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E Cobos,1 L Arias,1 JM Ruiz-Moreno,2,3 MJ Rubio,1 P Garcia-Bru,1 JM Caminal,1 J Catala,1 J Arruga11Department of Ophthalmology, Bellvitge University Hospital, Barcelona, Spain; 2Department of Ophthalmology, Castilla La Mancha University, Albacete, Spain; 3Alicante Institute of Ophthalmology, VISSUM, Vitreo-Retinal Unit, Alicante, SpainObjective: To demonstrate whether the preoperative integrity of the inner segment/outer segment (IS/OS) junction of photoreceptors studied by spectral-domain optical coherence tomography (SD-OCT) is a prognostic factor in epiretinal membrane surgery.Methods: We retrospectively studied patients with an idiopathic epiretinal membrane who underwent a 23-gauge vitrectomy to remove this membrane. Best-corrected visual acuity (BCVA) and SD-OCT scans were examined before and 6 months after the surgery. We studied the retinal microstructure, especially the IS/OS junction of the photoreceptors, and evaluated the intergroup differences between patients with an intact layer and those with an irregular or disrupted layer. We applied both the Wilcoxon and Mann–Whitney tests for statistical analysis.Results: In total, 51 eyes from 51 enrolled patients were examined in this study. The postoperative BCVA was significantly better for eyes that had an intact IS/OS junction than for eyes that had an irregular or disrupted IS/OS junction, as preoperatively observed with SD-OCT scans (P < 0.001). We also observed an important association between disrupted IS/OS junctions and the presence of cystic macular edema (P < 0.01).Conclusion: The presence of an intact IS/OS junction on the preoperative SD-OCT scan was an important predictor of better visual recovery after epiretinal membrane surgery. Keywords: epiretinal membrane, photoreceptors, inner segment/outer segment junction, spectral-domain optical coherence tomography

Purpose: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer., Methods: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1., Results: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA- mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs., Conclusion: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Background: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting., Methods: This observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible., Results: Forty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%)., Conclusions: This analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients., (© 2024. The Author(s).)

