clinician Scientist Award and Pangestu Family Foundation Gynaecological Cancer Research Fund. BJ Monk reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, VBL, Verastem, and Zentalis; and payment/honoraria from AstraZeneca, Clovis, Easai, Merck, Myriad, Roche/Genentech, and TESARO/GSK., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is associated with high mortality rates. Surgical outcome is one of the most important prognostic factors. There are no valid biomarkers to identify which patients may benefit from a primary debulking approach., Objective: Our study aimed to discover and validate a predictive panel for surgical outcome of residual tumor mass after first-line debulking surgery., Study Design: Firstly, "In silico" analysis of publicly available datasets identified 200 genes as predictors for surgical outcome. The top selected genes were then validated using the novel Nanostring method, which was applied for the first time for this particular research objective. 225 primary ovarian cancer patients with well annotated clinical data and a complete debulking rate of 60% were compiled for a clinical cohort. The 14 best rated genes were then validated through the cohort, using immunohistochemistry testing. Lastly, we used our biomarker expression data to predict the presence of miliary carcinomatosis patterns., Results: The Nanostring analysis identified 37 genes differentially expressed between optimal and suboptimal debulked patients (p < 0.05). The immunohistochemistry validated the top 14 genes, reaching an AUC Ø0.650. The analysis for the prediction of miliary carcinomatosis patterns reached an AUC of Ø0.797., Conclusion: The tissue-based biomarkers in our analysis could not reliably predict post-operative residual tumor. Patient and non-patient-associated co-factors, surgical skills, and center experience remain the main determining factors when considering the surgical outcome at primary debulking in high-grade serous ovarian cancer patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL)., Method: A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL., Results: Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points., Conclusion: Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research., Competing Interests: Declaration of Competing Interest YCL has received honoraria from GSK for participation on Advisory Board. FJ has received honoraria for educational events and consulting fees from AstraZeneca, Clovis, GSK, MSD, and Seagen. JS has received honoraria and fees from PharmaMar, Roche, Astra, GSK, Clovis, NovoCure, MSD, Tesaro. AO acknowledges institutional research grants from MSD K.K., Fuji Pharma Co., Kissei Pharmaceutical Co., Meiji Holdings Co., Taiho Pharmaceutical Co., Kaken Pharmaceutical Co., Chugai Pharmaceutical Co., Tsumura & Co, Daiichi Sankyo Co., Mochida Pharmaceutical Co., ASKA Pharmaceutical CO., Takeda, Pfizer, AstraZeneca, and Terumo Co.; and has received honoraria for educational events from Takeda, Eisai Co., AstraZeneca, Chugai Pharmaceutical Co, Kaken Pharmaceutical Co., MSD K.K. and Zeria Pharmaceutical. JAL acknowledges institutional research grants from AstraZeneca and MSD/Merck; has received honoraria for educational events from AstraZeneca, Neopharm, GSK and Pfizer; and participate on data safety monitoring board of Regeneron. EAL has received honoraria from Roche. MRS acknowledges institutional research grants from Amgen, Astellas, Astra Zeneca, Bayer, Beigene, BMS, Celgene, Medivation, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and Tilray. MF acknowledges institutional research grants from AstraZeneca, Novartis, and Beigene; has received honoraria (consultancy/educational events) from AstraZeneca, Novartis, GSK, MSD, Takeda, Lily, and ACT-Genomics; and participate on data safety monitoring board for AGITG. RC, MTK, RO, AL, FH, FR, JB, AMO, JSB, DB, AF, MK and KD have declared no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described., Patients and Methods: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields., Results: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months)., Conclusion: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors., Competing Interests: Declaration of Competing Interest The AGO CaRE-1 study was supported by medac oncology without restriction in protocol or analysis., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC., Design: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses., Results: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82-1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01)., Conclusion: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Complete macroscopic tumor resection is the strongest prognostic factor for patients with ovarian cancer, which requires complex surgery for achievement. Based on the mostly advanced tumor stage and high symptom burden many patients are classified as frail which may limit optimal surgical outcome. Aim of this study is to evaluate the predictive ability of Frailty Index for surgical outcomes in patients with ovarian cancer., Methods: This prospective study enrolled patients with ovarian cancer undergoing cytoreductive surgery. We classified frailty proposed by Mitnitski et al. regarding the cumulative deficit model of frailty. Utilizing Receiver Operator Characteristic (ROC) analysis and logistic regression, we determined predictive clinical factors for severe postoperative complications. The Kaplan-Meier method and log-rank test were used for overall survival analysis., Results: Out of f 144 enrolled patients, the overall prevalence of frailty based on a Frailty Index >0.26 and Frailty Index >0.15 was 33% and 74%, respectively. The logistic regression shows that frail patients with a Frailty Index >0.26 (Odds ratio (OR): 3.64, 95% CI: 1.34-9.85, p = 0.01), ECOG PS > 1 (OR 6.33, 95% CI:1.31-30.51, p = 0.02) and high surgical complexity score (OR 8.86, 95% CI:1.88-41.76, p = 0.006) had a significant higher risk for severe postoperative complications. According to multivariable cox regression Frailty Index >0.15 (hazard ratio (HR) (HR 1.87, 95% CI: 1.01-3.47, p = 0.048), residual tumor <1 cm (HR 2.75, 95%CI: 1.53-4.99, p = 0.001), residual tumor >1 cm (HR 5.00, 95% CI: 2.74-9.13, p < 0.001) and albumin<35.5 g/dl (HR 1.92, 95% CI: 1.08-3.43, p = 0.03) resulted as significant parameters for poor overall survival. Resulted as significant parameters for poor overall survival., Conclusion: Next to surgical complexity score, ECOG PS > 1 and recurrent surgery, Frailty Index >0.26 is associated with severe postoperative complications in patients with ovarian cancer. Besides tumor residuals and low