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High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation., Competing Interests: Disclosure JAL reports personal fees for advisory board membership from Artios Pharma, AstraZeneca, Bristol Myers Squibb (BMS), Clovis Oncology, Eisai, Ellipses, GSK, Immagene, ImmunoGen, Merck/MSD, Miltenyi, Novocure, Nuvation and VBL Therapeutics; personal fees as an invited speaker from AstraZeneca, Clovis Oncology, GSK and Neopharm; personal fees as an Independent Data Monitoring Committee (IDMC) member from Mersana and Sutro Bio; a remunerated leadership role as an Associate Editor of Therapeutic Advances in Medical Oncology (Sage Publishing); institutional research grants from AstraZeneca and MSD/Merck; non-remunerated roles at ESMO (Officer and Subject Editor for the Gynaecological CPGs); and a non-remunerated leadership role as Vice-President of ESGO (2019-2021). XMG reports personal fees for advisory board membership from Amgen, AstraZeneca, GSK, Janssen and Lilly; personal fees as an invited speaker from AstraZeneca, Clovis and GSK; and non-renumerated consultancy for AstraZeneca. FA reports personal fees for advisory board membership from MiMARK Diagnostics; and institutional funding from Estée Lauder. NCon reports personal fees for advisory board membership from AkesoBio, AstraZeneca, Eisai, eTheRNA Immunotherapies, GSK, ImmunoGen, Kartos, Mersana, Seagen and Seattle Genetics; personal fees as an invited speaker from Eickeler, Medconcept, Mediseminar, the Nordic Society Of Gynaecologic Oncology - Clinical Trial Unit (NSGO-CTU) and the North-Eastern German Society of Gynecological Oncology (NOGGO); travel compensation from Amgen, Genmab and Roche; compensation for educational activities from Kartos, Medscape Oncology, MSD and TouchIME; non-renumerated role as the Co-Chair of the Early Drug Development Network of European Network for Gynaecological Oncological Trial groups (ENGOT); non-renumerated role as the President of ESGO; and a non-renumerated role as a clinical trial principal investigator (PI) for Aldeyra, Clovis, Kartos, Mersana and Seagen. BD reports personal fees as an invited speaker from MSD. CFo reports personal fees as an invited speaker from Roche, AstraZeneca, MSD, Clovis, Sequana, GSK, Tesaro and Ethicon; and institutional fees as a member of the Board of Directors of the King Edward VII Hospital. AGM reports personal fees for advisory board membership from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Eisai, Genmab, GSK, HederaDx, Illumina, ImmunoGen, MacroGenics, Mersana, MSD, Novartis, Oncoinvent, PharmaMar, Regeneron, Roche, SOTIO, Sutro Biopharma and Tubulis; personal fees as an invited speaker from AstraZeneca, Clovis Oncology, GSK, MSD, Novocure, Roche, Takeda and Zai Lab; institutional funding as coordinating PI from Aravive, GSK, Novartis and Roche; and non-remunerated membership of a Steering Committee for MSD. CG reports personal and institutional fees for advisory board membership from AstraZeneca, GlaxoSmithKline and MSD; personal and institutional fees as an invited speaker from AstraZeneca, Chugai, Clovis, Eisai, GSK, MSD, Roche and Takeda; personal fees for a writing engagement from Cor2Ed and PeerVoice; institutional research grants from Aprea, AstraZeneca, Medannex, Novartis and Nucana; institutional research grants as a local PI from BerGenBio, Clovis, GlaxoSmithKline, MSD, Roche and Verastem; and non-renumerated membership of the Cancer Research UK Clinical Research Committee, the German Cancer Aid Scientific Review Committee and the International Clinical Cancer Research Committee. AL reports personal fees for advisory board membership from Zentalis Pharmaceuticals; personal fees as an invited speaker from GSK and Medscape; personal fees for consultancy from GLG; personal fees for a writing engagement from Onko+; institutional fees for advisory board membership from Ability Pharma, Apmonia, AstraZeneca, Blueprint, Clovis Oncology, GSK, Merck Serono and MSD; institutional fees as an invited speaker from AstraZeneca, Clovis Oncology and Kephren Publishing; institutional fees for consultancy from Orion and Owkin; institutional fees for Steering Committee membership for MSD; institutional funding as a PI in clinical trials from Agenus, AstraZeneca, BMS, GSK, Iovance; MSD and Roche; institutional funding as a Chief Investigator in clinical trials from AstraZeneca and OSE Immunotherapeutics; institutional research grants as a PI in translational research from Association de Recherche sur les CAncers dont GYnécologiques (ARCAGY)-Groupe d'Investigateurs Nationaux pour les Etudes des Cancers de l'Ovaire (GINECO), AstraZeneca and Sanofi; a non-remunerated role as an IDMC member for Clovis Oncology, as an IDMC Chair for Pfizer (proprietary information) and as a member of the Gynecologic Cancer InterGroup (GCIG); and non-remunerated academic research projects for LXRepair and Owkin. DL reports personal fees for advisory board membership from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar, Seagen and Sutro Biopharma; personal fees as an invited speaker from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, MSD, PharmaMar and Seagen; personal fees for consultancy from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, MSD, Novartis, PharmaMar and Seagen; travel grants from AstraZeneca, Clovis Oncology and GSK; institutional funding as coordinating PI from Clovis Oncology, Genmab and MSD; institutional funding for a clinical trial/contracted research from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, Roche and Seagen; institutional funding for founding an academic trial from Clovis Oncology, GSK, MSD and PharmaMar; a non-remunerated role as a PI in clinical trials for AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, PharmaMar, Roche and Seagen; and a non-remunerated role as a member of the Board of Directors of GCIG. SB reports personal fees for advisory board membership from Amgen, AstraZeneca, Eisai, Epsilogen, GSK, ImmunoGen, Mersana, MSD, Novartis, Oncxerna, Regeneron, Roche, Seagen, Shattuck Labs and Verastem; personal fees as an invited speaker from Amgen, AstraZeneca, Clovis, GSK, Medscape, Novacure, Peerview, Pfizer, Research to Practice and Takeda; ownership of stocks/shares of PerciHealth; institutional research grants from AstraZeneca and GSK; a non-remunerated role as a PI for AstraZeneca (academic-sponsored ENGOT-GYN1/ATARI phase II international trial), GSK (academic-sponsored MONITOR-UK trial) and Verastem (ENGOTov60/GOG3052/RAMP201 phase II clinical trial - global lead); a non-renumerated leadership role as Board member of the International Cancer Foundation; and a non-renumerated advisory role as a medical advisor of Ovacome Charity. LC reports personal fees as an invited speaker from AstraZeneca and Corza Medical; and institutional fees as an invited speaker from GSK and Roche. DC reports personal fees for advisory board membership from Akesobio, GSK, MSD, Novocure, Roche, Seagen and SOTIO; and personal fees as an invited speaker from AstraZeneca. NCol reports personal fees for advisory board membership from AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris and Roche; personal fees as an invited speaker from AstraZeneca and Novartis; institutional research grants from AstraZeneca, PharmaMar and Roche; a non-renumerated membership of the ESMO Guidelines Steering Committee; and a non-renumerated leadership role as Chair of the Alleanza Contro il Tumore Ovarico (ACTO) Scientific Committee. SC declares no conflicts of interest. AGE reports personal fees for advisory board membership from AstraZeneca; personal fees as an invited speaker from GSK and Intuitive Surgical; personal fees as the social media editor of the International Journal of Gynecologic Cancer; and a non-remunerated role as PI of the SENTICOL III trial in Norway for GINECO/NSGO. CFa reports personal fees for advisory board membership from Baxter, Chugai Pharma, Clovis Oncology, Eisai, GSK and Teva; personal fees as an invited speaker from Astellas Pharma, AstraZeneca, Biogaran, BMS, GSK, Janssen Oncology, Leo Pharma, Lilly, MSD Oncology, Novartis, Pfizer Seagen and Viatris; institutional funding as coordinating PI from Astellas Pharma, Chugai Pharma, Pfizer and Pierre Fabre; institutional funding as local PI from Pfizer; non-renumerated congress participation for AstraZeneca, Janssen Oncology, Leo Pharma and Pierre Fabre; and non-renumerated membership of the European Union of Geriatric Medicine Society, the French Society of Geriatrics and Gerontology, the International Society of Geriatric Oncology and the French Society of Geriatric Oncology. DF declares no conflicts of interest. PH reports personal fees for advisory board membership from AstraZeneca, Clovis Oncology, GSK, ImmunoGen, Mersana, Miltenyi, MSD, Novartis and Roche; personal fees as an invited speaker from Amgen, Eisai, Stryker and Zai Lab; personal fees for lectures from AstraZeneca, GSK, MSD and Roche; personal fees as an IDMC member from SOTIO; institutional funding as Trial Chair from AstraZeneca, GSK, ImmunoGen and Roche; institutional funding as local PI from Genmab; institutional funding from Clovis Oncology and Seagen; and a non-remunerated role as PI for AstraZeneca. FJ reports personal fees for advisory board membership from AstraZeneca, Bayer, BMS, Eisai, GSK, Ipsen, Janssen, MSD, Novocure and Seagen; personal fees as an invited speaker from Amgen, Astellas, AstraZeneca, Eisai, GSK, Ipsen, Janssen, MSD and Novartis/3A; institutional funding as coordinating PI from AstraZeneca and GSK; an institutional research grant from BMS; non-renumerated membership of GCIG; and travel compensation from Eisai, GSK, Ipsen and MSD. CLa personal fees for advisory board membership from AstraZeneca and Illumina; and institutional funding from AstraZeneca. CLo declares no conflicts of interest. SM reports personal fees and reimbursement for advisory board membership from AbbVie, AstraZeneca, Clovis, Eisai and Novartis; personal fees and reimbursement as an invited speaker from GSK, Hubro, MSD, Nykode, Pfizer, Roche and Tesaro; and institutional research grants from AstraZeneca, Eisai, Roche and Tesaro. FM reports personal fees for advisory board membership from AstraZeneca, Eisai, GenomicHealth, Gilead/Immunomedics, MSD, Myriad, Novartis, PharmaMar, Roche and Seagen; personal fees as an invited speaker from AstraZeneca, Clovis, GSK/Tesaro, Lilly and Pfizer; institutional fees for advisory board membership from Immunicom and Roche; institutional fees as an invited speaker from AstraZeneca, Daiichi Sankyo, GSK and Seagen; institutional funding as coordinating PI from AGO Research GmbH, AstraZeneca, the German Breast Group, Gilead/Immunomedics and Roche; institutional funding as local PI from Eisai, GSK, MSD, Novartis, Roche and Vaccibody; and institutional funding from AstraZeneca, Lilly and Seagen. CM reports personal fees for advisory board membership from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche Austria and Seagen; and personal fees as an invited speaker from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche and Seagen. WGM reports personal fees as an invited speaker from GSK. IAM reports personal fees for advisory board membership from Alkermes, AstraZeneca, Clovis Oncology, Duke Street Bio, GSK, OncoC4, Roche and Theolytics; personal fees for consultancy from Duke Street Bio; personal fees for travel from AstraZeneca and GSK; institutional funding from AstraZeneca; and a non-remunerated role as a member of the Board of Directors (Trustee) of Worldwide Cancer Research. PM reports personal fees for advisory board membership from AstraZeneca, GSK and ImmunoGen. SN reports personal fees for advisory board membership from AstraZeneca and GSK; personal fees as an invited speaker from AstraZeneca, Clovis and GSK; personal fees for Scientific Committee membership from GSK; ownership of stocks/shares of GSK; and institutional funding from AstraZeneca. AO reports personal fees for advisory board membership from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelisis, EMD Serono, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, Merck Sharps & Dohme de España, SA, Mersana Therapeutics, Novocure, OneXerna Therapeutics, Inc., PharmaMar, Regeneron, Sattucklabs, Seagen and Sutro Biopharma; personal fees for travel/accommodation from AstraZeneca, PharmaMar and Roche; institutional funding from Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, BMS, Clovis Oncology Inc., Eisai Ltd., F. Hoffmann-La Roche Ltd., ImmunoGen Inc., Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc., PharmaMar SA, Regeneron Pharmaceuticals and Tesaro Inc.; non-remunerated roles at ESMO (member, Officer, Co-Chair of the ESMO Gynaecological Cancers Congress 2023-2025, Chair of the Gynaecological Track ESMO 2019, Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022, member of the Gynaecological Cancers Faculty and Subject Editor for the Gynaecological CPGs); non-remunerated roles at GCIG [member and Cervix Cancer Chair on behalf of the Spanish Ovarian Cancer Research Group (GEICO)]; and memberships of the American Society of Clinical Oncology, the Gynecologic Oncology Group and the Spanish Association of Medical Oncology (SEOM). JAPF reports personal fees for advisory board membership from Abilify Pharma, AstraZeneca, Clovis, GSK, PharmaMar and Roche; personal fees as an invited speaker from AstraZeneca, Clovis, GSK and PharmaMar; employment as Associate Professor at the University of Valencia; institutional funding as coordinating PI from AstraZeneca; institutional funding from Novartis and GSK; institutional research grants from GSK and PharmaMar; personal fees as a member of a Steering Committee for Artios Pharma and AstraZeneca; a non-renumerated role as coordinating PI of a phase III trial for Novartis; non-renumerated membership of BIG, the Early Drug Development working group at ENGOT and the Adolescent and Young Adults working group at SEOM; a non-renumerated role as Co-chair of the Phase 2 group at GCIG; non-renumerated roles as member of the Executive Committee and Head of the Scientific Committee at GEICO; and non-renumerated roles as member of the Executive Committee and co-coordinator of Uterine Sarcoma Group at the Spanish Sarcoma Research Group. SP reports personal fees for advisory board membership from AstraZeneca, Clovis, GSK, MSD, PharmaMar and Roche; and institutional funding from AstraZeneca, MSD, Pfizer and Roche. PTR declares no conflicts of interest. IRC reports personal fees for advisory board membership from Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis Oncology, Daiichi Sankyo, Deciphera, EQRX, Eisai, GSK, MacroGenics, Merck Sereno, Mersana, Novartis, Oxnea, Roche and Sutro Biopharma; institutional fees for advisory board membership from MSD; institutional fees for translational research from BMS; a non-remunerated role as President of GINECO; and a non-remunerated role as PI for PAOLA-1. IR reports personal fees for advisory board membership and as an invited speaker from AstraZeneca, Clovis, GSK, PharmaMar and Roche; institutional funding from AstraZeneca; an institutional research grant from GSK; a non-renumerated advisory role at GEICO; and non-renumerated membership of SEOM. GS reports personal fees as an invited speaker from AstraZeneca/MSD, Baxter Healthcare, GlaxoSmithKline, Intuitive Surgical Inc., Johnson & Johnson and Olympus Europa; personal fees for expert testimony from Covidien AG (a Medtronic company); institutional funding as coordinating PI from AstraZeneca, Bayer AG, Clovis Oncology, Kiromic, Merck, Novocure Ltd. and Oncoquest Pharmaceuticals Inc. JS reports personal fees for advisory board membership from AstraZeneca, GSK, Immunogene, Incyte, MSD, Novocure, Roche, Tesaro and Tubulis; personal fees as an invited speaker from Eisai; institutional funding from AstraZeneca, GSK and Roche; non-renumerated ENGOT/NOGGO proprietary information; non-renumerated leadership roles at AGO (Arbeitsgemeinschaft für Gynäkologische Onkologie), NOGGO and PARSGO (Pan-Arabian Research Society of Gynecological Oncology); and non-renumerated membership of the ESGO Council. RSF reports personal fees for advisory board membership from MSD and Neopharm; personal fees as an invited speaker from AstraZeneca, BMS, Medison, MSD, Novartis and Roche; personal fees for consultancy from Medison; personal fees as a member of a Steering Committee for MSD and VBL; non-renumerated membership of a Steering Committee for AstraZeneca; and an institutional research grant from MSD. SS reports personal fees as an invited speaker from AstraZeneca, GSK and MSD; an institutional research grant from AOA Dx; and a leadership role for the National Ovarian Cancer Audit (UK). DSPT reports personal fees for advisory board membership from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche and Takeda; ownership of stocks/shares of Asian Microbiome Library (AMiLi); institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics and Roche; institutional funding as coordinating PI from AstraZeneca and Bergen Bio; institutional funding as local PI from Bayer, Byondis B.V. and Zeria Pharmaceutical Co Ltd.; a previous non-renumerated role as Chair of the Asia-Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; and product samples from AstraZeneca, Cyclacel