Background: The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone., Methods: In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m 2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m 2 , and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing., Findings: Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3-16·6) with atezolizumab and 10·4 months (9·7-11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49-0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3-36·8) versus 22·8 months (20·3-28·0), respectively (HR 0·68 [95% CI 0·52-0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1-2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab., Interpretation: Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests AO reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, Deciphera, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, MSD de España, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Shattuck Labs, iTeos, and Eisai; travel and accommodation support from AstraZeneca, PharmaMar, and Roche; and funding paid to institution from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology, Eisai, F Hoffmann-La Roche, Regeneron Pharmaceuticals, Immunogen, MSD de España, Takeda, PharmaMar, Tesaro, and Bristol Myers Squibb. LG reports support for attending meetings or travel from Viatris, GSK, and MSD; consulting fees paid to institution for participation in the advisory boards of Clovis, GSK, AstraZeneca, and Seagen; and speaker honoraria paid to institution from AstraZeneca, GSK, and Eisai. JM-G reports personal fees for participation in the advisory boards of AstraZeneca, Clovis, GSK, and PharmaMar; research grants paid to institution from GSK and Roche; and travel and accommodation expenses from GSK−Tesaro, Pfizer, and PharmaMar. GV reports honoraria for speaker engagements from MSD, Pierre Fabre, GSK, and Pfizer; and consulting fees from Reveal Genomics. UDG reports personal consulting fees from Amgen, AstraZeneca, Pfizer, BMS, Clovis Oncology, Dompé Farmaceutici, Merck, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, and Janssen; other funding paid to institution from AstraZeneca, Sanofi, and Roche; and support for attending meetings or travel from Pfizer, Ipsen, and AstraZeneca. KL reports personal honoraria from Eisai; participation on data safety monitoring or advisory boards of Eisai, MSD, Nykode, AstraZeneca, and GSK (honoraria paid to institution); and funding paid to institution from GSK. LW reports personal honoraria for participation in the advisory boards of AstraZeneca, Pfizer, GSK, Roche, MSD–Merck, Eisai, and Seagen; personal honoraria for speaker engagements from AstraZeneca, Eisai, GSK, Pfizer, Roche, MSD–Merck, and Seagen; and support for attending meetings or travel from GSK and MSD. NC reports consultancy or advisory roles for AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD−Merck, Nuvation Bio, OncXerna, Pfizer, Pieris, and Roche; promotional speaker roles for AstraZeneca, Novartis, Clovis Oncology, MSD−Merck, and GSK; research grants from AstraZeneca, GSK, and Roche; and support for attending meetings or travel from AstraZeneca and GSK. LD reports personal fees for scientific advisory boards from Aadi Bioscience and Regeneron; fees paid to institution for scientific advisory boards from Merck; membership of the British Journal of Obstetrics and Gynaecology Editorial Board; personal royalties for writing expert content for UpToDate, Wiley, and the American Society of Clinical Oncology; personal fees for continuing medical education activities for Advance Medical, CEA Group, and Clinical Care Options; research funding paid to institution for investigator-initiated trials from Merck; clinical trial grants paid to institution from Genentech−Roche, AbbVie (GOG 3005), Acrivon, Advaxis, Aduro BioTech, Alkermes, Blueprint, Constellation, Eisai, GSK–Novartis, Immunogen, Inovio, Iovance, Karyopharm, KSQ Therapeutics, Lycera, Merck, Morab, MorphoTek, Naveris, Nurix, OncoQuest, Pfizer, Syndax, Tesaro, and Zentalis; and fees paid to institution for membership of data and safety monitoring committees for Agenus and Inovio. AL reports personal fees for presentations or educational events from Medscape and PeerVoice; consulting fees paid to institution from Owkin; speaker honoraria paid to institution from MSD, GSK, AstraZeneca, and Eisai; fees paid to institution for participation in the advisory boards of AstraZeneca, MSD, Seagen, GSK, Genmab, Zentalis, and Blueprint; non-remunerated independent data safety monitoring board participation for Clovis and BMS; an educational grant paid to institution from AstraZeneca; and support for attending meetings or travel from OSE Immunotherapeutics. AG-O reports honoraria paid to institution for participation in the advisory board of Novartis; personal honoraria for speaker engagements from AstraZeneca, Pfizer, Novartis, and Lilly; and support for attending meetings or travel from Pfizer and Novartis. MJR reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, GSK, PharmaMar, MSD de España, Eisai, and Roche; personal fees for speaker engagements from MSD, AstraZeneca, Clovis Oncology, GSK, and PharmaMar; and travel and accommodation from AstraZeneca, PharmaMar, Roche, GSK, and MSD de España. LF-M reports honoraria paid to institution for participation in the advisory boards of GSK; honoraria paid to institution for speaker engagements from GSK, AstraZeneca–MSD, and Eisai; and support for attending meetings or travel from AstraZeneca–MSD and GSK. DL reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvent, PharmaMar, Seagen, and Sutro; personal fees for consultancy roles from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, Novartis, PharmaMar, and Seagen; clinical trial or research funding to institution from Clovis Oncology, GSK, MSD, and PharmaMar; other financial or non-financial interests from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, Oncoinvent, PharmaMar, Roche, Seagen, and Sutro; and travel grants from AstraZeneca, Clovis Oncology, and GSK. IR-C reports personal honoraria for participation in the advisory boards of Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis, Daiichi Sankyo, Deciphera, Eisai, EQRx, GSK, Merck Serono, MacroGenics, Mersana, Novartis, Onxeo, Roche, and Sutro Biopharma; honoraria paid to institution for participation in the advisory boards of MSD (translational research); and funding paid to institution for translational research from BMS. LM reports participation in the advisory board of Roche; and honoraria for speaker engagements from Roche, GSK, Clovis Oncology, AstraZeneca, Pfizer, Novartis, and Lilly. FJ reports honoraria for lectures, expert boards, and educational events from AstraZeneca, Clovis Oncology, GSK, and Seagen; travel and accommodation support from GSK, Eisai, and MSD; and financial support for national academic GINECO trials from GSK and AstraZeneca. JA reports honoraria for speaker bureaus from GSK, Roche, AstraZeneca, MSD, PharmaMar, and Clovis; and advisory boards for GSK, MSD, AstraZeneca, and Clovis. PF reports personal fees for expert testimony from Daiichi; personal fees for invited speaker engagements from GSK and MSD; and support for attending meetings or travel from Lilly, Novartis, and GSK. IR reports personal fees for advisory boards from AstraZeneca, Clovis Oncology, GSK, PharmaMar, Roche, and MSD; and travel and accommodation from AstraZeneca, PharmaMar, Roche, and GSK. CL reports honoraria for advisory board participation from GSK; personal honoraria for speaker engagements from GSK, Clovis Oncology, Eisai, and MSD; and support for attending meetings or travel from MSD and GSK. JAP-F reports honoraria for speaker engagements from AstraZeneca, PharmaMar, Pharma&, Clovis, and GSK; payment for expert testimony from AstraZeneca, GSK, Roche, and PharmaMar; support for attending meetings or travel from Karyopharm, AstraZeneca, Roche, and PharmaMar; grants paid to institution from GSK and PharmaMar; equipment, materials, drugs, medical writing, gifts, or other services paid to institution from GSK; participation on data safety monitoring or advisory boards for Ability Pharma; and has a patent pending in breast cancer. HD reports personal honoraria for advisory board participation from AstraZeneca. LMR reports honoraria for speaker engagements from Genmab−Seagen, Blueprint Oncology, Curio Science, and Physicians Education Resource; honoraria for participation in the advisory boards of AstraZeneca, Clovis Oncology, GOG Foundation, Aadi Biosciences, Seagen, OnTarget Laboratories, Merck, Mersana, Rubius Therapeutics, Myriad Genetics, Genentech−Roche, Eisai, Novocure, and Immunogen; consulting fees from the GOG Foundation; and funding paid to institution from Genentech−Roche, On Target Laboratories, Pfizer, Aivita Biomedical, Tesaro, AstraZeneca, Merck, Akeso Biopharma, and Grupo Español de Investigación en Cáncer ginecologico. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The aim of our study was to elucidate the impact of bevacizumab added to neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment and correlate the changes with the clinical outcome of the patients., Experimental Design: IHC and multiplex immunofluorescence for lymphoid and myeloid lineage markers were performed in matched tumor samples from 23 patients with ovarian cancer enrolled in GEICO 1205/NOVA clinical study before NACT and at the time of interval cytoreductive surgery., Results: Our results showed that the addition of bevacizumab to NACT plays a role mainly on lymphoid populations at the stromal compartment, detecting a significant decrease of CD4+ T cells, an increase of CD8+ T cells, and an upregulation in effector/regulatory cell ratio (CD8+/CD4+FOXP3+). None of the changes observed were detected in the intra-epithelial site in any arm (NACT or NACT-bevacizumab). No differences were found in myeloid lineage (macrophage-like). The percentage of Treg populations and effector/regulatory cell ratio in the stroma were the only two variables significantly associated with progression-free survival (PFS)., Conclusions: The addition of bevacizumab to NACT did not have an impact on PFS in the GEICO 1205 study. However, at the cellular level, changes in CD4+, CD8+ lymphocyte populations, and CD8+/CD4+FOXP3 ratio have been detected only at the stromal site. On the basis of our results, we hypothesize about the existence of mechanisms of resistance that could prevent the trafficking of T-effector cells into the epithelial component of the tumor as a potential explanation for the lack of efficacy of ICI in the first-line treatment of advanced epithelial ovarian cancer. See related commentary by Soberanis Pina and Oza, p. 12., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objective: Our aim was to reach a consensus on the management of the most controversial issues of advanced ovarian cancer., Methods: Nominal group and Delphi techniques were used. A steering committee of 5 experts analyzed current management of advanced ovarian cancer, identified controversies, critically analyzed the evidence, and formulated guiding statements for clinicians. Subsequently, a panel of 15 experts was selected to test agreement with the statements through two Delphi rounds. Items were scored on a 4-point Likert scale from 1 (totally disagree) to 4 (totally agree). In the first and second rounds, consensus was considered if ≥70% of answers pertained to category 1 or category 4., Results: Overall, 112 statements were incorporated in the following areas: 1) biomarkers and hereditary ovarian cancer; 2) first-line treatment; 3) recurrent disease when platinum might be the best option; and 4) post-poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors setting. In the first Delphi round, 37 statements reached consensus and did thus not pass to the second round. After the second round, another 18 statements reached consensus. Forty-six of the consensus were with the agreement and 9 with the disagreement., Conclusion: Through the methodology used, a consensus was reached in approximately half of the statements. The results of this work may be useful in addressing the most controversial issues on the management of advanced ovarian cancer., Competing Interests: Andrés Redondo has received support for the present manuscript from Pharmamar; Consulting fees from Astra-Zeneca, MSD, GSK, Pharmamar, Clovis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra-Zeneca, MSD, GSK, Pharmamar, Clovis; Support for attending meetings and/or travel from Astra-Zeneca, Pharmamar, Clovis., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole., Methods: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings., Results: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies., Conclusion: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857)., Gov Identifier: NCT01584297., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

