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A single monolayer of iron selenide grown on strontium titanate shows an impressive enhancement of superconductivity compared with the bulk, as well as a novel Fermi surface topology 2-5 , extreme two-dimensionality, and the possibility of phonon-enhanced electron pairing. For films thicker than one unit cell, however, the electronic structure is markedly different, with a drastically suppressed superconductivity and strong nematicity appearing 1,5 . The physics driving this extraordinary dichotomy of superconducting behaviour is far from clear. Here, we use low-temperature scanning tunnelling microscopy to study multilayers of iron selenide grown by molecular beam epitaxy, and find a stripe-type charge ordering instability that develops beneath the nematic state. The charge ordering is visible and pinned in the vicinity of impurities. And as it emerges in the strong limit of nematicity, it suggests that a magnetic fluctuation with a rather small wavevector may be competing with the ordinary collinear antiferromagnetic ordering in multilayer films. The existence of stripes in iron-based superconductors, which resemble the stripe order in cuprates, not only suggests that electronic anisotropy and correlation are playing an important role, but also provides a platform for probing the complex interactions between nematicity, charge ordering, magnetism and superconductivity in high-temperature superconductors.

A quantum spin Hall (QSH) insulator is a novel two-dimensional quantum state of matter that features quantized Hall conductance in the absence of a magnetic field, resulting from topologically protected dissipationless edge states that bridge the energy gap opened by band inversion and strong spin-orbit coupling. By investigating the electronic structure of epitaxially grown monolayer 1T'-WTe 2 using angle-resolved photoemission (ARPES) and first-principles calculations, we observe clear signatures of topological band inversion and bandgap opening, which are the hallmarks of a QSH state. Scanning tunnelling microscopy measurements further confirm the correct crystal structure and the existence of a bulk bandgap, and provide evidence for a modified electronic structure near the edge that is consistent with the expectations for a QSH insulator. Our results establish monolayer 1T'-WTe 2 as a new class of QSH insulator with large bandgap in a robust two-dimensional materials family of transition metal dichalcogenides (TMDCs).

We investigate the lattice coupling to the spin and charge orders in the striped nickelate, La1.75Sr0.25NiO4, using time-resolved resonant x-ray scattering. Lattice-driven dynamics of both spin and charge orders are observed when the pump photon energy is tuned to that of an Eu bond- stretching phonon. We present a likely scenario for the behavior of the spin and charge order parameters and its implications using a Ginzburg-Landau theory.

The nematic state, where a system is translationally invariant but breaks rotational symmetry, has drawn great attention recently due to the experimental observations of such a state in both cuprates and iron-based superconductors. The origin of nematicity and its possible tie to the pairing mechanism of high-Tc, however, still remain controversial. Here, we study the electronic structure of a multilayer FeSe film using angle-resolved photoemission spectroscopy. The band reconstruction in the nematic state is clearly delineated. We find that the energy splitting between dxz and dyz bands shows a nonmonotonic distribution in momentum space. From the Brillouin zone center to the Brillouin zone corner, the magnitude of splitting first decreases, then increases, and finally reaches the maximum value of ∼70 meV. Moreover, besides the dxz and dyz bands, band splitting was also observed on the dxy bands with a comparable energy scale around 45 meV. Our results suggest that the electronic anisotropy in the nematic state cannot be explained by a simple on-site ferro-orbital order. Instead, strong anisotropy exists in the hopping of all dxz,dyz, and dxy orbitals, the origin of which holds the key to a microscopic understanding of the nematicity in iron-based superconductors.

The level of electronic correlation has been one of the key questions in understanding the nature of superconductivity. Among the iron-based superconductors, the iron chalcogenide family exhibits the strongest electron correlations. To gauge the correlation strength, we performed a systematic angle-resolved photoemission spectroscopy study on the iron chalcogenide series Fe1+ySexTe1-x (0

1 The binding of bupivacaine (400 ng/ml) to isolated alpha 1-acid glycoprotein was studied at two protein concentrations. At 20 mg/100 ml the extent of bupivacaine binding was 31.0 +/- 1.8% (mean +/- s.d., n = 4), and at a protein concentration of 60 mg/100 ml binding of bupivacaine was 85.8 +/- 1.5% (n = 4). 2 Bupivacaine and alpha 1-acid glycoprotein concentrations were measured in plasma samples collected from a maternal peripheral vein and the umbilical vein at delivery (n = 23). The ratio of the foetal:maternal bupivacaine concentrations ranged from 0.17 to 0.52, while the foetal:maternal ration for alpha 1-acid glycoprotein concentrations ranged from 0.20 to 0.96. A positive relationship emerged between the two ratios (P less than 0.01). 3 The alpha 1-acid glycoprotein concentration gradient across the placenta, and interindividual variability in the gradient appear to contribute to the low and variable transplacental bupivacaine concentration ratio observed. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the efficacy of cediranib, olaparib, and cediranib/olaparib compared with standard-of-care chemotherapy (SOC) in platinum-resistant or platinum-refractory epithelial ovarian cancer (PROC)., Patients and Methods: NRG-GY005 is an open-label, four-arm, phase II/III superiority trial enrolling patients with high-grade serous/endometrioid PROC and one to three previous therapies. Key exclusion criteria included previous receipt of poly(ADP-ribose) polymerase inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Treatment arms (SOC [once weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin], cediranib, olaparib, or cediranib/olaparib) were equally randomized. A preplanned interim futility analysis on the basis of progression-free survival (PFS) selected treatment arms to advance to phase III. PFS and overall survival (OS) were phase III coprimary end points, with hierarchical testing of PFS followed by OS to preserve type 1 error control, designed to have 90% power for a 0.625 PFS hazard ratio (HR). OS was tested after PFS in the multiple hierarchical testing procedure. Secondary end points included objective response rate (ORR) and patient-reported outcomes., Results: Five hundred sixty-two eligible patients were enrolled for phase II/III. Three arms met PFS criteria to carry forward to phase III (SOC, cediranib/olaparib, and cediranib). Median PFS was 3.4, 5.2, and 4 months with SOC, cediranib/olaparib, and cediranib, respectively, with a median follow-up duration of 42.2 months. PFS HR estimates for cediranib/olaparib and cediranib ( v SOC) were 0.796 (98.3% CI, 0.597 to 1.060) and 0.972 (98.3% CI, 0.726 to 1.300), respectively. Median OS was 13.6, 12.8, and 10.5 months, and of 443 patients with measurable disease, ORR was 8.6%, 24.7%, and 13.1% for SOC, cediranib/olaparib, and cediranib, respectively. No new safety signals were identified. In patients receiving cediranib/olaparib, no statistically significant difference was observed on the NFOSI-DRS-P subscale compared with SOC (98.3% CI, -1.3 to 1.5, P = .8725)., Conclusion: The cediranib-containing arms demonstrated clinical activity on the basis of PFS but were not superior compared with SOC.