albumin levels a Frailty Index >0.15 predicts poor survival., Competing Interests: Declaration of Competing Interest MGI reports grants from ALLIMOGI-Foundation during the conduct of the study; JS reports other from Medac, Roche, AstraZeneca, PharmaMar, personel fee and others outside the submitted work; HWs travel expenses were sponsored by Medac. The other authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse., Methods: This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [<50 yrs. (n = 220), 50-69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months., Results: At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (<0.001), larger tumor diameter (<0.001), poorer ECOG status (<0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (<0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50-69 yrs) and 81.1% (<50 yrs), respectively (p < 0.001)., Conclusions: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease., Competing Interests: Declaration of Competing Interest Dr. Prieske reports personal fees from AstraZeneca, Molecular Health,Gsk, Roche, Clovis Oncology outside the submitted work. Prof. Woelber reports grants from medac oncology, during the conduct of the study; personal fees from med update GmbH, grants, personal fees and non-financial support from medac oncology, personal fees from promedics GmbH, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Tesaro, personal fees from Teva, personal fees from OmniaMed, personal fees from Pfizer, personal fees from Greiner, outside the submitted work; Prof. Hilpert discloses personal fees and other from AstraZeneca, Tesaro/ Gsk, PharmaMar, Roche, Clovis and MSD outside the submitted work. Dr. DeGregorio reports personal fees non-financial support from AstraZeneca, Roche, Gsk and MSD as well as personal fees from Clovis and Amgen outside the submitted work. Dr. Harter 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 and personal fees from Public funding (ASCO, DKH, DFG), 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. Prof. Mahner reports grants and personal fees from MEDAC, during the conduct of the study; grants and personal fees from AstraZeneca, personal fees from Clovis, grants and personal fees from Medac, grants and personal fees from MSD, personal fees from Novartis, personal fees from Olympus Europa, grants and personal fees from PharmaMar, grants and personal fees from Roche, personal fees from Sensor Kinesis, grants and personal fees from TESARO, grants and personal fees from Teva, personal fees from AbbVie, personal fees from GSK, personal fees from Pfizer, outside the submitted work; All other authors report no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Objective: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer., Methods: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m 2 , Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d., Results: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm., Conclusions: Addition of ralimetinib to GC resulted in a modest improvement in PFS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Our aim was to investigate the prevalence and potential risk factors for persistent and troublesome physical and psychological symptoms following treatment for ovarian cancer (OC)., Methods: OvQuest is an international, internet-based, cross-sectional questionnaire which explored symptom burden and quality of life (QOL) after treatment for OC. Eligible women were aged 18 and over, diagnosed with OC at least 6 months previously and had received chemotherapy. Self-report data were collected including demographics, diagnosis and treatment, and standardised instruments for treatment-related toxicities, QOL, physical activity (PA) and supportive care needs., Results: The survey included 1360 patients, of whom 421 (31%) had been treated for recurrent OC. 78% reported symptoms of peripheral neuropathy, 60% significant fatigue, 48% mood disturbance and 59% moderate-severe insomnia. Rates of fatigue, mood disorders, neuropathy and insomnia did not differ between women with or without recurrence. The majority of respondents were overweight or obese (high BMI, 59%) and 35% reported low PA. Low PA and high BMI were associated with poorer QOL scores and higher symptom burden across a range of domains., Conclusion: Women living after a diagnosis of OC report a substantial and ongoing symptom burden which impacts significantly on their quality of life across multiple domains. The reported associations between obesity, physical inactivity and poor QOL warrant prospective evaluation of lifestyle interventions to improve QOL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Low-grade epithelial ovarian cancers (EOC), constitute the minority among all epithelial cancers. Our study objective was to focus on low-grade recurrent EOC and compare the survival with high-grade disease, as well as in regard to "platinum-sensitive" and "-resistant" recurrences according to platinum-free interval., Methods: This is an exploratory analysis within the North-Eastern German Society of Gynecological Oncology (NOGGO) database including five randomized phase II/III trials comparing different chemotherapy regimens in recurrent EOC. We conducted survival analyses and cox-proportional regression models., Results: Out of 1050 patients having the first recurrence, 42 (4%) patients had low-grade and 1008 (96%) patients had high-grade disease. In the subgroup of platinum-sensitive recurrences, progression-free survival (PFS) (8.7 m vs 9.7 m, p = 0.7) and overall survival (OS) (23.9 m vs 24.8 m, p = 0.9) did not differ between low-grade and high-grade diseases. In platinum-resistant recurrences, patients with low-grade ovarian cancer had significantly better PFS (7.6 m vs 3.6 m, p = 0.03) and OS (41.9 m vs 9.5 m p = 0.002) in comparison to those with high-grade cancer. At low-grade EOC, there were no significant PFS (p = 0.91) and OS (p = 0.25) differences between platinum-sensitive and -resistant recurrences. Patients with low-grade non-serous histology had lower PFS with compared to those with low-grade serous histology (p = 0.004). At cox regression analysis presence of ascites and residual disease after secondary cytoreductive surgery were independently associated with poor PFS within low-grade recurrent EOC., Conclusion: Our study indicates, platinum-free interval does not have any prognostic significance at recurrent low-grade EOC and non-serous histology is associated with poorer outcome in recurrence. Secondary surgical cytoreduction to no-gross residual disease and ascites are independently associated with disease progression., (Copyright © 2019. Published by Elsevier Inc.)