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: To determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin., Methods: ROLANDO was a single-arm phase II trial that included patients with high-grade serous or endometrioid tumors and at least one previous platinum-resistant recurrence regardless of BRCA status. Patients received 6 cycles of pegylated liposomal doxorubicin every 28 days plus olaparib 300 mg twice daily. followed by olaparib 300 mg twice daily; monotherapy until progression or unacceptable toxicity. Prognostic factors including previous lines (and platinum-containing ones), BRCA mutation status, previous bevacizumab, CA-125 levels, and the neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and platelet/lymphocyte ratio calculated at inclusion were analyzed through a multivariate logistic regression and factor analysis of mixed data., Results: Thirty-one patients were included. Median age was 57 years (range 43-75), Eastern Cooperative Oncolgy Group performance status 0/1: 32.3%/67.7% and BRCA mutated: 16.1%. Prior treatment lines were >2 lines: 14 (45.2%) patients, ≥2 platinum lines: 21 patients (67.7%) and previous bevacizumab 19 (61.3%) patients. CA-125 was >2 upper limit normal in 24 (77.4%) patients. A high neutrophil/lymphocyte ratio was associated with worse overall survival by univariate/multivariate regression model (HR=11.18; 95% CI 1.1 to 114.5; p=0.042). No other factors were associated with overall survival in the multivariate model. A multifactorial signature based on clinical and molecular baseline characteristics was capable of defining six patient clusters. Three of these clusters had significantly better prognosis, with a median overall survival of 21.3 months (95% CI 12.2 to not reached)., Conclusions: High neutrophil/lymphocyte ratio at platinum-resistant relapse indicated poor prognosis in patients treated with olaparib plus pegylated liposomal doxorubicin. A multifactorial clinical signature was more precise than single variables for implying the prognosis and may help in therapeutic assignment after further validation in large prospective cohorts., Competing Interests: Competing interests: MJR has served on advisory boards for MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, and received support for travel or accommodation from Roche, AstraZeneca, MSD and PharmaMar. YGG declares participating in advisory boards from GSK, AstraZeneca, and Pharmamar, and declares fees from travel grants and speaker’s bureau from Roche, AstraZeneca, Pharmamar, MSD, GSK. ASB declares participating in advisory boards for MSD, AstraZeneca, GSK, Clovis, PharmaMar, and declares receiving support for travel from MSD and GSK, and speaker's bureau from MSD, AstraZeneca, GSK, Clovis. PE-G has served on advisory boards for MSD, AstraZeneca, GSK, Clovis, PharmaMar, and received support for travel or accommodation from GSK, AstraZeneca, MSD, and PharmaMar. All the other authors declare no conflicts of interest., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The Neurosurgery Education and Development (NED) Foundation (NEDF) started the development of local neurosurgical practice in Zanzibar (Tanzania) in 2008. More than a decade later, multiple actions with humanitarian purposes have significantly improved neurosurgical practice and education for physicians and nurses., Research Question: To what extent could comprehensive interventions (beyond treating patients) be effective in developing global neurosurgery from the outset in low and middle-income countries?, Material and Method: A retrospective review of a 14- year period (2008-2022) of NEDF activities highlighting landmarks, projects, and evolving collaborations in Zanzibar was carried out. We propose a particular model, the NEDF model, with interventions in the field of health cooperation that have simultaneously aimed to equip, treat, and educate in a stepwise manner., Results: 138 neurosurgical missions with 248 NED volunteers have been reported. In the NED Institute, between Nov 2014-Nov 2022, 29635 patients were seen in the outpatient clinics and 1985 surgical procedures were performed. During the course of NEDF's projects, we have identified three different levels of complexity (1, 2 and 3) that include the areas of equipment ("equip"), healthcare ("treat") and training ("educate"), facilitating an increase of autonomy throughout the process., Discussion and Conclusion: In the NEDF's model, the interventions required in each action area (ETE) are coherent for each level of development (1, 2 and 3). When applied simultaneously, they have a greater impact. We believe the model can be equally useful for the development of other medical and/or surgical specialties in other low-resource healthcare settings., 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., (© 2023 The Authors.)