Pharmaceuticals, Eisai and MSD (non-financial interest). CT declares no conflicts of interest. WJvD declares no conflicts of interest. IV reports past personal fees for advisory board consultancy from Agenus, Aksebio China, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, F. Hoffmann-La Roche Ltd., Genmab, GSK, ImmunoGen Inc., Jazzpharma, Karyopharm, Molecular Partners, MSD, Novartis, Novocure, Oncoinvent AS, Regeneron, Seagen and SOTIO a.s.; past institutional fees for advisory board consultancy from Amgen (Europe), AstraZeneca, Carrick Therapeutics, Clovis Oncology Inc., Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann-La Roche Ltd., Genmab, GSK, Mersana, Millennium Pharmaceuticals, MSD, Oncoinvent AS, SOTIO a.s., Verastem Oncology and Zentalis; and institutional research grants from Amgen, Genmab, Oncoinvent AS and Roche. FP declares no conflicts of interest. CS reports personal fees as a Gynaeco-oncology Certificate of Advanced Studies Coordinator for the European School of Oncology; personal fees as a DMC member from Merck; non-renumerated advisory roles for ESMO as a member of the Compliance Committee and an ESMO extended member of the Women for Oncology Committee; and a non-renumerated role as an advisor for the ESMO Living Guidelines. AF reports personal fees for advisory board membership from AstraZeneca and MSD; personal fees as an invited speaker from Fondazione Internazionale Menarini, GSK, Johnson & Johnson and PharmaMar; and institutional funding as coordinating PI from AstraZeneca, Johnson & Johnson and Roche., (Copyright © 2024 European Society for Medical Oncology, European Society of Gynecological Oncology, European Society of Pathology. Published by Elsevier Ltd.. All rights reserved.)

It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites. We discuss the use of mutation profiling to discern clonality and highlight how this information may inform the clinical management of such cases., Competing Interests: 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., (© 2022 The Authors.)

The incidence and mortality rates of ovarian cancer are increasing globally. Ovarian cancer is diagnosed at an advanced stage in 80% of women. After standard, platinum-based, front-line chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents are successfully employed as maintenance strategies for newly diagnosed, advanced ovarian cancer patients. Landmark clinical studies, including SOLO-1, PAOLA-1, PRIMA, and VELIA, have provided crucial insights on optimizing first-line maintenance treatment using PARP inhibitors. A group of ovarian cancer experts, primarily from low- and middle-income countries, met in September 2019 to discuss new developments for the first-line treatment of ovarian cancer and its implications. Key implications of the evolving clinical data included: (1) olaparib or niraparib maintenance therapy appears to be the preferred choice for patients with BRCA 1/2 mutations; hence, BRCA testing is beneficial in identifying these patients; (2) niraparib monotherapy and olaparib in combination with bevacizumab have demonstrated significant benefit in progression-free survival (PFS) in homologous recombination deficiency (HRD)-positive patients; (3) bevacizumab, niraparib alone, or observation can be an alternative for HRD-negative patients; (4) further data is warranted to explore the role of PARP inhibitors in treating HRD-negative, ovarian cancer patients to confirm findings of the exploratory analysis of PRIMA; (5) PARP inhibitors may be beneficial for stage IV ovarian cancer patients with inoperable disease and patients with prior neoadjuvant chemotherapy; and (6) there is an urgent need to increase awareness in both clinicians and patients on BRCA and HRD testing for optimizing treatment decision-making and improving clinical outcomes in newly diagnosed, advanced ovarian cancer patients. In clinical medicine, the limited availability of family history (FH) information and the complexity of FH criteria has hampered the implementation of BRCA testing. Moreover, many cancer patients with BRCA mutations are not tested because they do not meet the criteria for FH. Consequently, BRCA testing in many high income countries, including the US and Australia, is underused and used inappropriately, which has resulted in the loss of valuable opportunities for better cancer management and cancer prevention., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey C.H. Goh – has been Advisory Board member, received sponsorship for conference and speaker’s bureau from AstraZeneca and Advisory Board Member for Tesaro. Charlie Gourley- has been part of advisory boards of Roche, Astrazeneca, MSD, Tesaro, Nucana, Clovis Foundation One, Sierra and has received research funding for Astrazeneca, Novartis, Aprea, Nucana and Tesaro. David SP Tan- has received research support from Astra Zeneca, Karyopharm Therapeutics, Bayer, Roche. Has been a part of Advisory Boards for Astra Zeneca, Roche, Bayer, MSD, Eisai, and Tessa Therapeutics and received honoraria from Astra Zeneca, Novartis, Roche, MSD, Bayer, Eisai, Takeda and Eisai. Angelica Nogueira-Rodrigues has been consultant for Eurofarma, Roche, Astra Zeneca, MSD, GSK and Eisai and received educational training from Roche, Eurofarma, Astra Zeneca, MSD. Hesham Elghazaly- No conflicts of interest. Marc Edy Pierre- No conflicts of interest. Gonzalo Giornelli- has been part of Adboard for AstraZeneca, Roche, MSD, Janssen Cilag and Speaker for AstraZeneca, MSD. Byoung-Gie Kim- No conflicts of interest. Flavia Morales – Vasquez- No conflicts of interest. Alexandra Tyulyandina- has received research support from Astra Zeneca, Roche, MSD and received honoraria from Astra Zeneca, Roche, MSD, Biocad, Tekeda, Pfiser, Eisai., (© 2022 The Authors.)