Objective: In vulvar cancer (VSCC), the course of disease with regard to localization of recurrence and relation of different recurrence sites is poorly described., Methods: The AGO CaRE-1 study is a retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Patients (pts) with primary VSCC, FIGO stage ≥1B treated in Germany from 1998 to 2008 were included in a centralized database (n = 1618). In the current subgroup analysis, different sites of primary recurrence and their impact on disease course and survival were analyzed using multistate and competing risks methods., Results: 1249 pts with surgical groin staging and known lymph-node status (35.8% N+) were included in the analysis. 360 pts (28.8%) developed disease recurrence; thereof 193 (53.6%) at the vulva only, with a cumulative incidence of 12.6% after 2 years. Generally, prognosis after disease depended on recurrence site: Hazard ratios (HRs) (95% confidence interval) to die for pts with compared to without recurrence at the same time: vulvar only: 5.9 (4.3-8.2); groins only: 6.0 (3.0-10.2); vulvar and groins: 14.1 (7.6-26.4); pelvic/distant: 21.2 (15.3-29.4). Fifty-eight (30.1%) pts with local recurrence developed second recurrence. 2-year mortality after any recurrence was 56.3%. After vulvar recurrence pts had a 2-year and 5-year overall survival rate of 82.2% and 66.9%., Conclusions: Prognosis after recurrence is highly depending on recurrence site. Pts with isolated vulvar recurrence have an impaired prognosis as many affected pts develop second recurrences., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Lymph node ratio (LNR) can predict treatment outcome and prognosis in patients with solid tumors. Aim of the present analysis was to confirm the concept of using LNR for assessing outcome in patients with vulvar cancer after surgery with inguinal lymphadenectomy in a large multicenter project., Methods: The AGO-CaRE-1 study multicenter database was used for analysis. LNR was defined as ratio of number of positive lymph nodes (LN) to the number of resected. Previously established LNR risk groups were used to stratify patients. LNR was investigated with respect to clinical parameters. Univariate and multivariable survival analyses were performed to assess the value of LNR in order to predict overall (OS) and progression-free (PFS) survival., Results: In total, 1047 patients treated with surgery including inguinal lymph node resection for squamous cell carcinoma of the vulva were identified from the database. Of these, 370 (35.3%) were found to have positive inguinal LN. In total, 677 (64.7%) had a LNR of 0% (N0), 255 (24.4%) a LNR of >0% < 20%, and 115 (11%) a LNR of ≥20%. Patients with higher LNR were found to have larger tumor size (P < .001), advanced tumor stage (P < .001), high tumor grade (P < .001), and deep stromal invasion (P < .001), more frequently. Three-year PFS rates were 75.7%, 44.2%, and 23.1% and three-year OS rates were 89.7%, 65.4%, and 41.9%, in patients with LNRs 0%, >0% < 20%, and ≥20%, respectively (P < .001, P < .001). On multivariable analyses LNR (HR 7.75, 95%-CI 4.01-14.98, P < .001), FIGO stage (HR 1.41, 95%-CI 1.18-1.69, P < .001), and patient's performance status (HR 1.59, 95%-CI 1.39-1.82, P < .001), were associated with PFS. In addition, LNR (HR 12.74, 95%-CI 5.64-28.78, P < .001), and performance status (HR 1.72, 95%-CI 1.44-2.07, P < .001) were also the only two parameters independently associated with OS. LNR generally showed stronger correlation than number of affected LN when comparing the two different multivariable models., Conclusions: In women with vulvar cancer LNR appears to be a consistent, independent prognostic parameter for both PFS and OS and allows patient stratification into three distinct risk groups. In survival analyses, LNR outperformed nodal status and number of positive nodes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings., Methods: Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed., Results: Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth., Conclusions: Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted., (Copyright © 2018. Published by Elsevier Inc.)