Research Question: Is the DuoStim strategy an effective alternative to two conventional ovarian stimulation cycles in poor-prognosis patients undergoing preimplantation genetic testing for aneuploidies (PGT-A) to improve euploidy rates and obtain the first euploid embryo in less time?, Design: This randomized controlled trial was performed at IVI Madrid between June 2017 and December 2020 and included 80 patients with a suboptimal profile aged 38 or older undergoing PGT-A cycles. Patients were blindly randomized into two groups: 39 women underwent two ovarian stimulations in consecutive cycles (control group), whereas the double stimulation strategy was applied to 41 women (DuoStim group). The main outcome was the euploidy rate in each group. The secondary outcomes were the time it took to obtain a euploid embryo and the main cycle outcomes., Results: The baseline characteristics of the patients were similar. No differences were found between the control group and the DuoStim group in the mean days of stimulation (21.3 ± 1.6 versus 23.0 ± 1.4, P = 0.10), total gonadotrophins (4005 ± 450 versus 4245 ± 430, P = 0.43), metaphase II oocytes (8.7 ± 1.8 versus 6.8 ± 1.7, P = 0.15) or euploid embryos obtained (0.8 ± 0.4 versus 0.6 ± 0.4, P = 0.45). The euploid rate per randomized patient (ITT) was 16.1% in the control group versus 22.7% in the DuoStim group, with P-values of 0.371, and the euploidy rate per patient treated was 39.0% versus 45.7% in the control versus DuoStim groups. However, there was a significant difference in the average number of days it took to obtain a euploid blastocyst, favouring the DuoStim group (44.1 ± 2.0 versus 23.3 ± 2.8, P < 0.001)., Conclusions: The use of the DuoStim strategy in poor-prognosis patients undergoing PGT-A cycles maintains a similar euploidy rate while reducing the time required to obtain a euploid blastocyst., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. 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.)

Purpose: The aim of this review was to systematically collect the published evidence to assess the effect of recreational physical activity (PA) in reducing breast cancer (BC) recurrence in female survivors., Methods: A bibliographic search was carried out in PubMed Medline, CINAHL Complete, Scopus and Lilacs until June 2021. We selected observational studies or clinical trials comprising women diagnosed with BC, in which the risk of recurrence of BC was measured before or after performing recreational PA. As a secondary outcome, we analyzed disease free survival for recurrence/disease-specific mortality. The methodological quality of observational studies was assessed with the Newcastle-Ottawa Scale and clinical trials with the PEDro scale. A random effects model was used to estimate the relative risks (RR) and their 95% confidence intervals (CI) to infer the results for any female survivor of BC. We performed separate meta-analyses for prediagnosis and postdiagnosis recreational PA., Results: Eleven studies were included, providing data from 29,677 surviving women with BC with an age range of 18-79 years old. Postdiagnosis recreational PA reduced the risk of BC recurrence by 16% (RR, 0.84; 95% CI: 0.78 to 0.91) and the risk of recurrence/disease-specific mortality by 23% (RR, 0.77; 95% CI: 0.66 to 0.93). Prediagnosis PA reduced the risk of BC by 18% (RR, 0.82; 95% CI: 0.74 to 0.91)., Conclusion: This systematic review with meta-analysis shows that recreational PA can be an interesting therapeutic tool to protect against recurrence of BC in female survivors., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

The 2019 coronavirus disease (COVID-19) and the recommended social isolation presented a challenge to people's mental health status. Optimism is a psychological factor that plays a key role in the evaluation of stressful situations. The purpose of this study was to investigate the mediating role of perceived stress and Covid-19-related stress anticipation in the relationship between optimism and post-traumatic stress symptoms. Our sample included 1015 participants ranging in age from 18 to 79 years, 80% of whom were Spaniards. At the beginning of the worldwide pandemic, participants were confined to their homes for at least seven days and completed an online survey measuring various sociodemographic and psychological variables. We found an indirect effect of optimism on intrusion and hyperarousal through perceived stress and stress anticipation. In addition, we observed an indirect effect of optimism on avoidance through perceived stress. Finally, the results showed a significant indirect effect of optimism on the total post-traumatic stress symptoms score through perceived stress and stress anticipation. Our results indicate that positive beliefs inherent to optimism are related to less psychological impact of the COVID-19 outbreak., Competing Interests: Conflicts of InterestThe authors report no conflicts of interest. Moreover, they have read and followed the Current Psychology instructions for authors, and they alone are responsible for the content and writing of the paper. The paper has been seen and approved by all authors. Authors has full control of all primary data and agree to allow the journal to review their data if requested. There were no previous published research about the topic of this manuscript. Moreover, there were no potential conflicts of interest with the organization that sponsored the research. This reported research is unpublished and not under consideration for publication elsewhere, and it does not contain data that are currently submitted or published elsewhere., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1-5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian ( n = 46), endometrial ( n = 26), and triple-negative breast cancer ( n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0-5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance ( p = 0.055). Globally, the total number of LOHs might be associated with the ORR ( p =0.074). The most common grade 3-4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.