Background: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported., Patients and Methods: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024)., Results: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed., Conclusions: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Circulating Tumor Cells (CTCs) may serve as a non-invasive source of tumor material to investigate an individual's disease in real-time. The Parsortix ® PC1 System, the first FDA-cleared medical device for the capture and harvest of CTCs from peripheral blood of metastatic breast cancer (MBC) patients for use in subsequent user-validated downstream analyses, enables the epitope-independent capture of CTCs with diverse phenotypes based on cell size and deformability. The aim of this study was to determine the proportion of MBC patients and self-declared female healthy volunteers (HVs) that had CTCs identified using immunofluorescence (IF) or Wright-Giemsa (WG) staining. Peripheral blood from 76 HVs and 76 MBC patients was processed on Parsortix ® PC1 Systems. Harvested cells were cytospun onto a charged slide and immunofluorescently stained for identification of CTCs expressing epithelial markers. The IF slides were subsequently WG-stained and analyzed for CTC identification based on morphological features of malignant cells. All testing was performed by operators blinded to the clinical status of each subject. CTCs were identified on the IF slides in 45.3% (≥ 1) / 24.0% (≥ 5) of the MBC patients (range = 0 - 125, mean = 7) and in 6.9% (≥ 1) / 2.8% (≥ 5) of the HVs (range = 0 - 28, mean = 1). Among the MBC patients with ≥ 1 CTC, 70.6% had only CK + /EpCAM- CTCs, with none having EpCAM + /CK- CTCs. CTC clusters were identified in 56.0% of the CTC-positive patients. On the WG-stained slides, CTCs were identified in 42.9% (≥ 1) / 21.4% (≥ 5) of the MBC patients (range = 0 - 41, mean = 4) and 4.3% (≥ 1) / 2.9% (≥ 5) of the HVs (range = 0 - 14, mean = 0). This study demonstrated the ability of the Parsortix ® PC1 System to capture and harvest CTCs from a significantly larger proportion of MBC patients compared to HVs when coupled with both IF and WG cytomorphological assessment. The presence of epithelial cells in subjects without diagnosed disease has been previously described, with their significance being unclear. Interestingly, a high proportion of the identified CTCs did not express EpCAM, highlighting the limitations of using EpCAM-based approaches., (© 2024. The Author(s).)