Background: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized., Methods: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape., Results: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas., Conclusion: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To investigate the association of cancer stem cell biomarker aldehyde dehydrogenase-1 (ALDH1) with ovarian cancer patients' prognosis and clinico-pathological characteristics., Methods: The electronic searches were performed in January 2018 through the databases PubMed, MEDLINE and Scopus by searching the terms: "ovarian cancer" AND "immunohistochemistry" AND ["aldehyde dehydrogenase-1" OR "ALDH1" OR "cancer stem cell"]. Studies evaluating the impact of ALDH1 expression on ovarian cancer survival and clinico-pathological variables were selected., Results: 233 studies were retrieved. Thirteen studies including 1885 patients met all selection criteria. ALDH1-high expression was found to be significantly associated with poor 5-year OS (OR = 3.46; 95% CI: 1.61-7.42; P = 0.001, random effects model) and 5-year PFS (OR = 2.14; 95% CI: 1.11-4.13; P = 0.02, random effects model) in ovarian cancer patients. No correlation between ALDH1 expression and tumor histology (OR = 0.60; 95% CI: 0.36-1.02; P = 0.06, random effects model), FIGO Stage (OR = 0.65; 95% CI: 0.33-1.30; P = 0.22, random effects model), tumor grading (OR = 0.76; 95% CI: 0.40-1.45; P = 0.41, random effects model) lymph nodal status (OR = 2.05; 95% CI: 0.81-5.18; P = 0.13, random effects model) or patients' age at diagnosis (OR = 0.83; 95% CI: 0.54-1.29; P = 0.41, fixed effects model) was identified., Conclusions: Basing on the available evidence, this meta-analysis showed that high levels of ALDH1 expression correlate with worse OS and PFS in ovarian cancer patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown., Methods: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two-tailed Chi 2 or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis., Results: In EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC-positive patients, both at diagnosis and at follow-up in platinum-sensitive disease., Conclusions: We observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Aberrant homeobox (HOX) gene expression is reported in high-grade serous ovarian carcinoma (HGSOC), however, its prognostic significance remains unclear., Methods: HOX genes associated with progression-free survival (PFS) in a discovery cohort of primary HGSOC samples with RNA sequencing data, and those previously reported to be associated with clinical outcomes, were selected for qPCR testing in an independent training cohort of primary HGSOC samples (n=71). A prognostic model for PFS was developed using univariate and multivariate Cox regression. Patients were stratified into risk groups that optimized the test statistic. The model was tested in an independent HGSOC cohort from The Cancer Genome Atlas (TCGA) (n=320). The effect of selected HOX genes on drug sensitivity and reactive oxygen species (ROS) accumulation was examined in vitro., Results: Of 23 HOX genes tested in the training cohort, HOXA4 (HR=1.20, 95% CI=1.07-1.34, P=0.002) and HOXB3 (HR=1.09, 95% CI=1.01-1.17, P=0.027) overexpression were significantly associated with shorter PFS in multivariate analysis. Based on the optimal cutoff of the HOXA4/HOXB3 risk score, median PFS was 16.9months (95% CI=14.6-21.2months) and not reached (>80months) for patients with high and low risk scores, respectively (HR=8.89, 95% CI=2.09-37.74, P<0.001). In TCGA, the HOXA4/HOXB3 risk score was significantly associated with disease-free survival (HR=1.44, 95% CI=1.00-2.09, P=0.048). HOXA4 or HOXB3 overexpression in ovarian cancer cells decreased sensitivity to cisplatin and attenuated the generation of cisplatin-induced ROS (P<0.05)., Conclusions: HOXA4/HOXB3 gene expression-based risk score may be useful for prognostic risk stratification and warrants prospective validation in HGSOC patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS)., Methods: mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. χ 2 tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS)., Results: Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with ≥3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p<0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p=0.02). Worse PS and higher mGPS were associated with poorer HRQL (p<0.001). Higher mGPS was associated with worse HRQL, independent of PS., Conclusion: The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Background: Ovarian cancer is mostly diagnosed in the elderly woman who is likely to have comorbid disease and to take several comedications on a regular basis. Aim of this study was to evaluate the influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival., Patients and Methods: In this individual participant data meta-analysis the original data of three phase II/III studies of the North-Eastern German Society of Gynecological Oncology (NOGGO) were analyzed using multivariate logistic and Cox regression., Results: Overall, 1213 patients with recurrent ovarian cancer were included in these analyses. An increasing amount of medication was associated with overall grade III/IV toxicity (p<0.001; OR 1.120), and hematological (p<0.001; OR 1.056) and non-hematological (p<0.001; OR 1.134) toxicities. Prior discontinuation of chemotherapy was not influenced by an increasing amount of medication (p=0.196). There was no association of polypharmacy with overall survival (p=0.068)., Conclusion: As polypharmacy does not influence survival ovarian cancer patients taking several comedications may be included in clinical trials and should not be deprived of adequate cancer treatment. However, a thorough monitoring is mandatory due to the increased risk of toxicities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Wilms tumor protein 1 (WT1) expression is used in gynecological pathology as a diagnostic marker of serous differentiation, and is frequently co-expressed with ER-α. Early phase studies on WT1 vaccine in gynecological cancers are ongoing. In this study we aimed to determine the prognostic value of WT1 in high-grade serous ovarian carcinoma., Methods: WT1 protein expression was determined by immunohistochemistry in a cohort of 207 primary high-grade serous ovarian carcinomas. WT1 mRNA expression was evaluated in a cohort of 1137 ovarian carcinomas from publically available gene expression datasets., Results: High WT1 expression was a significant positive prognostic factor in primary high-grade serous ovarian carcinoma regarding overall survival (OS, p=0.008) and progression free survival (PFS, p=0.015), which was independent of age, stage, and residual tumor (OS: p=0.024, PFS: p=0.047). The prognostic significance of immunohistochemical WT1 expression could be reproduced in an independent cohort of 72 patients. On the mRNA level the prognostic significance was validated in silico in publically available gene expression datasets including TCGA data (OS: p=0.002, PFS: p=0.011). WT1 expression was significantly linked to ER-α expression (p=0.001), and tumors that co-expressed both markers (WT1+/ER-α+) had a longer survival time than tumors of all other marker combinations (OS: p=0.002, PFS: p=0.013)., Conclusion: We present WT1 as a robust prognostic marker in high-grade serous ovarian carcinoma, which adds prognostic information to ER-α. This should be kept in mind when WT1 is used as a biomarker in the context of WT1-targeting therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To analyze the feasibility of total mesometrial resection by laparoscopy (L-TMMR) in a multicentric series of early stage cervical cancer., Method: We prospectively evaluated a consecutive series of cervical cancer patients with pre-operative FIGO stages IA2-IB1 at the Catholic University in Rome and in Campobasso and the Charitè University in Berlin. All cases were assessed at pre-operative MRI scan and clinically confirmed by investigation under anesthesia, adhering strictly to the FIGO criteria. The surgical and post-surgical data were collected., Results: 104 women with cervical cancer were admitted between July 2013 and August 2014 and among them 71 patients with pre-operative FIGO stages IA2-IB1 were treated with L-TMMR. One laparotomic conversion was registered. The median operative time was 260min (120-670min), estimated blood loss was 100cm(3) (25-900cm(3)), and the median length of hospital stay was 6days (2-26days). We observed 8 intra-operative complications including a vascular injury of the left internal iliac vein that caused conversion, 6 vesical injuries and 1 ureteral injury managed laparoscopically. Two vescico-vaginal fistula and one hemoperitoneum were observed as major post-operative complications (4.2%)., Conclusion: L-TMMR can be safely performed in selected cervical cancer patients. Further larger prospective trials are needed to evaluate the oncological outcome of patients undergoing this surgical procedure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer is usually a cancer of the older age group. Comorbidities and comedications increase with rising age. Aim of this study was to evaluate association of comorbidity and comedication with grade III/IV toxicities and prior cessation of chemotherapy in ovarian cancer patients., Patients and Methods: As an individual participant data meta-analysis this study analyzes the original data of three phase II/III chemotherapy studies of the North-Eastern German Society of Gynecological Oncology (NOGGO). Risk scores for certain combinations of risk factors were calculated based on stepwise regression analyses., Results: Altogether, 1213 patients were included in the study. Cardiovascular disease was the most frequent comorbidity (47.5%). In multivariate analyses it was associated with hematological, non-hematological, pulmonary and renal grade III/IV toxicities (p=0.002; p<0.001; p=0.005; p<0.001). Renal toxicity was more frequent when using diuretics and ACE-inhibitors (p<0.001; p=0.002). Prior cessation of therapy was e.g. associated with use of diuretics, insulin and digitalis (p=0.001; p=0.04; p=0.03). The risk for renal grade III/IV toxicities was more than 16 times higher when using both a diuretic and an ACE-inhibitor., Conclusions: Regimens of ovarian cancer treatment should not be restricted to direct cancer therapy but rather include additional individualized treatment of comorbidities. Comedications such as diuretics increase grade III/IV toxicities and patients at risk should be closely monitored., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The role of secondary cytoreductive surgery (SCR) in platinum-sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis., Methods: Using data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery., Results: Of the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001)., Conclusion: SCR was associated with improved OS in platinum-sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response., Methods: SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227)., Results: We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26)., Conclusions: We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors., Methods: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267mg/m(2) equimolar to 76.8mg/m(2) of free doxorubicin) every 3weeks as a two hour i.v. infusion., Results: Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12weeks (95% CI: 8-20weeks), and median overall survival was 53weeks (95% CI: 39-73weeks). Toxicity profile was favorable., Conclusion: AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Cytoreductive surgery and platinum-based systemic therapy constitute the standard treatment of patients with advanced ovarian cancer. The aim of the present study was to evaluate whether the time interval from surgery to start of chemotherapy has an impact on clinical outcome., Methods: Data of 191 patients with advanced serous (FIGO III-IV) ovarian cancer from the prospective multicenter study OVCAD (OVarian CAncer Diagnosis) were analyzed. All patients underwent primary surgery followed by platinum-based chemotherapy., Results: The 25%, 50%, and 75% quartiles of intervals from surgery to start of chemotherapy were 22, 28, and 38 days, respectively (range, 4-158 days). Preoperative performance status (P<0.001), extent of surgery (P<0.001), and perioperative complications (P<0.001) correlated with intervals from surgery to initiation of chemotherapy. Timing of cytotoxic treatment [≤ 28 days versus >28 days; hazard ratio (HR) 1.73 (95% confidence interval 1.08-2.78), P=0.022], residual disease [HR 2.95 (95% confidence interval 1.87-4.67), P<0.001], and FIGO stage [HR 2.26 (95% confidence interval 1.41-3.64), P=0.001] were significant prognostic factors for overall survival in multivariate analysis. While the interval from surgery to start of chemotherapy did not possess prognostic significance in patients without postoperative residual disease (n=121), it significantly correlated with overall survival in patients with postoperative residual disease [n=70, HR 2.24 (95% confidence interval 1.08-4.66), P=0.031]., Conclusion: Our findings suggest that delayed initiation of chemotherapy might compromise overall survival in patients with advanced serous ovarian cancer, especially when suboptimally debulked., (© 2013.)

Objectives: Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented., Methods: Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS)., Results: Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ≥ grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%)., Conclusions: Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer., Methods: In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175 mg/m(2) iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability., Results: A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR=1.46, [80% CI: 1.10-1.94]; P=0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: -16%; paclitaxel: -14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43-48% of patients)., Conclusions: Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified., (Copyright © 2012. Published by Elsevier Inc.)