Objective: In the hospital of La Princesa, the "Sepsis Code" (CSP) began in 2015, as a multidisciplinary group that provides health personnel with clinical, analytical and organizational tools, with the aim of the detection and early treatment of patients with sepsis. The objective of this study is to evaluate the impact of CSP implantation on mortality and to determine the variables associated with an increase in it., Methods: A retrospective analytical study of patients with CSP alert activation from 2015 to 2018 was conducted. Clinical-epidemiological variables, analytical parameters, and severity factors such as admission to critical care units (UCC) and the need for amines were collected. Statistical significance was established at p < 0.05., Results: We included 1,121 patients. The length of stay was 16 days and 32% required admission to UCC. Mortality showed a statistically significant linear downward trend from 24% in 2015 to 15% in 2018. The predictive mortality variables with statistically significant association were lactate > 2 mmol/L, creatinine > 1.6 mg/dL and the need for amines.>5.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%., Conclusions: The implementation of Sepsis Code decreases the mortality of patients with sepsis and septic shock. The presence of a lactate > 2 mmol/L, creatinine > 1.6 mg/dL and/or the need to administer amines in the first 24 hours, are associated with an increase in mortality in the patient with sepsis., (©The Author 2021. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Background: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy., Primary Objective: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease., Study Hypothesis: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers)., Trial Design: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no)., Major Inclusion/exclusion Criteria: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded., Primary Endpoints: Progression-free and overall survival (dual primary endpoints)., Sample Size: About 875 patients., Estimated Dates for Completing Accrual and Presenting Results: Enrollment is expected to take approximately 24 months, with presentation of results in 2022., Trial Registration: ClinicalTrials.gov, NCT03884101., Competing Interests: Competing interests: CM: funded research, EU, FWF, AstraZeneca, and Roche; honoraria/expenses, Roche, Novartis, Amgen, Merck, Pharmamar, AstraZeneca, Tesaro, and GSK; consulting/advisory board, Roche, Novartis, Amgen, Merck, AstraZeneca, Pfizer, Pharmamar, Cerulean, Vertex, GSK, Seagen, and Eisai. AT: funded research, AstraZeneca, Roche, MSD, and RUSSCO; honoraria/expenses, AstraZeneca, Roche, MSD, Eisai, Biocad, and RUSSCO; consulting/advisory board, AstraZeneca, Pfizer, MSD, Eisai, Tesaro, and Biocad. SP: honoraria, MSD, Eisai, GSK, AstraZeneca, Clovis, Pfizer, Pharmamar, and Roche. LG: institutional grants from AstraZeneca, Pfizer, Merck Sharp & Dohme, Karyopharm, Tesaro, IMV, Alkermes, Clovis, ImmunoGen Inc, Roche, Mersana, Esperas, Novocure GmbH, and OncoQuest Pharmaceuticals; advisory boards, AstraZeneca, GSK, Eisai, Eisai-Merck, and Alkermes. DK: clinical trials, Roche, Lilly Oncology, Clovis, MSD, Abbvie, Takeda, Novartis, Pfizer, Array BioPharma Inc, Servier, Nektar Therapeutics, Merck Healthcare KGaA, and GlaxoSmithKline; consultancy, Roche, Boehringer Ingelheim, Pfizer, MSD, BMS, Novartis, AstraZeneca, Raffo-tecnofarma, Varifarma, and Bayer. MJR: consulting/advisory board, MSD, AstraZeneca, GSK, Pharmamar, and Roche. SF: consulting/advisory board, Akesobio; honoraria/expenses, Amgen. MM-M: consulting/advisory board, Roche, Eli-Lilly, BMS, AstraZeneca, Teva, Amgen, Bayer, and Pfizer. RB: travel expenses, Clovis Oncology, Roche, and MSD. CV: study funding for present publication from MSD; institutional grant, MSD; consulting fees, Janssen-Cilag, Roche, GSK, Atheneum Partners, Astellas Pharma, MSD, BMS, and Leo-Pharma; payment or honoraria for presentations, Janssen Cilag, Leo Pharma, and Bayer; payment or honoraria for advisory boards, Janssen Cilag, Leo Pharma, MSD, GSK, and AstraZeneca; support for travel, Roche and Pfizer. KH: funded research, MSD, Ono, Takeda, Daiichi-Sankyo, and Eisai; honoraria, Takeda, Chugai, Kyowa-Kirin, Genmab, AstraZeneca, and MSD; consulting/advisory board, MSD, Eisai, and Takeda. EB: funded research, EU, DLR, AstraZeneca, Roche Diagnostics, and Bayer; honoraria/expenses, Roche, Merck, AstraZeneca, Tesaro, GSK, Clovis, Roche Diagnostics, Molecular Health, and Eisai; consulting/advisory board, Roche, Eisai, Merck, AstraZeneca, GSK, and Clovis. JM: employee of Eisai Inc, Woodcliff Lake, New Jersey, USA. JJL: employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, New Jersey, USA and stockholder in Merck & Co. VM: study support (all funding to institution)/consultant/advisory board membership, Merck, Eisai, Karyopharm, AstraZeneca, Clovis, Moreo, Takeda, Zymeworks, and Genentech; supported in part by the NIH/NCI Cancer Center Support grant P30 CA008748., (© IGCS and ESGO 2022. Re-use permitted under CC BY. Published by BMJ.)

Humans have made such dramatic and permanent changes to Earth's landscapes that much of it is now substantially and irreversibly altered from its preanthropogenic state. Remote islands, until recently isolated from humans, offer insights into how these landscapes evolved in response to human-induced perturbations. However, little is known about when and how remote systems were colonized because archaeological data and historical records are scarce and incomplete. Here, we use a multiproxy approach to reconstruct the initial colonization and subsequent environmental impacts on the Azores Archipelago. Our reconstructions provide unambiguous evidence for widespread human disturbance of this archipelago starting between 700 -60 +50 and 850 -60 +60 Common Era (CE), ca. 700 y earlier than historical records suggest the onset of Portuguese settlement of the islands. Settlement proceeded in three phases, during which human pressure on the terrestrial and aquatic ecosystems grew steadily (i.e., through livestock introductions, logging, and fire), resulting in irreversible changes. Our climate models suggest that the initial colonization at the end of the early Middle Ages (500 to 900 CE) occurred in conjunction with anomalous northeasterly winds and warmer Northern Hemisphere temperatures. These climate conditions likely inhibited exploration from southern Europe and facilitated human settlers from the northeast Atlantic. These results are consistent with recent archaeological and genetic data suggesting that the Norse were most likely the earliest settlers on the islands., Competing Interests: The authors declare no competing interest.