Background: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma., Methods: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m 2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40-50 mg/m 2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m 2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting., Findings: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9-15·0) compared with 7·2 months (5·6-9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36-0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths., Interpretation: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma., Funding: NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis., Competing Interests: Declaration of interests DMG reports payments made to his institution from the National Cancer Institute (NRG Oncology), Novartis, and the GOG Foundation for this study; royalties or licenses from Elsevier and UpToDate outside the submitted work; consulting fees from Genentech outside the submitted work; personal fees for service as a member of the Committee of the National Cancer Institute outside the submitted work; and stock or stock options from Johnson & Johnson, Bristol Myers Squibb, and Biogen outside the submitted work. AM reports service as a masked study statistician for VBL Therapeutics; provision of statistical institutional support for Advaxis; service as a data safety monitoring board reporting statistician for Regeneron; and service on a study steering committee for Genentech and AstraZeneca, all outside the submitted work. RLC reports consulting fees from AstraZeneca, Merck–GlaxoSmithKline, and Clovis; grants from Genmab, Genentech–Roche, Janssen, Agenus, Regeneron, and OncoQuest; payments or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AstraZeneca, Merck–GlaxoSmithKline, and Clovis; and service on a data safety monitoring board or an advisory board for Janssen, VBL Therapeutics, and AstraZeneca, all outside the submitted work. KNM reports service on advisory boards for Alkemeres, AstraZeneca, Aravive, Blueprint Medicines, Eisai, Elevar, GlaxoSmithKline–Tesaro, Genentech–Roche, Hengrui, Immunogen, IMab, Merck, Mereo, Mersana, Myriad, OncXerna, Onconova, Novartis, Sorrento, Tarveda, and VBL Therapeutics, all outside the submitted work; grant funding from PTC Therapeutics, Lilly, Merck, and Genentech–Roche outside the submitted work; funding paid to her institution from Cyteir, Immunocore, Bolt Bio, Amgen, Artios, GlaxoSmithKline–Tesaro, Mereo, Regeneron, Aravive, Verastem, and AstraZeneca, for all of which she also serves as a local principal investigator; serving as national principal investigator for the IMaGYN050 trial of ovarian cancer (Genentech–Roche), the MIRASOL trial of ovarian cancer (Immunogen), the Relevare study of ovarian cancer (OncXerna), the FIRST study of ovarian cancer (GlaxoSmithKline–Tesaro), and the ETCTN 10422 study of ovarian cancer (National Cancer Institute); being the associate director for GOG Partners, on the GOG Foundation board of directors, and the NRG Oncology chair of the ovarian cancer committee; and receiving speaking reimbursement from PER, Research to Practice, Medscape, Great Debates and Updates, and Gyn Mal, all of which are outside the scope of this work but were active during the conduct of this study. SB reports grants paid to their institution from AstraZeneca, Tesaro, and GlaxoSmithKline; personal fees for participation in advisory boards from Amgen, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Merck Serono, Mersana, Oncxerna, Seagen, Shattuck Lab, and Epsilogen; and personal fees for lectures from Amgen, AstraZeneca, Clovis, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana, Pfizer, Roche, and Takeda, all outside the submitted work. AAS reports a National Cancer Trial Network grant; grants paid to her institution from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Clovis, Eisai, Immutep, Merck, OncoQuest, PharmaMar, Genentech–Roche, Seagen, Tesaro–GlaxoSmithKline, and VBL Therapeutics; consulting fees from Aravive, AstraZeneca, Clovis, Cordgenics, Eisai, Merck, Mersana, Myriad, Oncoquest, Genentech–Roche, and Tesaro–GlaxoSmithKline; presentations for educational events on cervical cancer sponsored by Research to Practice; service on advisory boards (uncompensated) for AbbVie and Regeneron; service on clinical trial steering committees (all uncompensated) for the AtTEnd trial (Hoffman-LaRoche), the Oval Trial (VBL Therapeutics), and the FLORA-5 trial (Oncoquest); and service on the GOG Foundation Board of Directors, the Society of Gynecologic Oncology Board of Directors, and the American Association of Obstetricians and Gynecologists Foundation Board of Trustees, all outside the submitted work. DMO reports National Cancer Institute support for this clinical trial; research funding paid to their institution from AstraZeneca, Tesaro–GlaxoSmithKline, Immunogen, Janssen–Johnson & Johnson, AbbVie Regeneron, Amgen, Novocure, Genentech–Roche, VentiRx Array Biopharma EMD Serono, Ergomed, Ajinomoto, Ludwig Cancer Research Stemcentrx, Cerulean Pharma, the GOG Foundation, the National Cancer Institute, Bristol Myers Squibb, C Serono, TRACON Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, inVentiv Health Clinical, Iovance Biotherapeutics, PRA Intl, Eisai, Agenus, Merck, GenMab, SeaGen, Mersana, and Clovis; personal fees for consulting or advisory board membership, or both, from AstraZeneca, Tesaro–GlaxoSmithKline, Immunogen, Ambry, Janssen–Johnson & Johnson, BBI, Agenus, AbbVie, Regeneron, Amgen, Novocure, Genentech–Roche, GOG Foundation, Iovance Biotherapeutics, Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubius, and Elevar, all outside the submitted work. OD reports grants or contracts from AstraZeneca, Clovis, Genentech, AbbVie, IMV, Millenium, and Pharmamar; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Tesaro–GlaxoSmithKline and AstraZeneca; payment for expert testimony in one legal case unrelated to the current study; and participation on a data safety monitoring board or advisory board for Merck, Clovis, PACT, and Genentech, all outside the submitted work. SG reports financial support paid to her institution for the present study from the National Clinical Trials Network; grants or contracts from AstraZeneca, AbbVie, Pfizer, Rigel, Iovance, Tesaro, Genentech–Roche, PharmaMar, and GlaxoSmithKline; patents licensed to