Objective: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy., Methods: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD)., Results: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups., Conclusion: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age., Competing Interests: Declaration of competing interest Dr. Valabrega reports consulting fees from GSK; honoraria from AstraZeneca, Eisai, GSK, and MSD; travel support from AstraZeneca and PharmaMar; and participation in advisory boards for AstraZeneca, Eisai, GSK, and MSD. Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, GSK, I-Mab, Immunogen, Incyte, Karyopharm, Merck, Mersana, Onconova, SeaGen, Sutro, and Toray; consulting fees from AstraZeneca, GOG Foundation, GSK, Merck, and Seagen; support for attending meetings from GOG Partners; and advisory board fees from Arquer Diagnostics, Atossa, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-Mab, Immunogen, Lily, Merck, Mersana, Natera, Onconova, Regeneron, Sutro Biopharma, Tesaro/GSK, Toray, and VBL Therapeutics. Dr. Oaknin reports institutional grants from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics AB, BMS, Clovis Oncology, Eisai, F. Hoffmann–La Roche, Immunogen, MSD de España SA, Millennium Pharmaceuticals, PharmaMar SA, Regeneron Pharmaceuticals, and Tesaro; consulting fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelixis, EMD Serono, F. Hoffmann–La Roche, Genmab, GSK, ImmunoGen, Iteos, MSD de España SA, Mersana Therapeutics, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Shattuck Labs, Seagen, and Sutro Biopharma; honoraria from Asociación Colombiada de Ginecológos Oncólogos, AstraZeneca, ESO, GSK, Medscape, NSGO, Peerview, and Peervoice; individual travel support from AstraZeneca, PharmaMar, and Roche; and advisory board participation for Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelixis, EMD Serono, F. Hoffmann–La Roche, Genmab, GSK, ImmunoGen, Iteos, MSD de España SA, Mersana Therapeutics, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Seagen, Shattuck Labs, and Sutro Biopharma. Dr. Graybill reports consulting and speaker fees from GSK. Dr. Sánchez reports consulting fees from AstraZeneca, GSK, and MSD; honoraria from AstraZeneca, GSK, and MSD; and travel support from AstraZeneca, GSK, and MSD. Dr. McCormick reports personal fees for advisory boards for Clovis, GSK, ImmunoGen, and Merck. Dr. Baurain reports consulting fees from AstraZeneca, BMS, GSK, Immunocore, Merck, MSD, Novartis, Pfizer, Pierre-Fabre, Regeneron, Sanofi, and Sun Pharma. Dr. Tinker reports honoraria from AstraZeneca, Eisai, GSK, and Merck and travel support from GSK. Dr. Denys reports an institutional research grant from Gilead; consulting fees from Gilead and GSK; honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Leo Pharma, MSD, and Roche; travel support from AstraZeneca, Gilead, GSK, MSD, Pfizer, PharmaMar, Roche, and Teva; and participation on advisory boards for AstraZeneca, Eli Lilly, Gilead, GSK, Menarini, MSD, and Pfizer. Dr. O'Cearbhaill reports institutional research support from NIH/NCI Cancer Center Support Grant (P30 CA008748) and support grants from AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Regeneron, Sellas Life Sciences, StemcentRx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Fresenius Kabi, Immunogen, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health; and service as a noncompensated steering committee member for the DUO-O (olaparib) and PRIMA and Moonstone (niraparib) studies. Dr. Hietanen reports consulting fees from AstraZeneca, Eisai, GSK, and MSD and honoraria from AstraZeneca and GSK. Dr. Moore reports institutional grants from Angle Plc and Fujirebio Diagnostics and personal fees from Fujirebio Diagnostics. Dr. Knudsen has nothing to disclose. Dr. de La Motte Rouge reports receiving consulting fees from AstraZeneca, Clovis Oncology, Eisai, Gilead, GSK, MSD, Novartis, Pfizer, and Sanofi; receiving honoraria from AstraZeneca, GSK, MSD, NetCancer, and Pfizer; and travel support from Gilead, MSD, and Pfizer. Dr. Heitz reports honoraria from AstraZeneca, GSK, Roche, and Tesaro and consulting fees from AstraZeneca, GSK, Roche, and Tesaro. Dr. Levy has nothing to disclose. Dr. Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers' bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. Dr. González-Martín reports for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis. Ms. York is a current employee of GSK. Dr. Gupta is a former employee of GSK and Mersana Therapeutics and is currently an employee of Cullinan Oncology., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A two-dimensional (2D) Weyl semimetal, akin to a spinful variant of graphene, represents a topological matter characterized by Weyl fermion-like quasiparticles in low dimensions. The spinful linear band structure in two dimensions gives rise to distinctive topological properties, accompanied by the emergence of Fermi string edge states. We report the experimental realization of a 2D Weyl semimetal, bismuthene monolayer grown on SnS(Se) substrates. Using spin and angle-resolved photoemission and scanning tunneling spectroscopies, we directly observe spin-polarized Weyl cones, Weyl nodes, and Fermi strings, providing consistent evidence of their inherent topological characteristics. Our work opens the door for the experimental study of Weyl fermions in low-dimensional materials., (© 2024. The Author(s).)

The unique spin texture of quantum states in topological materials underpins many proposed spintronic applications. However, realizations of such great potential are stymied by perturbations, such as temperature and local fields imposed by impurities and defects, that can render a promising quantum state uncontrollable. Here, we report room-temperature scanning tunneling microscopy/spectroscopy observation of interaction between Rashba states and topological surface states, which manifests local electronic structure along step edges controllable by the layer thickness of thin films. The first-principles theoretical calculation elucidates the robust Rashba states coexisting with topological surface states along the surface steps with characteristic spin textures in momentum space. Furthermore, the Rashba edge states can be switched off by reducing the thickness of a topological insulator Bi 2 Se 3 to bolster their interaction with the hybridized topological surface states. The study unveils a manipulating mechanism of the spin textures at room temperature, reinforcing the necessity of thin film technology in controlling the quantum states.