Background: There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status., Patients and Methods: Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m 2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m 2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest., Results: From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%)., Conclusions: The PLD-olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m 2 is better tolerated in the combination., Competing Interests: Disclosure JAP-F has participated in the advisory boards for AstraZeneca, GSK, Clovis, and Ability Pharma and has participated as a speaker and received travel and accommodation grants from AstraZeneca and GSK. MI has participated in advisory and consultancy boards for Roche, GSK, Tesaro (A GSK Company), and PharmaMar; participated in the speakers bureau for AstraZeneca, Roche, GSK, Tesaro (A GSK Company), Eisai, Clovis, and PharmaMar; and received travel/accommodation expenses from Novartis, AstraZeneca, MSD, Tesaro (A GSK Company), PharmaMar, Roche, GSK, Pfizer, and Eisai. AC reports consulting or advisory role for Lilly, Clovis; is on the speaker bureau for GSK, Roche Genentech, AstraZeneca, Eisai, MSD, Pfizer; and has received research funding from Pfizer; travel, accommodation, and other expenses were covered by Pfizer and Roche Genentech. EG has received advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK- Tesaro (A GSK Company), PharmaMar, and Roche; has received speaker bureau/expert testimony honorarium from AstraZeneca, PharmaMar, Roche, and GSK; and has received travel/accommodation/expenses from Roche, Tesaro (A GSK Company), and Baxter. AR reports receiving honoraria from and plays advisory/consultancy roles for MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, and Amgen; research grant/funding to his institution from Eisai, PharmaMar, and Roche; travel/accommodation/expenses from AstraZeneca, Tesaro (A GSK Company), PharmaMar, and Roche; and serves on the speakers bureau of MSD, AstraZeneca, Roche, GSK, Clovis, and PharmaMar, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To examine whether the educational level moderates the relationship between baseline depressive symptoms and cognitive functioning at 5- and 10-year follow-ups in older adults, considering the association between cognitive functioning and difficulty with activities of daily living (ADL)., Design: Using a prospective design, a path analysis was performed., Setting: In-home, face-to-face interviews and self-administered questionnaires, within the National Social Life, Health, and Aging Project., Participants: In total, 1,461 participants (mean age = 66.62) were followed up from Wave 1 (baseline) to Wave 2 (at 5 years) and Wave 3 (at 10 years)., Measurements: Depressive symptoms were assessed at baseline. Cognitive functioning and difficulty with ADL were assessed at baseline and at 5 and 10 years., Results: Educational level moderates the relationship between depressive symptoms and cognitive functioning at 5 years (β = 0.07, SE = 0.03, p = 0.04, Cohen's f2 = 0.02), being depressive symptoms related to poor cognitive functioning only at low educational levels. Cognitive functioning predicts difficulty with ADL at 5 and 10 years (β = -0.08, SE = 0.03, p = 0.008, Cohen's f2 = 0.01; β = -0.09, SE = 0.03, p = 0.006, Cohen's f2 = 0.02). The proposed model yielded excellent fit (CFI = 1.00, RMSEA = 0.0001, 90% CI 0.0001-0.03, SRMR = 0.004, and χ2(8) = 7.16, p = 0.52)., Conclusions: Cognitive reserve may act as a protective factor against the effect of depressive symptoms on cognition in older adults, which, in turn, is relevant to their functional independence.

Habituation to ethnic ingroup members has been reported to be greater than to ethnic outgroup members. This pattern could be due to the lack of perceptive experience (familiarity) with outgroup facial morphs or, alternatively, to the prejudice held toward that outgroup. We explored this disjunctive in 71 participants, all Spanish, who were experimentally habituated to faces from their Ingroup and to faces from two unfamiliar outgroups, one for which there is low probability of prejudice in this population (Non-prejudiced Outgroup), and one for which the probability of prejudice is higher (Prejudiced Outgroup). We indexed habituation through event-related potentials, concretely as the differential amplitude of the face-sensitive N170 component from Initial to Final trials of each group. Afterward, participants completed several prejudice measures. N170 showed significant habituation to all faces, though it did not differ among groups. However, a regression analysis revealed that individual habituation to the Outgroup faces was inversely related to implicit prejudice scores. Importantly, N170 amplitudes were maximal for the Prejudiced Outgroup in both Initial and Final trials. We conclude that these effects are explained by the prejudice held toward a specific outgroup rather than perceptive experience.

Background: To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors., Methods: The questionnaire was developed by the byline authors. All questions but one were answered using a 9-item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale., Results: In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented., Conclusions: This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO-ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues.

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease.The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.

Objective: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC)., Methods: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3., Results: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events., Conclusions: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies., Competing Interests: Declaration of Competing Interest Ignacio Romero: consulting or advisory role for AstraZeneca Spain, GSK Tesaro Spain, Roche Spain, Clovis Spain. Juan-Antonio Schoenenberger: funds from MedSIR for the submitted work. Eva Maria Guerra: consulting fees and advisory board fees from Roche, Clovis Oncology, GSK Tesaro, PharmaMar, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, GSK Tesaro and Baxter. Alfonso Cortés: consulting fees or speaker bureau from AstraZeneca, Roche-Genentech, Pfizer, Lilly, Ferrer. Juan Fernando Cueva: consulting fees from AstraZeneca. Lourdes Gómez and Andrea Malfettone: full-time employees of MedSIR. Miguel Sampayo: consulting fees from Syntax for Science, Nestle Health Science, Laboratorios Leti, Roche, Ability Pharma and Allergan; part-time employee of MedSIR. Antonio Llombart-Cussac: leadership of Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; stock or other ownership of MedSIR, Initia-Research; consulting or advisory role for Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK; speakers' bureau from Lilly, AstraZeneca, MSD; research funding from Roche, Foundation Medicine, Pierre-Fabre, Agendia; travel, accommodations, expenses from Roche, Lilly, Novartis, Pfizer, AstraZeneca. Andrés Poveda: consulting or advisor role for AstraZeneca, PharmaMar, Clovis Oncology, Roche, GSK Tesaro. M. Jesús Rubio, Manuel Medina, Xavier Matias-Guiu, Maria Santacana, Lucas Minig, and Pluvio Coronado: no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m 2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days., Material and Methods: Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1., Results: ORR was 60.0 % (95 %CI, 36.1-86.9), with a median duration of response of 5.5 months (95 %CI, 2.9-11.2) and disease control rate of 95.0 % (95 %CI, 75.1-99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6-7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported., Conclusion: Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Exogenous attention allows the automatic detection of relevant stimuli and the reorientation of our current focus of attention towards them. Faces from an ethnic outgroup tend to capture exogenous attention to a greater extent than faces from an ethnic ingroup. We explored whether prejudice toward the outgroup, rather than lack of familiarity, is driving this effect. Participants (N = 76) performed a digit categorization task while distractor faces were presented. Faces belonged to (i) a prejudiced outgroup, (ii) a non-prejudiced outgroup and (iii) their ingroup. Half of the faces were previously habituated in order to increase their familiarity. Reaction times, accuracy and event-related potentials (ERPs) were recorded to index exogenous attention to distractor faces. Additionally, different indexes of explicit and implicit prejudice were measured, the latter being significantly greater towards prejudiced outgroup. N170 amplitude was greater to prejudiced outgroup-regardless of their habituation status-than to both non-prejudiced outgroup and ingroup faces and was associated with implicit prejudice measures. No effects were observed at the behavioral level. Our results show that implicit prejudice, rather than familiarity, is under the observed attention-related N170 effects and that this ERP component may be more sensitive to prejudice than behavioral measures under certain circumstances., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy., Methods: In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m 2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972., Findings: Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported., Interpretation: Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial., Funding: Pharma Mar., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cervical cancer (CC) is the fourth most common cancer in women worldwide, strongly linked to high-risk human papilloma virus infection. In high-income countries, the screening programs have dramatically decreased the incidence of CC; however, the lack of accessibility to them in developing countries makes CC an important cause of mortality. Clinical stage is the most relevant prognostic factor in CC. The new FIGO staging system published in 2018 is more accurate than the previous one since it takes into account the lymph node status. In early stages, the primary treatment is surgery-with some concerns recently raised regarding minimally invasive surgery because it might decrease survival-or radiotherapy, whereas concomitant chemo-radiotherapy is the conventional approach in locally advanced stages. For recurrent or metastatic CC, the combination of chemotherapy plus bevacizumab is the preferred therapy. Immunotherapy approach based on checkpoint inhibitors is evolving as the election therapy following failure to platinum therapy.