Sermonix (US patent numbers 10,905,659 and 10,258,604); participation on a data safety monitoring board or advisory board for Sermonix, Elevar Therapeutics, and GlaxoSmithKline; and service as an NRG Oncology phase 1 subcommittee co-chair, all outside the submitted work. BS reports personal fees for service on advisory boards for Abbvie, AstraZeneca, Bostongene, Clovis, Eisai, Genentech, GlaxoSmithKline, Jazz Pharmaceticals, Lilly, Merck, Myriad, Novartis, Nuvation, Onconova, and Seagen; and consulting for the GOG Foundation, all outside the submitted work. AE reports grants or contracts from UKRI for a post-doctoral fellowship outside the submitted work. CG reports grants from GlaxoSmithKline and Novartis for this study (trametinib, the test drug, was sold by GlaxoSmithKline to Novartis during the course of the study). WEB, JP, KCa, WR, DM, KCo, HG, PH, JF, MC, RLH, CSH, HQH, and LW declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Disease relapse is the primary cause of death from ovarian carcinoma. Isolated lymph node relapse is a rare pattern of ovarian carcinoma recurrence, with a reported median postrelapse survival of 2.5 to 4 years. To date, investigations have not compared isolated lymph node relapse ovarian carcinoma directly to a matched extranodal relapse cohort or performed molecular characterization of cases that subsequently experience isolated lymph node relapse., Objective: Here we seek to compare the clinical outcome, tumor-infiltrating lymphocyte burden, and frequency of known prognostic genomic events in isolated lymph node relapse ovarian carcinoma vs extranodal relapse ovarian carcinoma., Study Design: Forty-nine isolated lymph node relapse ovarian carcinoma patients were identified and matched to 49 extranodal relapse cases using the Edinburgh Ovarian Cancer Database, from which the clinical data for identified patients were retrieved. Matching criteria were disease stage, histologic subtype and grade, extent of residual disease following surgical debulking, and age at diagnosis. Clinicopathologic factors and survival data were compared between the isolated lymph node relapse and extranodal relapse cohorts. Genomic characterization of tumor material from diagnosis was performed using panel-based high-throughput sequencing and tumor-infiltrating T cell burden was assessed using immunohistochemistry for CD3+ and CD8+ cells., Results: Isolated lymph node relapse cases demonstrated significantly prolonged postrelapse survival and overall survival vs extranodal relapse upon multivariable analysis (HR multi  = 0.52 [0.33-0.84] and 0.51 [0.31-0.84]). Diagnostic specimens from high-grade serous ovarian carcinomas that subsequently displayed isolated lymph node relapse harbored significantly greater CD3+ and CD8+ cell infiltration compared to extranodal relapse cases (P = .001 and P = .009, Bonferroni-adjusted P = .003 and P = .019). Isolated lymph node relapse high-grade serous ovarian carcinoma cases did not show marked enrichment or depletion of cases with BRCA1/2 mutation or CCNE1 copy number gain when compared to their extranodal relapse counterparts (24.4% vs 19.4% and 18.2% vs 22.6%, P = .865 and P = .900)., Conclusion: Isolated lymph node relapse ovarian carcinoma represents a distinct clinical entity with favorable outcome compared to extranodal relapse. There was no clear enrichment or depletion of BRCA1/2 mutation or CCNE1 gain in the isolated lymph node relapse ovarian carcinoma cohort compared with extranodal relapse cases, suggesting that these known prognostic genomically defined subtypes of disease do not display markedly altered propensity for isolated lymph node relapse. Diagnostic tumor material from isolated lymph node relapse patients demonstrated greater CD3+ and CD8+ cell infiltration, indicating stronger tumor engagement by T cell populations, which may contribute to the more indolent disease course of isolated lymph node relapse., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Epithelial ovarian cancer generally presents at an advanced stage and is the most common cause of gynaecological cancer death. Treatment requires expert multidisciplinary care. Population-based screening has been ineffective, but new approaches for early diagnosis and prevention that leverage molecular genomics are in development. Initial therapy includes surgery and adjuvant therapy. Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1). Rapidly evolving techniques to measure genomic changes in tumour and blood allow for assessment of sensitivity and emergence of resistance to therapy, and might be accurate indicators of residual disease. Recurrence is usually incurable, and patient symptom control and quality of life are key considerations at this stage. Treatments for recurrence have to be designed from a patient's perspective and incorporate meaningful measures of benefit. Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Comorbid major depression has been associated with worse survival in patients with cancer. However, we do not know if treating depression improves survival. In the SMaRT Oncology-2 (good prognosis cancers) and SMaRT Oncology-3 (lung cancer, a poor prognosis cancer) trials, we found that a depression treatment programme, Depression Care for People with Cancer (DCPC), was effective in reducing comorbid major depression. In this analysis, we aimed to identify whether DCPC also had an effect on survival., Methods: The trials were conducted in three cancer centres and their associated clinics in Scotland, UK. In SMaRT Oncology-2, outpatients with good prognosis cancers and major depression were randomly assigned in a 1:1 ratio to DCPC or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. In SMaRT Oncology-3, outpatients with lung cancer and major depression were randomly assigned (1:1 ratio) to DCPC or usual care with stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. For this analysis, we obtained long-term data on deaths (all causes) in the SMaRT Oncology-2 and 3 trial participants, censored at July 31, 2015, and analysed survival as a trial outcome. We estimated unadjusted hazard ratios (HRs) for each trial using Cox regression, and pooled the log HRs in a fixed-effects meta-analysis., Findings: We recruited 642 participants; between May 12, 2008, and May 13, 2011, 500 participants were recruited to the SMaRT Oncology-2 trial and between Jan 5, 2009, and Sept 9, 2011, 142 participants were recruited to the SMaRT Oncology-3 trial. We followed up SMaRT Oncology-2 and SMaRT Oncology-3 participants for a median of 5 years and 1 year, respectively. 