Objective: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study., Methods: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021)., Results: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1 - and BRCA2 -mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions)., Conclusions: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy., Trial Registration Number: NCT02655016., Competing Interests: Competing interests: WSG reports consulting and speaker fees from GSK. BPB reports honoraria, support for attending meetings and/or travel from AstraZeneca, Clovis, GSK, MSD, and PharmaMar and advisory board fees from AstraZeneca, Clovis, GSK, and MSD. DMO reports personal fees (consulting and/or advisory boards) and funding for clinical research from AbbVie, Amgen, AstraZeneca, Clovis, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance, Janssen/J&J, Merck, Mersana, Novocure, Regeneron, SDP Oncology (BBI), Seagen, and Tesaro/GSK; funding for clinical research from Ajinomoto, Array Biopharma, Bristol-Myers Squibb, Cerulean Pharma, EMD Serono, Ergomed, Genmab, INC Research, inVentiv Health Clinical, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA Intl, Serono, Stemcentrx, TRACON Pharmaceuticals, VentiRx, and Yale University; personal fees from Myriad Genetics, Rubis, and Tarveda; personal fees and funding for clinical research from Agenus; and personal fees (consulting and/or advisory boards) from Ambry, Arquer Diagnostics, Celsion, Corcept Therapeutics, Elevar, InxMed, Novartis, Roche Diagnostics MSA, Sorrento, Takeda, and Toray. IV reports institutional payments for corporate-sponsored research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Octimet Oncology, Oncoinvent AS, Sotio AS, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharma, and Oncoinvent AS; honoraria payment from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Jazz Pharma, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio AS; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; and advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, MSD, Novartis, Novocure, Seagen (2021), and Sotio AS. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. AA reports advisory board fees from GSK and MSD. LJC reports institutional research funding from AbbVie, Advaxis, Agenus, Ajinomoto, Arcus Biosciences, Array BioPharma, AstraZeneca, BeiGene USA, BMS, Cerulean Pharma, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Exelixis, Genentech/Roche, Genmab, GSK, Hoffman–LaRoche, Immunogen, Incyte Corporation, Iovance Biotherapeutics, InVentiv Health Clinical, Jansen R&D, Karyopharm, Leap Therapeutics, Ludwig Institute of Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, OncoQuest, OvaGene, Pfizer, PharmaMar, PRA International, Precision Therapeutics, Regeneron, Sanofi, Seattle Genetics, Serono, Stemcentrx, Sumitomo Dainippon Pharma Oncology, Sutro Biopharma, Tesaro (GSK), TRACON Pharm, and Verastem; personal advisory board fees from A28 Therapeutics, Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, GSK, Immunogen, InxMed, Luzsana Biotechnology, Myriad Genetics, Onconova, Rubius Therapeutics, Sorrento Therapeutics, Toray Industries, and VBL Therapeutics; and member of the data monitoring committee for Corcept Therapeutics. RS reports support for attending meetings from MSD and advisory board fees from Clovis Oncology, GSK, and MSD. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. PF reports payment or honoraria and payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Duality Bio, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Seagen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, BioNtech, Clovis Oncology, Eisai, GOG Foundation, Lily, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Onconova, and Toray; and travel support from GSK and BioNtech. EIB reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). CM reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. AY reports a GEICO grant by GSK. RGM reports personal fees from Fujirebio Diagnostics and research funding from Angle plc. PV reports payment of honoraria to self from MSD, Novartis, and Roche. NR-J reports advisory board fees from Eisai. WY and JH are employees of GSK. AG-M reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Eisai, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC), and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet-promoting weight loss is feasible and might improve QOL., Methods: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline., Results: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3 % total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8 % to 20.4 % percent calories from fat, p < 0.001) and fiber content (12.7 to 30.8 g fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95 % confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011)., Conclusions: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted., Trial Registration: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the 'fittest hit' to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow., (© 2024. The Author(s).)

Purpose: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy., Methods: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks., Results: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline., Conclusion: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017., (© 2024. The Author(s).)

Purpose: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer., Methods: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually., Results: Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV., Conclusion: While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

Background: Multiple antigens, autoantibodies (AAb), and antigen-autoantibody (Ag-AAb) complexes were compared for their ability to complement CA125 for early detection of ovarian cancer., Methods: Twenty six biomarkers were measured in a single panel of sera from women with early stage (I-II) ovarian cancers (n = 64), late stage (III-IV) ovarian cancers (186), benign pelvic masses (200) and from healthy controls (502), and then split randomly (50:50) into a training set to identify the most promising classifier and a validation set to compare its performance to CA125 alone., Results: Eight biomarkers detected ≥ 8% of early stage cases at 98% specificity. A four-biomarker panel including CA125, HE4, HE4 Ag-AAb and osteopontin detected 75% of early stage cancers in the validation set from among healthy controls compared to 62% with CA125 alone (p = 0.003) at 98% specificity. The same panel increased sensitivity for distinguishing early-stage ovarian cancers from benign pelvic masses by 25% (p = 0.0004) at 95% specificity. From 21 autoantibody candidates, 3 AAb (anti-p53, anti-CTAG1 and annt-Il-8) detected 22% of early stage ovarian cancers, potentially lengthening lead time prior to diagnosis., Conclusion: A four biomarker panel achieved greater sensitivity at the same specificity for early detection of ovarian cancer than CA125 alone., (© 2024. The Author(s).)

Forchlorfenuron (FCF) is a widely used plant cytokinin that enhances fruit quality and size in agriculture. It also serves as a crucial pharmacological tool for the inhibition of septins. However, the precise target of FCF has not yet been fully determined. This study reveals a novel target of FCF and elucidates its downstream signaling events. FCF significantly impairs mitochondrial respiration and mediates metabolic shift toward glycolysis, thus making cells more vulnerable to glycolysis inhibition. Interestingly, FCF's impact on mitochondrial function persists, even in cells lacking septins. Furthermore, the impaired mitochondrial function leads to the degradation of HIF-1α, facilitated by increased cellular oxygen. FCF also induces AMPK activation, suppresses Erk1/2 phosphorylation, and reduces the expression of HER2, β-catenin, and PD-L1. Endometrial cancer is characterized by metabolic disorders such as diabetes and aberrant HER2/Ras-Erk1/2/β-catenin signaling. Thus, FCF may hold promise as a potential therapeutic in endometrial cancer.

Metastable phases present a promising route to expand the functionality of complex materials. Of particular interest are light-induced metastable phases that are inaccessible under equilibrium conditions, as they often host new, emergent properties switchable on ultrafast timescales. However, the processes governing the trajectories to such hidden phases remain largely unexplored. Here, using time- and angle-resolved photoemission spectroscopy, we investigate the ultrafast dynamics of the formation of a hidden quantum state in the layered dichalcogenide 1 T -TaS 2 upon photoexcitation. Our results reveal the nonthermal character of the transition governed by a collective charge-density-wave excitation. Using a double-pulse excitation of the structural mode, we show vibrational coherent control of the phase-transition efficiency. Our demonstration of exceptional control, switching speed, and stability of the hidden state are key for device applications at the nexus of electronics and photonics.