Objectives: Epithelial ovarian cancer (EOC) is the major cause of death due to gynecological malignancies. The most important prognostic factors are residual tumor mass after surgery and platinum-response. No predictive biomarkers are available to identify patients who will benefit from standard treatment. The aim of our study was to analyze the role of HE4 in predicting surgical and clinical outcome in primary EOC., Methods: In the European multicentric project "OVCAD", 275 consecutive patients with primary EOC were enrolled. Patients were eligible if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Plasma and ascites samples were collected before or during surgery. The concentrations of HE4 and CA125 was determined using ELISA and Luminex technique, respectively., Results: Median age at first diagnosis was 58 years (range 18-85 years). Most patients presented with advanced stage disease, FIGO III or IV (94.6%), grades II-III (96%) and serous histology (86.2%). In most cases a complete cytoreduction to no residual tumor mass was achieved (68.4%). Higher plasma HE4 levels correlated with poor surgery outcome in terms of macroscopically residual tumor mass (p<0.001) and platinum-resistance (p=0.009). Plasma CA125 and the risk index (HE4 and CA125) were independent predictive factors for surgical outcome (p=0.001, OR=3.37, 95% CI=1.61-7.06 and p<0.001, OR=6,041, 95% CI=2.33-15.65, respectively). FIGO stage III was an independent predictive factor for platinum response (p=0.039, OR=0.436, 95% CI=0.198-0.960)., Conclusions: The presented data are showing that the combination of HE4 and CA125 expression in plasma might predict the surgical outcome in EOC and by this may have a prognostic impact on PFS and OS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The study aims at identifying novel markers for circulating tumor cells (CTCs) in patients with epithelial ovarian cancer (EOC), and at evaluating their impact on outcome., Methods: Microarray analysis comparing matched EOC tissues and peripheral blood leucocytes (N=35) was performed to identify novel CTC markers. Gene expression of these novel markers and of EpCAM was analyzed using RT-qPCR in blood samples taken from healthy females (N=39) and from EOC patients (N=216) before primary treatment and six months after adjuvant chemotherapy. All samples were enriched by density gradient centrifugation. CTC positivity was defined by over-expression of at least one gene as compared to the healthy control group., Results: CTC were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two thirds were identified by overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. The presence of CTCs at baseline correlated with the presence of ascites, sub-optimal debulking, and elevated CA-125 and HE-4 levels, whereas CTC during follow-up occurred more often in older and platinum resistant patients. PPIC positive CTCs during follow-up were significantly more often detected in the platinum resistant than in the platinum sensitive patient group, and indicated poor outcome independent from classical prognostic parameters., Conclusions: Molecular characterization of CTC is superior to a mere CTC enumeration or even be the rationale for CTC diagnostics at all. Ultimately CTC diagnostics may lead to more personalized treatment of EOC, especially in the recurrent situation., (Copyright © 2012. Published by Elsevier Inc.)

Objective: Comparative proteomics identified the plasma protein afamin as potential biomarker for ovarian cancer (OC). Significantly decreased afamin plasma concentrations in pre-therapeutic OC patients reconstituted to control values after successful tumor surgery. This study evaluates the association of afamin with survival and response to therapy in serous OC patients within the OVCAD consortium project., Methods: We measured afamin in 215 pre-therapeutic plasma samples, 246 tumor lysates and 109 plasma samples taken 6months after finishing platinum-based chemotherapy. Differences in afamin plasma concentrations among FIGO stages were tested by Kruskal-Wallis test; association of afamin concentrations with overall and progression-free survival was evaluated using Kaplan-Meier survival plots and multivariate adjusted COX regression analysis., Results: Pre-therapeutic afamin correlated significantly with FIGO stages (p=0.012) and was lower in the presence of metastases (p=0.013) and poorly differentiated OC in patients responding to therapy (p=0.016). Afamin ≥48.0mg/L was also associated with a lower hazard ratio for recurrent disease as compared to afamin <48.0mg/L (p=0.007). Post-therapeutic afamin ≥48mg/L was positively correlated with overall (p<0.001) and progression-free (p=0.012) survival and was lower in non-responders than in responders (p=0.048). Thus, afamin returned post-therapeutically to values of healthy controls in responders (p<0.001) but not in non-responders (p=0.114). Afamin in tumor lysates was lower in poorly differentiated OC than in G 1+2 tumors (p=0.041). Higher afamin concentrations in tumor lysates were associated with increased overall survival (p=0.003)., Conclusion: These data indicate that afamin is associated with therapy response and survival rate in advanced OC patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS)., Patients and Methods: We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy., Results: 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8))., Conclusion: The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Carboplatin-based combinations are commonly used in platinum-sensitive ovarian cancer (PSOC). Pemetrexed in combination with carboplatin has been shown to be feasible in a phase I study in PSOC. The primary objective of this subsequent phase II study was to determine the overall response rate (ORR; defined by Response Evaluation Criteria in Solid Tumors) of this combination in patients with recurrent PSOC. Secondary objectives included progression-free survival (PFS), overall survival (OS), and toxicity., Methods: Patients with PSOC (defined by recurrence ≥ 6 months after completion of up to two lines of prior platinum-based therapy), measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. Pemetrexed 500 mg/m(2) was administered as a 10-minute infusion followed by carboplatin AUC 6 as a 30-minute infusion on day 1 of a 21-day cycle., Results: Sixty-six patients were treated. Of the 61 patients evaluable for response, there were 20 responders (one complete response and 19 partial responses), for an ORR of 32.8% (95% CI: 21.3%, 46.0%). For the intent-to-treat population (all 66 patients), the median PFS