135 (27%) of 500 SMaRT Oncology-2 participants and 114 (80%) of 142 SMaRT Oncology-3 participants died within this period. We found no significant effect of DCPC on survival in the total follow-up period for either SMaRT Oncology 2 (HR 1·02, 95% CI 0·72-1·42, p=0·93) or SMaRT Oncology-3 (HR 0·82, 95% CI 0·56-1·18, p=0·28; pooled HR 0·92, 95% CI 0·72-1·18, p=0·51)., Interpretation: DCPC is highly effective in improving depression and quality of life in depressed patients with cancer, but there was no evidence for a significant effect on survival. Despite the absence of an effect on length of life, the management of depression remains important for its beneficial effect on quality of life., Funding: NIHR CLAHRC Oxford, Cancer Research UK, and the Chief Scientist Office of the Scottish Government., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC., Experimental Design: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project., Results: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012)., Conclusions: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics., (Copyright © 2018. Published by Elsevier Inc.)

Background: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC)., Patients and Methods: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL)., Results: Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57-1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) P = 0.40. The i.p. carboplatin-based regimen was well tolerated with no reduction in QOL or increase in toxicity compared with i.v. administration alone., Conclusion: In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is well tolerated and associated with an improved PD9 compared with i.v. carboplatin-based chemotherapy., Clinical Trial Number: clinicaltrials.gov, NCT01622543., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Proximity to facilities emitting polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) has been associated with increased risk of non-Hodgkin lymphoma (NHL). There is limited information about whether proximity to industrial sources leads to indoor PCDD/F contamination of homes. We measured carpet dust concentrations (pg/g) of 17 toxic PCDD/F congeners and calculated their toxic equivalence (TEQ) in 100 homes in a population-based case-control study of NHL in Detroit, Los Angeles, Seattle, and Iowa (1998-2000). We took global positioning system readings at residences and obtained coordinates and PCDD/F emissions (ng TEQ/yr) from an Environmental Protection Agency database for 6 facility types: coal-fired electricity generating plants, cement kilns burning non-hazardous waste, hazardous waste incinerators, medical waste incinerators, municipal solid waste incinerators, and sewage sludge incinerators. For each residence, we computed an inverse distance-squared weighted average emission index (AEI [pg TEQ/km 2 /yr]) for all facilities within 5km from 1983 to 2000. We also computed AEIs for each of the 6 facility types. We evaluated relationships between PCDD/F dust concentrations and the all-facility AEI or categories of facility-type AEIs using multivariable linear regression, adjusting for study center, demographics, and home characteristics. A doubling of the all-facility AEI was associated with a 4-8% increase in PCDD/F dust concentrations of 7 of 17 PCDD/F congeners and the TEQ (p-value<0.1). We also observed positive associations between PCDD/F dust concentrations and facility-type AEIs (highest vs. lowest exposure category) for municipal solid waste incinerators (9 PCDD/F, TEQ), and medical waste incinerators (7 PCDD/F, TEQ) (p<0.1). Our results from diverse geographical areas suggest that industrial PCDD/F emission sources contribute to residential PCDD/F dust concentrations. Our emissions index could be improved by incorporating local meteorological data and terrain characteristics. Future research is needed to better understand the links between nearby emission sources, human exposure pathways, and health risks., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Medical conditions are often complicated by major depression, with consequent additional impairment of quality of life. We aimed to compare the effectiveness of an integrated treatment programme for major depression in patients with cancer (depression care for people with cancer) with usual care., Methods: SMaRT Oncology-2 is a parallel-group, multicentre, randomised controlled effectiveness trial. We enrolled outpatients with major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with cancer intervention or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. Depression care for people with cancer is a manualised, multicomponent collaborative care treatment that is delivered systematically by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. Outcome data were collected up until 48 weeks. The primary outcome was treatment response (≥50% reduction in Symptom Checklist Depression Scale [SCL-20] score, range 0-4) at 24 weeks. Trial statisticians and data collection staff were masked to treatment allocation, but participants could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN40568538., Findings: 500 participants were enrolled between May 12, 2008, and May 13, 2011; 253 were randomly allocated to depression care for people with cancer and 247 to usual care. 143 (62%) of 231 participants in the depression care for people with cancer group and 40 (17%) of 231 in the usual care group responded to treatment: absolute difference 45% (95% CI 37-53), adjusted odds ratio 8·5 (95% CI 5·5-13·4), p<0·0001. Compared with patients in the usual care group, participants allocated to the depression care for people with cancer programme also had less depression, anxiety, pain, and fatigue; and better functioning, health, quality of life, and perceived quality of depression care at all timepoints (all p<0·05). During the study, 34 cancer-related deaths occurred (19 in the depression care for people with cancer group, 15 in the usual care group), one patient in the depression care for people with cancer group was admitted to a psychiatric ward, and one patient in this group attempted suicide. None of these events were judged to be related