The current challenge to realizing continuously tunable magnetism lies in our inability to systematically change properties, such as valence, spin, and orbital degrees of freedom, as well as crystallographic geometry. Here, we demonstrate that ferromagnetism can be externally turned on with the application of low-energy helium implantation and can be subsequently erased and returned to the pristine state via annealing. This high level of continuous control is made possible by targeting magnetic metastability in the ultrahigh-conductivity, nonmagnetic layered oxide PdCoO 2 where local lattice distortions generated by helium implantation induce the emergence of a net moment on the surrounding transition metal octahedral sites. These highly localized moments communicate through the itinerant metal states, which trigger the onset of percolated long-range ferromagnetism. The ability to continuously tune competing interactions enables tailoring precise magnetic and magnetotransport responses in an ultrahigh-conductivity film and will be critical to applications across spintronics.

Purpose: To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016)., Methods: Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported., Results: In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature., Conclusions: Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified., Competing Interests: Declaration of Competing Interest Dr. González-Martín reports support for the manuscript funding from GSK; grants or contracts from GSK and Roche; consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, MacroGenics, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, and Sutro; honoraria fees from AstraZeneca, Clovis, GSK, PharmaMar, and Roche; and support for attending meetings from AstraZeneca, GSK, PharmaMar, and Roche. Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Genentech/Roche, Karyopharm, Merck, Mersana, GSK, Sutro, Toray, Incyte, Imab, Onconova, VBL Therapeutics, and Clovis Oncology; consulting fees from AstraZeneca, GSK, SeaGen, and Merck; advisory board fees from Eisai, Lily, Merck, Sutro Biopharma, Tesaro/GSK, Astra Zeneca, and GOG Foundation. Dr. Vergote reports institutional payments for corporate sponsorship research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology Inc, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Oncoinvent AS, Octimet Oncology, Sotio, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharmaceuticals, and Oncoinvent AS; honoraria payments from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Jazz Pharmaceuticals, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, MSD, Novartis, Novocure, Seagen (2021), and Sotio. Dr. Graybill reports advisory board and speaker fees from GSK. Dr. Lorusso reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck, and PharmaMar; and grants from Merck and PharmaMar. Dr. McCormick reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. Dr. Freyer reports personal fees from AstraZeneca, Biogaran, Bristol Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer Inc., Roche Holding AG, S.A.S., and Tesaro; grants from AstraZeneca, Mylan, and Roche Holding AG. Dr. Backes reports personal fees from Agenus, CEC Oncology, Clovis, Eisai, Merck, AstraZeneca and GSK. ImmunoGen, Myriad; grants from Clovis, Eisai, Immunogen, and Merck, Beigene, Natera. Dr. Heitz reports honoraria from Roche, AstraZeneca, GSK, NovoCure, and PharmaMar; advisory board fees from NovoCure; and leadership role with AGO study group. Dr. Redondo reports institutional grants from Eisai, PharmaMar, and Roche; honoraria fees from AstraZeneca, MSD, Clovis, GSK, PharmaMar, and Eisai; advisory board roles at AstraZeneca, MSD, Clovis, GSK, PharmaMar, and Eisai; and travel support from AstraZeneca, GSK, and PharmaMar. Dr. Moore reports personal fees from Abcodia Inc, Fujirebio Diagnostics Inc, and Humphries Pharmaceutical; and institutional grants from Angle Plc. Dr. Vulsteke reports medical writing support to GSK; consulting fees from Atheneum Partners, Bristol Myers Squibb, GSK, Janssen-Cilag, Leo-Pharma, Merck Sharp & Dohme, and Roche; advisory board fees from AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; and travel support from Pfizer and Roche. Dr. O'Cearbhaill reports participating in advisory boards with 2seventy bio, Bayer, Carina Biotech, Fresenius Kabi, Immunogen, GSK, Miltenyi Biotec, Regeneron, and Seattle Genetics; personal fees from GOG Foundation; travel fees from Hitech Health and Gathering Around Cancer, Ireland; service as a noncompensated steering committee member for the PRIMA and Moonstone (niraparib) and DUO-O (olaparib) studies; institutional research support grants from Acrivon Therapeutics, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Immunopharma, Regeneron, Sellas Life Sciences, StemcentRx, Syndax, TapImmune Inc, and TCR2 Therapeutics. Drs. Malinowska and Shtessel are employees of GSK. Ms. Compton is a former employee of GSK and currently receiving consulting fees from GSK. Dr. Mirza reports consulting and advisory role fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zai Lab; speakers’ bureau fees from AstraZeneca and GSK; institutional research funding from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors). Dr. Monk reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novocure, Novartis, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL; and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8 + T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Background: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear., Methods: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort., Results: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy., Conclusions: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.)., (Copyright © 2023 Massachusetts Medical Society.)

The interface between 2D topological Dirac states and an s-wave superconductor is expected to support Majorana-bound states (MBS) that can be used for quantum computing applications. Realizing these novel states of matter and their applications requires control over superconductivity and spin-orbit coupling to achieve spin-momentum-locked topological interface states (TIS) which are simultaneously superconducting. While signatures of MBS have been observed in the magnetic vortex cores of bulk FeTe 0.55 Se 0.45 , inhomogeneity and disorder from doping make these signatures unclear and inconsistent between vortices. Here superconductivity is reported in monolayer (ML) FeTe 1-y Se y (Fe(Te,Se)) grown on Bi 2 Te 3 by molecular beam epitaxy (MBE). Spin and angle-resolved photoemission spectroscopy (SARPES) directly resolve the interfacial spin and electronic structure of Fe(Te,Se)/Bi 2 Te 3 heterostructures. For y = 0.25, the Fe(Te,Se) electronic structure is found to overlap with the Bi 2 Te 3 TIS and the desired spin-momentum locking is not observed. In contrast, for y = 0.1, reduced inhomogeneity measured by scanning tunneling microscopy (STM) and a smaller Fe(Te,Se) Fermi surface with clear spin-momentum locking in the topological states are found. Hence, it is demonstrated that the Fe(Te,Se)/Bi 2 Te 3 system is a highly tunable platform for realizing MBS where reduced doping can improve characteristics important for Majorana interrogation and potential applications., (© 2023 Wiley-VCH GmbH.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m 2 intravenously once every 3 weeks or paclitaxel 80 mg/m 2 intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.