was 9.4 months (95% CI: 8.3, 11.1), with 22.7% censoring. Median OS was not reached due to the high censoring rate. There was one drug-related death (multi-organ failure). The most common drug-related grade 3/4 toxicities were neutropenia (39.4%), thrombocytopenia (24.2%), carboplatin hypersensitivity (9.1%), nausea (6.1%), and vomiting (6.1%)., Conclusions: Carboplatin AUC 6 and pemetrexed 500 mg/m(2) has a low incidence of serious toxicities. Defining the platinum-based combination with the best therapeutic index would require a prospective phase III study., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response., Methods: Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 μg) or high dose (10, 20, 50 and 100 μg). Responders were patients with either a complete (CR) or partial (PR) response., Results: Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions., Conclusion: Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Granulosa-cell-tumors of the ovary (GCT) constitute a rare group of neoplasms with malignant potential. Due to the rarity of the disease intraoperative tumor-dissemination-patterns are not well defined and are mostly based on retrospective data. Aim of the present study was to describe surgical and clinical outcome and dissemination pathways in the primary and recurrent situation of the disease., Methods: All primary and relapsed GCT-patients, operated between 01/2001 and 02/2010 in our institution were evaluated using a systematic intraoperative documentation-tool (IMO). Surgical outcome, intraoperative tumor-dissemination-pattern and pathological and findings were separately analyzed for the primary and recurrent situation., Results: Overall, 45 patients were analyzed; including eighteen patients with primary and 27 patients with recurrent GCT. Tumor-dissemination-patterns differed significantly between primary and recurrent patients, by the latter having significantly higher rates of diffuse peritoneal involvement (15.8% vs. 52%; p=0.027) and of extraovarian tumor involvement of the middle (15.8% vs. 48.1%; p=0.05) and upper abdomen (0 vs. 33.3%; p=0.006). While all primary patients could be operated tumor-free, this was the case for 85.2% of the relapsed patients (p=0.13). A multivisceral operative approach with extensive peritonectomy, intestinal or diaphragmatic resection, splenectomy and partial hepatectomy/panceratectomy had to be performed only in recurrent GCT (55.6%)., Conclusions: Tumor-dissemination-pathways followed in primary and recurrent GCT differ significantly by higher rates of multivisceral tumor involvement in the recurrent situation of the disease. While at primary presentation extrapelvic involvement with peritoneal carcinosis appears only rare, surgical cytoreduction during relapse is more challenging involving a multivisceral approach., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: Transforming growth factor beta (TGF-beta) signaling via Smads plays a central role in carcinogenesis. Bmp and activin membrane-bound inhibitor (BAMBI) was initially described as a pseudoreceptor antagonizing TGF-beta receptor activation, thus impairing signaling. Here we wanted to estimate the role of BAMBI in ovarian cancer., Methods: The function of BAMBI was studied using a cell line model and intracellular localization experiments. The impact of BAMBI expression on patient outcome was estimated by real-time PCR and immunohistochemistry., Results: We demonstrate for the first time a nuclear co-translocation of BAMBI with Smad2/3 upon TGF-beta treatment. Moreover, overexpression of BAMBI in an in vitro model led to significantly increased proliferation (doubling time -37.0%, P=0.010), migration (+581.2%, P=0.004) and resistance to TGF-beta-mediated apoptosis (decrease of apoptosis from 30% in the control cells to 7% in the BAMBI-overexpressing cells). Although-prima facie-this fits to the thesis of BAMBI as a pseudoreceptor, it may also be explained by modulation of TGF-beta signaling in the nucleus, leading to the observed pro-oncogenic properties. The tumor promoting impact of BAMBI mRNA overexpression in vitro could not be confirmed in primary tumor samples, and while nearly all tumor samples showed up-regulation of BAMBI (37.3% 1+, 39.2% 2+, and 16.7% 3+, respectively) compared to undetectable BAMBI in healthy pre- and post-menopausal ovarian epithelia, no impact of BAMBI expression on recurrence free and overall survival could be observed., Conclusion: These findings provide new insights into the Smad-mediated pathway by inferring that BAMBI is a novel modulator of TGF-beta signaling., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: ATP-binding Cassette (ABC) transporters are thought to cause multiple drug resistance (MDR) in various carcinomas. Gene expression data from individual transporters in ovarian cancer tissue is contradictory and also scarce for some of them. RNA levels of a panel of ABC transporters were collected and analyzed to get a more detailed overview which transporters are of importance in resistance to chemotherapeutic agents in ovarian carcinoma., Methods: Real-time PCR was used to determine RNA expression levels of 9 ABC transporters in 50 benign tissue samples and 50 recurrent ovarian cancer samples. Genes exhibiting a significant difference between those two groups were further evaluated in 50 primary cancer samples. Data were analyzed with receiver operating characteristic (ROC) curves and multiple Wilcoxon-Mann-Whitney U-tests with Shaffer correction., Results: Gene expression of four transporters (ABCC1, ABCC2, ABCC3, and ABCB3) was significantly elevated in recurrent cancer lesions compared to benign tissue. Expression levels of these 4 ABC transporters were further analyzed in primary ovarian cancer lesions. A significant difference between primary and recurrent tumor tissue was found in all four genes. Changes in gene expression between benign samples and primary lesions were minor and not relevant., Conclusions: Four of the examined ABC transporters are likely to play a role in the MDR of ovarian carcinoma. Gene expression of these transporters seems only up regulated through chemotherapy. The thesis that MDR in ovarian cancer is acquired through therapy itself and not present ab initio is supported by these findings., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Background: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index., Methods: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally., Results: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+)., Conclusion: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.