to the trial treatments or procedures., Interpretation: Our findings suggest that depression care for people with cancer is an effective treatment for major depression in patients with cancer. It offers a model for the treatment of depression comorbid with other medical conditions., Funding: Cancer Research UK and Chief Scientist Office of the Scottish Government., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Feed conversion into milk, nutrient excretion in manure and subsequent environment impacts of manure management are highly influenced by the diets that farmers feed their lactating cows (Bos taurus). On confinement-based dairy farms, determinations of diet composition are relatively straightforward because the types, amounts and nutrients contained in stored feeds are often well known. However, on grazing-based dairy farms, diet composition is more difficult to determine because forage intake during grazing must be estimated. The objectives of this study were to determine relationships between (1) feed N intake (NI), milk production, milk urea N (MUN), feed N use efficiency (FNUE) and excreted manure N (ExN); and (2) between feed P intake (PI), dung P concentrations (g/kg dry matter (DM)) and excreted manure P (ExP) for grazing-based lactating cows having a very wide range of diets and milk production. An additional objective was to evaluate how well these relationships compare with similar relationships based on more direct measurement of feed-milk-manure on confinement-based dairy farms. Four dairy farms located in southeastern Australia were visited during autumn and spring, and data were collected on feed, milk and dung of 18 cows on each farm. Estimated dry matter intake (DMI) from pasture comprised 12% to 75% of total diet DMI, and the crude protein (CP) concentrations in the total diets ranged from 167 to 248 g/kg. During spring, as diet CP increased FNUE declined. Total diet DMI and NI provided the best predictors of ExN, and PI provided the most accurate prediction of ExP. These results indicated accuracy in the study's indirect estimates of pasture DMI. Likely due to high levels and great variability in dietary CP and P concentrations associated with use of diet supplements, MUN did not appear to be a good indicator of dietary CP, and P in dung was not a good indicator of dietary P.

Determinants of levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) in dust in U.S. homes are not well characterized. We conducted a pilot study to evaluate the relationship between concentrations of PCDD/F in house dust and residential proximity to known sources, including industrial facilities and traffic. Samples from vacuum bag dust from homes of 40 residents of Detroit, Los Angeles, Seattle, or Iowa who participated in a population-based case-control study of non-Hodgkin lymphoma conducted in 1998-2000 were analyzed using high resolution gas chromatography/high resolution mass spectrometry for 7 PCDD and 10 PCDF congeners considered toxic by the U.S. Environmental Protection Agency (EPA). Locations of 10 types of PCDD/F-emitting facilities were obtained from the EPA; however only 4 types were located near study homes (non-hazardous waste cement kilns, coal-fired power plants, sewage sludge incinerators, and medical waste incinerators). Relationships between concentrations of each PCDD/F and proximity to industrial facilities, freight routes, and major roads were evaluated using separate multivariate regression models for each congener. The median (inter-quartile range [IQR]) toxic equivalence (TEQ) concentration of these congeners in the house dust was 20.3 pg/g (IQR=14.3, 32.7). Homes within 3 or 5 km of a cement kiln had 2 to 9-fold higher concentrations of 5 PCDD and 5 PCDF (p<0.1 in each model). Proximity to freight routes and major roads was associated with elevated concentrations of 1 PCDD and 8 PCDF. Higher concentrations of certain PCDD/F in homes near cement kilns, freight routes, and major roads suggest that these outdoor sources are contributing to indoor environmental exposures. Further study of the contribution of these sources and other facility types to total PCDD/F exposure in a larger number of homes is warranted., (Published by Elsevier B.V.)

The Anterior Gradient (AGR) genes AGR2 and AGR3 are part of the Protein Disulfide Isomerase (PDI) family and harbour core thioredoxin folds (CxxS motifs) that have the potential to regulate protein folding and maturation. A number of proteomics and transcriptomics screens in the fields of limb regeneration, cancer cell metastasis, pro-oncogenic oestrogen-signalling, and p53 regulation have identified AGR2 as a novel component of these signalling pathways. Curiously, despite the fact that the AGR2 and AGR3 genes are contiguous on chromosome 7p21.1-3, the AGR3 protein has rarely been identified in such OMICs screens along with AGR2 protein. Therefore there is little information on how AGR3 protein is expressed in normal and diseased states. A panel of three monoclonal antibodies was generated towards AGR3 protein for identifying novel clinical models that can be used to define whether AGR3 protein could play a positive or negative role in human cancer development. One monoclonal antibody was AGR3-specific and bound a linear epitope that could be defined using both pep-scan and phage-peptide library screening. Using this monoclonal antibody, endogenous AGR3 protein expression was shown to be cytosolic in four human ovarian cancer subtypes; serous, endometrioid, clear cell, and mucinous. Mucinous ovarian cancers produced the highest number of AGR3 positive cells. AGR3 expression is coupled to AGR2 expression only in mucinous ovarian cancers, whereas AGR3 and AGR2 expressions are uncoupled in the other three types of ovarian cancer. AGR3 expression in ovarian cancer is independent of oestrogen-receptor expression, which is distinct from the oestrogen-receptor dependent expression of AGR3 in breast cancers. Isogenic cancer cell models were created that over-express AGR3 and these demonstrated that AGR3 mediates cisplatin-resistance in mouse xenografts. These data indicate that AGR3 is over-expressed by a hormone (oestrogen-receptor α)-independent mechanism and identify a novel protein-folding associated pathway that could mediate resistance to DNA-damaging agents in human cancers., (Copyright © 2012 Elsevier B.V. All rights reserved.)