Debulking surgery, followed by taxane/platinum-based chemotherapy has traditionally been the first-line treatment for advanced ovarian cancer. However, most patients will experience recurrence afterwards, and receive subsequent lines of therapy. It has been proposed that extending the treatment-free interval of platinum can improve the response to a subsequent platinum-based chemotherapy, and reduce associated toxicities in women with recurrent, platinum-sensitive ovarian cancer. The aim was to determine the impact, in clinical practice, of trabectedin with pegylated liposomal doxorubicin (trabectedin/PLD) on the subsequent platinum-based therapy in these patients, and to explore the prognosis for breast cancer gene status and the expression of diverse genes. This was a multicenter, retrospective, postauthorization study that involved 79 patients. Germline or somatic mutations of breast cancer gene 1/2 were present in 21.5%. The median time between trabectedin/PLD and the onset of the subsequent treatment was 6.7 months. The overall response rate during the trabectedin/PLD period was 36.7%. In the subsequent first-line platinum-based therapy, the overall response rate was 51.4%. Progression-free survival and overall survival were 11.8 and 25.4 months, respectively, from the onset of trabectedin/PLD treatment. Partially platinum-sensitive (between 6 and 12 months) and platinum-sensitive patients (treatment-free interval of platinum≥12 months) showed no differences in progression-free survival and overall survival. Grade 3 neutropenia and asthenia were reported in 15.2 and 10.1% of patients, respectively. Most frequent adverse events in more than 10% of patients were neutropenia (45.6%), asthenia (43.0%), nausea (25.3%), and anemia (13.9%). The intercalation with a nonplatinum regimen may improve the response to a subsequent platinum-based therapy in women with recurrent, platinum-sensitive ovarian cancer.

Objective: To assess the impact of the first months of application of a Code Sepsis in a high complexity hospital, analyzing patient´s epidemiological and clinical characteristics and prognostic factors., Methods: A long-term observational study was carried out throughout a consecutive period of seven months (February 2015 - September 2015). The relationship with mortality of risk factors, and analytic values was analyzed using uni- and multivariate analyses., Results: A total of 237 patients were included. The in-hospital mortality was 24% at 30 days and 27% at 60 days. The mortality of patients admitted to Critical Care Units was 30%. Significant differences were found between the patients who died and those who survived in mean levels of creatinine (2.30 vs 1.46 mg/dL, p <0.05), lactic acid (6.10 vs 2.62 mmol/L, p <0.05) and procalcitonin (23.27 vs 12.73 mg/dL, p<0.05). A statistically significant linear trend was found between SOFA scale rating and mortality (p<0.05). In the multivariate analysis additional independent risk factors associated with death were identified: age > 65 years (OR 5.33, p <0.05), lactic acid > 3 mmol/L (OR 5,85, p <0,05), creatinine > 1,2 mgr /dL (OR 4,54, p <0,05) and shock (OR 6,57, P <0,05)., Conclusions: The epidemiological, clinical and mortality characteristics of the patients in our series are similar to the best published in the literature. The study has identified several markers that could be useful at a local level to estimate risk of death in septic patients. Studies like this one are necessary to make improvements in the Code Sepsis programs., (©The Author 2019. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Seventy four Reference Sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) have been recognised by the European Commission in 2016 for their commitment to excellence in investing and scaling up innovative solutions for active and healthy ageing. The Reference Site Collaborative Network (RSCN) brings together the EIP on AHA Reference Sites awarded by the European Commission, and Candidate Reference Sites into a single forum. The overarching goals are to promote cooperation, share and transfer good practice and solutions in the development and scaling up of health and care strategies, policies and service delivery models, while at the same time supporting the action groups in their work. The RSCN aspires to be recognized by the EU Commission as the principal forum and authority representing all EIP on AHA Reference Sites. The RSCN will contribute to achieve the goals of the EIP on AHA by improving health and care outcomes for citizens across Europe, and the development of sustainable economic growth and the creation of jobs.