Circulating tumor cells (CTCs) captured from the blood of cancer patients may serve as a surrogate source of tumor material that can be obtained via a venipuncture (also known as a liquid biopsy) and used to better understand tumor characteristics. However, the only FDA-cleared CTC assay has been limited to the enumeration of surface marker-defined cells and not further characterization of the CTCs. In this study, we tested the ability of a semi-automated device capable of capturing and harvesting CTCs from peripheral blood based on cell size and deformability, agnostic of cell-surface markers (the Parsortix ® PC1 System), to yield CTCs for evaluation by downstream techniques commonly available in clinical laboratories. The data generated from this study were used to support a De Novo request (DEN200062) for the classification of this device, which the FDA recently granted. As part of a multicenter clinical trial, peripheral blood samples from 216 patients with metastatic breast cancer (MBC) and 205 healthy volunteers were subjected to CTC enrichment. A board-certified pathologist enumerated the CTCs from each participant by cytologic evaluation of Wright-Giemsa-stained slides. As proof of principle, cells harvested from a concurrent parallel sample provided by each participant were evaluated using one of three additional evaluation techniques: molecular profiling by qRT-PCR, RNA sequencing, or cytogenetic analysis of HER2 amplification by FISH. The study demonstrated that the Parsortix ® PC1 System can effectively capture and harvest CTCs from the peripheral blood of MBC patients and that the harvested cells can be evaluated using orthogonal methodologies such as gene expression and/or Fluorescence In Situ Hybridization (FISH).

Purpose: The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer., Patients and Methods: PARP inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined., Results: Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8-55.1], while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group., Conclusions: Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Objective: To evaluate the detection of malignancy in women with a pelvic mass by using multiplexed gene expression analysis of cells captured from peripheral blood., Methods: This was an IRB-approved, prospective clinical study. Eligible patients had a pelvic mass and were scheduled for surgery or biopsy. Rare cells were captured from peripheral blood obtained preoperatively by using a microfluidic cell capture device. Isolated mRNA from the captured cells was analyzed for expression of 72 different gene transcripts. Serum levels for several commonly assayed biomarkers were measured. All patients had a tissue diagnosis. Univariate and multivariate logistic regression analyses for the prediction of malignancy using gene expression and serum biomarker levels were performed, and receiver operating characteristic curves were constructed and compared., Results: A total of 183 evaluable patients were enrolled (average age 56 years, range 19-91 years). There were 104 benign tumors, 17 low malignant potential tumors, and 62 malignant tumors. Comparison of the area under the receiver operating characteristic curve for individual genes and various combinations of genes with or without serum biomarkers to differentiate between benign conditions (excluding low malignant potential tumors) and malignant tumors showed that a multivariate model combining the expression levels of eight genes and four serum biomarkers achieved the highest area under the curve (AUC) (95.1%, 95% CI 92.0-98.2%). The MAGIC (Malignancy Assessment using Gene Identification in Captured Cells) algorithm significantly outperformed all individual genes (AUC 50.2-65.2%; all P <.001) and a multivariate model combining 14 different genes (AUC 88.0%, 95% CI 82.9-93.0%; P =.005). Further, the MAGIC algorithm achieved an AUC of 89.5% (95% CI 81.3-97.8%) for stage I-II and 98.9% (95% CI 96.7-100%) for stage III-IV patients with epithelial ovarian cancer., Conclusion: Multiplexed gene expression evaluation of cells captured from blood, with or without serum biomarker levels, accurately detects malignancy in women with a pelvic mass., Clinical Trial Registration: ClinicalTrials.gov, NCT02781272., Funding Source: This study was funded by ANGLE Europe Limited (Surrey Research Park, Guildford, Surrey, United Kingdom)., Competing Interests: Financial Disclosure Richard G. Moore disclosed receiving consulting payments from Fujirebio Diagnostic Inc. and Abcodia Inc. He receives research funding from ANGLE Europe Limited. Michael C. Miller is a full-time employee of ANGLE North America, while Kelly Seto and David Englert are full-time employees of ANGLE Biosciences, Inc. Brent DuBeshter disclosed that money was paid to his institution from Angle PLC. The other authors did not report any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