Objective: We evaluated the long-term results of sigmoid vaginoplasty in women with gynecologic malignancies after radical pelvic surgery, with specific focus on safety and effects of the procedure on patients' sexuality and self image., Methods: This prospective study included women with gynecologic malignancies who underwent partial or complete colpectomy as part of the cancer treatment. In all cases a pedicled sigmoid loop was used for the neovaginal reconstruction. Systematic clinical examination was performed and validated questionnaires about sexuality (Female Sexual Function Index), quality of life (SF-12) and susceptibility to depression (ADSk-15) were answered by all patients at the earliest 6 months after vaginoplasty., Results: Seven patients with sigmoid vaginoplasty, recruited between 11/2003 and 02/2008, were evaluated in the present analysis. Mean patients age was 48+/-8.49 years. Mean neovaginal length was 6.4 cm (range: 2-12 cm). The mean Female Sexual Function Index (FSFI)-score of all patients was 16.6+/-12.6. In the subset of sexually active patients the mean FSFI-score was 22.5+/-9.4 higher. Regarding early operative morbidity and complications, sigmoid vaginal reconstruction appears to be a safe procedure, though in a long-term assessment 85% of the patients developed a vaginal stenosis with the need for operative bougienage., Conclusions: The vaginal reconstruction using a sigmoid loop is a safe and well accepted procedure in patients with gynecologic malignancies. However lower sexuality scores seem to be achieved than in non-cancer patients after equivalent vaginoplasty. Cancer-related physical and psychological comorbidity seem to have negative effects on the overall outcome and patient's satisfaction.

Objective: CD24 is an established marker for poor prognosis in ovarian and other carcinomas. Acquisition of cytoplasmic CD24, as opposed to membranous expression, has been correlated with a higher invasiveness of tumor cells. Exosomes are small vesicles of endosomal origin that are often secreted by tumor cells. Given the emerging role of exosomes in tumor progression, we investigated whether cytoplasmic CD24 expression is correlated with the secretion of CD24 in exosomes., Methods: We used CD24 transfected carcinoma cell lines, ovarian carcinoma cell lines and malignant ascites fluid of ovarian carcinoma patients. Exosomes were isolated via ultracentrifugation and sucrose density fractionation and subsequently examined by Western blot analysis and gelatine zymography. In tissue sections CD24 was detected by immunohistochemical staining., Results: We show that CD24 is released by transfected as well as endogenously expressing cells in vesicles that represent exosomes. CD24 was also identified in exosomes isolated from ascites fluid of ovarian carcinoma patients. In 16 ovarian carcinomas analyzed no correlation between CD24 in tumor tissue sections and the appearance of CD24 in exosomes was detected. Furthermore, we provide evidence that the epithelial cell adhesion molecule (EpCAM), known to be overexpressed in ovarian carcinomas, is secreted in exosomes. The ascites exosomes contain gelatinolytic enzymes., Conclusions: Our study identifies CD24 and EpCAM as cargo proteins of exosomes of cultured cell lines and malignant ascites. The exosome-associated proteolytic activity in the tumor vicinity might augment tumor invasion into the stroma.

Objective: The plasminogen activator system (PA) plays an important role in invasion and metastasis of solid tumors. The PA Inhibitor type 1 (PAI-1) is the main physiologic regulator of plasminogen activation. A recently characterized protein, PAI-RBP1 (PAI-1 mRNA Binding Protein 1), appears to regulate the stability of PAI-1 mRNA. Expression of PAI-RBP1 (the new, approved gene symbol is SERBP1) has not been previously analyzed in human tumors. We present herein for the first time expression analysis of PAI-RBP1 in epithelial ovarian cancer., Methods: PAI-RBP1 was identified as gene overexpressed in ovarian cancer by an in silico approach using EST database mining. A thorough expression analysis of PAI-RBP1 and PAI-1 was performed in normal ovary (n=4), benign (n=6) and malignant (n=42) ovarian lesions using non-radioactive RNA in situ hybridization and immunohistochemistry, respectively., Results: PAI-RBP1 mRNA and PAI-1 were significantly overexpressed in tumor epithelial cells as compared to benign and normal ovarian tissue. A significant correlation between PAI-RBP1 expression and advanced disease stage (FIGO) was found (p=0.042)., Conclusion: In ovarian cancer, PAI-RBP1 is significantly overexpressed in tumor epithelial cells, suggesting a biological role in tumor invasion and metastasis. Its expression is higher in advanced disease, thus the prognostic significance of PAI-RBP1 in ovarian cancer remains to be evaluated in further studies.

Background: Tamoxifen and gefitinib (IRESSA) combination therapy was studied in patients with ovarian cancer refractory or resistant to platinum- and taxane-based therapy., Patients and Methods: In this phase II study, 56 patients with epithelial ovarian carcinoma or cancer of the fallopian tube or peritoneum received oral tamoxifen 40 mg/day and gefitinib 500 mg/day until progression or unacceptable toxicity., Results: Seventeen patients (mean age: 59.6 years) had previously received first-line platinum/taxane treatment only, while 39 had received 2-8 (median 2) prior chemotherapy regimens. Gefitinib dose reduction to 250 mg/day was performed in 10 patients (14.9%), predominantly due to diarrhea (6 patients [10.7%]). Trial medication was discontinued in 6 patients (10.7%) due to adverse events (AEs). The most frequent drug-related AEs were diarrhea and acne-like skin rash. There were no tumor responses, but 16 patients had stable disease. Median time-to-progression was 58 days (95% CI, 55-71 days) and median survival was 253 days (95% CI, 137-355 days)., Conclusion: Gefitinib plus tamoxifen did not appear to be efficacious in the treatment of patients with refractory/resistant ovarian cancer. The addition of tamoxifen did not worsen the known side effects of gefitinib, or induce additional side effects.