Purpose: The purpose of this study was to demonstrate the existence of a bimodal survival pattern in metastatic uveal melanoma. Secondary aims were to identify the characteristics and prognostic factors associated with long-term survival and to develop a clinical decision tree., Materials and Methods: The medical records of 99 metastatic uveal melanoma patients were retrospectively reviewed. Patients were classified as either short (≤ 12 months) or long-term survivors (> 12 months) based on a graphical interpretation of the survival curve after diagnosis of the first metastatic lesion. Ophthalmic and oncological characteristicswere assessed in both groups., Results: Of the 99 patients, 62 (62.6%) were classified as short-term survivors, and 37 (37.4%) as long-term survivors. The multivariate analysis identified the following predictors of long-term survival: age ≤ 65 years (p=0.012) and unaltered serum lactate dehydrogenase levels (p=0.018); additionally, the size (smaller vs. larger) of the largest liver metastasis showed a trend towards significance (p=0.063). Based on the variables significantly associated with long-term survival, we developed a decision tree to facilitate clinical decision-making., Conclusion: The findings of this study demonstrate the existence of a bimodal survival pattern in patients with metastatic uveal melanoma. The presence of certain clinical characteristics at diagnosis of distant disease is associated with long-term survival. A decision tree was developed to facilitate clinical decision-making and to counsel patients about the expected course of disease.

Objective: To determine the incidence of serous tubal intraepithelial carcinoma (STIC) after risk reduction salpingo-oophorectomy(RRSO), and to describe oncological outcomes after RRSO., Materials and Methods: BRCA pathogenic mutation carriers who had undergone an RRSO were evaluated in this retrospective multicenter observational study. Patients were only included when fallopian tubes were analyzed following the protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Surgeries were performed between June 2010 and April 2017 at eight Spanish hospitals., Results: A total of 359 patients met the inclusion criteria. STIC was diagnosed in 3 (0.8%) patients; one of them underwent surgical staging due to positive peritoneal washing, with absence of disease at the final pathology report. None of the three patients received adjuvant chemotherapy and were free of disease at last follow-up. Fallopian tube and ovarian carcinoma were diagnosed in 5 (1.4%) and 1 (0.3%), respectively. At a median (range) follow-up time of 29 (3-92) months, five patients had a newly diagnosed breast cancer. Other types of cancer, which were diagnosed during the follow-up time, included: serous primary peritoneal carcinoma (n = 1), serous endometrial carcinoma (n = 1), colon (n = 1), pancreas (n = 1), jaw (n = 1), and lymphoma (n = 1). Seven patients died due to different types of cancer: breast (n = 4), pancreas (n = 1), jaw (n = 1), and colon (n = 1)., Conclusion: The incidence of STIC after RRSO in BRCA mutation carriers is low (0.8%) and it presents an excellent oncological outcome. Patients after RRSO, however, run the risk to develop other types of cancer during follow-up and should be properly advised before the prophylactic surgery.

Trichomoniasis, caused by Trichomonas vaginalis, is the leading nonviral sexually transmitted infection worldwide. We report the selection of a DNA aptamer against a T. vaginalis adhesion protein, AP65, using a microtiter plate-based in vitro combinatorial chemistry process termed systematic evolution of ligands by exponential enrichment. The enriched library pool was sequenced by next-generation sequencing, and several aptamer candidates with high affinity and specificity were identified. The aptamer with the highest affinity and specificity had a K D in the low nanomolar range, as confirmed by three different techniques: surface plasmon resonance, enzyme-linked aptamer assay, and biolayer interferometry. The selected aptamer was demonstrated to have a high specificity to the AP65 protein and to T. vaginalis cells with no cross-reactivity to other enteric and urogenital microorganisms. Current work is focused on the development of inexpensive and easy-to-use aptamer-based diagnostic assays for the reliable and rapid detection of T. vaginalis in vaginal swabs.

Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs. On the other hand, STC2 -/- mice that exhibited neonatal and adult overweight further presented deregulated glycaemia when they were feed with a hypercaloric diet (breeding pellet, BP). This alteration is more evident at the early stages of the animal life. Deregulated glycaemia in these mice was confirmed using glucose oral test. In addition, STC2 -/- mice present enhanced pancreas size; thus, the histological analysis reveals that WT mice respond to BP diet by increasing the size of the pancreatic islets through inducing cell division, and STC2 -/- mice lack this compensatory mechanism. Contrary, BP fed STC2 -/- mice show enhanced number of islets but of similar size than those fed with regular pellet. Histopathological analysis demonstrates tissue structure disruption and erythrocytes infiltrations in STC2 -/- mice, possibly due to the stress evoked by the BP diet. Finally, enhanced glucagon immunostaining was observed in the islet of STC2 -/- mice, and the glucagon ELISA assay confirmed the increase in the circulating glucagon. Summarizing, we present evidence of the role of STCs, mainly STC2, as a possible early marker during development of diabetes mellitus., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Exogenous attention is a set of mechanisms that allow us to detect and reorient toward salient events-such as appetitive or aversive-that appear out of the current focus of attention. The nature of these mechanisms, particularly the involvement of the parvocellular and magnocellular visual processing systems, was explored. Thirty-four participants performed a demanding digit categorization task while salient (spiders or S) and neutral (wheels or W) stimuli were presented as distractors under two figure-ground formats: heterochromatic/isoluminant (exclusively processed by the parvocellular system, Par trials) and isochromatic/heteroluminant (preferentially processed by the magnocellular system, Mag trials). This resulted in four conditions: SPar, SMag, WPar, and WMag. Behavioral (RTs and error rates in the task) and electrophysiological (ERPs) indices of exogenous attention were analyzed. Behavior showed greater attentional capture by SMag than by SPar distractors and enhanced modulation of SMag capture as fear of spiders reported by participants increased. ERPs reflected a sequence from magnocellular dominant (P1p, ≃120 msec) to both magnocellular and parvocellular processing (N2p and P2a, ≃200 msec). Importantly, amplitudes in one N2p subcomponent were greater to SMag than to SPar and WMag distractors, indicating greater magnocellular sensitivity to saliency. Taking together, results support a magnocellular bias in exogenous attention toward distractors of any nature during initial processing, a bias that remains in later stages when biologically salient distractors are present.

This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and children (uveal melanoma and retinoblastoma, respectively). We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis. Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma. Loss of methylation of the oncogenic mir-17-92 cluster was detected in primary tissues but also in blood from patients.