The recently discovered insecticidal protein Mpp75Aa1.1 from Brevibacillus laterosporus is a member of the ETX&#95;MTX family of beta-pore forming proteins (β-PFPs) expressed in genetically modified (GM) maize to control western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte). In this manuscript, bioinformatic analysis establishes that although Mpp75Aa1.1 shares varying degrees of similarity to members of the ETX&#95;MTX2 protein family, it is unlikely to have any allergenic, toxic, or otherwise adverse biological effects. The safety of Mpp75Aa1.1 is further supported by a weight of evidence approach including evaluation of the history of safe use (HOSU) of ETX&#95;MTX2 proteins and Breviballus laterosporus. Comparisons between purified Mpp75Aa1.1 protein and a poly-histidine-tagged (His-tagged) variant of the Mpp75Aa1.1 protein demonstrate that both forms of the protein are heat labile at temperatures at or above 55°C, degraded by gastrointestinal proteases within 0.5 min, and have no adverse effects in acute mouse oral toxicity studies at a dose level of 1920 or 2120 mg/kg body weight. These results support the use of His-tagged proteins as suitable surrogates for assessing the safety of their non-tagged parent proteins. Taken together, we report that Mpp75Aa1.1 is the first ETX-MTX2 insecticidal protein from B. laterosporus and displays a similar safety profile as typical Cry proteins from Bacillus thuringiensis., Competing Interests: NO authors have competing interests

Objective: To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer., Methods: This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety., Results: Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52-71%) in the overall population and 76% (95% CI 61-87) in the homologous recombination deficient (HRd), 47% (95% CI 31-64%) in the HR proficient (HRp), and 56% (95% CI 31-79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9-32.5 months), median PFS was 19.6 months (95% CI 16.5-25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9-NE), 14.2 months (95% CI 8.6-16.8), and 12.1 months (95% CI 8.0-NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff)., Conclusion: Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy., Competing Interests: Declaration of Competing Interest MMH reports honoraria from Clinical Care Operations and GlaxoSmithKline; and advisory board fees from AstraZeneca-Merck, Immunogen and GlaxoSmithKline. TCK reports consulting and speakers' bureau fees from GlaxoSmithKline. GSW reports she served as PI for a clinical trial for which the institute received payment for conducting the trial from Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cascadian Therapeutics, Celgene, Celldex Therapeutics, Daiichi Sankyo Pharma, Dana Farber Cancer Institute, G1Therapeutics, Genentech, H3BioMedicine Inc., Hoffmann-LaRoche, ImmunoGen, Incyte, Innocrin Pharm, Jansen, Lilly, Macrogenics, Medivation, Merrimack, NanoString Technologies, Novartis, Nucana, Odonate Therapeutics, Pfizer, Seattle Genetics, Sermonix Pharm, Taiho Oncology, and Tesaro. EH reports institutional research grant from Tesaro/GSK, Abbvie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Arvinas, AtlasMedX, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Dana Farber Cancer Inst, Deciphera, eFFECTOR Therapeutics, Ellipses Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millenium, Molecular Templates, Myraid Genetic Labs, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Repertoire Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, Zymeworks and institional consulting fees from Arcus, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, SeaGen, Silverback Therapeutics. ELF has nothing to disclose. JB is an employee of GlaxoSmithKline. EKK is a former employee of GlaxoSmithKline and reports stock and stock option ownership at the time of GSK employment. PW is an employee of GlaxoSmithKline. DG is an employee of GlaxoSmithKline. AC reports consulting fees from Tempus and advisory board fees from GlaxoSmithKline. HJG has nothing to disclose. GEK reports speaker bureau fees from AstraZeneca, Clovis, GlaxoSmithKline/Tesaro, and Myriad Genetics. RGM reports personal fees from Fujirebio Diagnostics Inc., and Humphries Pharmaceutical; and institutional grants from Angle Plc. DLR reports research contracts paid to her institution from Aravive, Arch Oncology, Celsion, Clovis, Deciphera, Fujifilm, GlaxoSmithKline, Harpoon, Karyopharm, Mersana, Plexxikon, Roche, Shattuck Labs, Syros, and Tesaro; honoraria fees from GOG Foundation; travel support from Tesaro; advisory board fees from AstraZeneca, Bayer, Deciphera, Foundation Medicine, Genentech, Mersana, and Tesaro/GlaxoSmithKline; and unpaid leadership as the vice chair of board of directors for National Ovarian Cancer Coalition., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background:  Uterine transplantation (UTx) is acknowledged to be on the second (2A) of five steps of development in accordance with the staging system for the evaluation of surgical innovations. Accordingly, we aimed to systematically review the available evidence of the surgical techniques and outcomes of UTx in terms of graft survival., Methods:  A comprehensive search was conducted across PubMed Medline, Cochrane-EBMR, Scopus, Web of Science, and CENTRAL through November 2020., Results:  Forty studies, reporting 64 recipients and 64 donors, satisfied inclusion criteria. The surgical time and the estimated blood loss were 515 minutes and 679 mL for graft procurement via laparotomy, 210 minutes and 100 mL for laparoscopic-assisted graft harvest, and 660 minutes and 173 mL for robotic-assisted procedures, respectively. Urinary tract infections ( n  = 8) and injury to the urinary system ( n  = 6) were the most common donor complications. Using the donor's internal iliac system, two arterial anastomoses were performed in all cases. Venous outflow was accomplished through the uterine veins (UVs) in 13 cases, a combination of the UVs and the ovarian/uteroovarian veins (OVs/UOVs) in 36 cases, and solely through the OVs/UOVs in 13 cases. Ischemia time was 161 and 258 minutes when using living donors (LD) and deceased donors (DD), respectively. Forty-eight uteri were successfully transplanted or fulfilled the purpose of transplantation, 41 from LDs and 7 from DDs. Twenty-five and four live childbirths from LDs and DDs have been reported, respectively., Conclusion:  UTx is still experimental. Further series are required to recommend specific surgical techniques that best yield a successful transplant and reduce complications for donors and recipients., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence., Methods: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population., Results: In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37)., Conclusions: In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance., Competing Interests: Declaration of Competing Interest REO reports participating in advisory boards with Bayer, Fresenius Kabi, GlaxoSmithKline, Immunogen, Regeneron, and Seattle Genetics; personal fees from GOG Foundation; and service as a noncompensated steering committee member for the PRIMA (niraparib) and DUO-O (olaparib) studies; institutional research support grants from AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GlaxoSmithKline, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Regeneron, Sellas Life Sciences, Stem CentRx, Syndax, TapImmune Inc., and TCR2 Therapeutics. JAPF reports personal fees from Abilify Pharma, Amgen, AstraZeneca, Clinigen, Clovis, GlaxoSmithKline, and Roche; and institutional grants from GlaxoSmithKline. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novartis, Novocure, Regeneron, Sorrento, Pfizer, Puma, US Oncology Research, and VBL; speaker's bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, TESARO/GSK; and is an investigator for US Oncology Research. IT reports personal fees from Celgene and Roche Pharma AG; institutional grants from Roche; and travel support from Roche. RGM reports personal fees from Abcodia Inc., Fujirebio Diagnostics Inc., and Humphries Pharmaceutical; and institutional grants from Angle Plc. MSS reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck, and Pacira Pharmaceuticals Inc.; and institutional grants from GlaxoSmithKline. DO reports personal fees from Agenus, Eisai, GlaxoSmithKline, and Immunogen; consultant/advisory board for Abbvie, Ambry, Amgen, Array Biopharma, Clovis, EMD Serono, Ergomed, Janssen/J&J, INC Research Inc., inVentiv Health Clinical, Iovance Biotherapeutics Inc., Myriad Genetics, Novacure, Regeneron, Tarveda, and VentiRx; steering committee for Genentech/Roche and Merck; institutional funding from Ajinomoto Inc., Bristol Myers Squibb, Cerulean Pharma, GOG Foundation, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA International, Stemcentrx Inc., Serono Inc., Tracon Pharmaceuticals, and Yale University. BMS reports consulting/advisory fees from Abbvie, AstraZeneca, Clovis, Eisai, Genentech, GlaxoSmithKline, GOG Foundation, Merck, and Myriad. FS reports personal fees from AstraZeneca, Clovis, GlaxoSmithKline, MSD, PharmaMar, and Roche; and travel support from AstraZeneca, GlaxoSmithKline, MSD, PharmaMar, and Roche. AK reports personal fees from AstraZeneca and GlaxoSmithKline. AGM reports consulting or advisory roles at Amgen, AstraZeneca, Clovis, Genmab, GlaxoSmithKline, Merck & Co., Mersana, Immunogen, Roche, Sotio, and Takeda; speaker's bureau compensation from AstraZeneca, Clovis, GlaxoSmithKline, Merck & Co., and Roche; institutional research funding from Roche and GlaxoSmithKline; and travel support from AstraZeneca, GlaxoSmithKline, and Roche. CM, CV, JF, FF, WHB, SH, AD, KB, PMC, GA, and TL have nothing to disclose. IAM and DG are employees of GlaxoSmithKline. YL was an employee at GlaxoSmithKline at the time of the analysis; currently an employee of Adagio Therapeutics Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy., Patients and Methods: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA -mutated or wild-type subgroups and patient-reported outcomes (PROs)., Results: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed., Conclusion: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity., Competing Interests: Joyce F. LiuConsulting or Advisory Role: Tesaro, Mersana, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, Regeneron, AstraZenecaResearch Funding: Genentech/Roche (Inst), AstraZeneca (Inst), Boston Biomedical (Inst), Acetylon Pharmaceuticals (Inst), Bristol Myers Squibb (Inst), Agenus (Inst), CytomX Therapeutics (Inst), Regeneron (Inst), Tesaro (Inst), Clovis Oncology (Inst), Surface Oncology (Inst), 2X Oncology (Inst), Vigeo Therapeutics (Inst), Aravive (Inst), Arch Oncology (Inst)Travel, Accommodations, Expenses: AstraZeneca, MerckUncompensated Relationships: Merck Mark F. BradyConsulting or Advisory Role: Cel-Sci Ursula A. MatulonisHonoraria: Advaxis, Alkermes, SymphogenConsulting or Advisory Role: Merck, Novartis, NextCure, AstraZeneca, Blueprint Medicines, Trillium Therapeutics, GlaxoSmithKline, AgenusResearch Funding: Merck, Novartis, Tesaro, Syndax, Immunogen, Mersana, Leap Therapeutics, Fujifilm, SQZ BiotechTravel, Accommodations, Expenses: AstraZeneca Austin MillerConsulting or Advisory Role: AstraZeneca/Merck, Regeneron (Inst)Uncompensated Relationships: Genetect Elizabeth M. SwisherLeadership: IDEAYA Biosciences David CellaStock and Other Ownership Interests: FACIT.orgConsulting or Advisory Role: AbbVie, GlaxoSmithKline, Pfizer, Astellas Pharma, Novartis, Bristol Myers Squibb, Asahi Kasei, Ipsen, Mei PharmaResearch Funding: Novartis (Inst), Ipsen (Inst), Pfizer (Inst), PledPharma (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Regeneron (Inst), Clovis Oncology (Inst) Noelle G. ClovenConsulting or Advisory Role: Toray Industries Carolyn Y. MullerResearch Funding: AstraZeneca (Inst), Genmab (Inst), VBL Therapeutics (Inst), Roche/Genentech (Inst), TapImmune Inc (Inst), Linnaeus Therapeutics (Inst), agenus (Inst), Incyte (Inst), Merck (Inst)Patents, Royalties, Other Intellectual Property: Have a pending patent on the cancer use for R-ketorolac - not yet its own new drug (Inst)Other Relationship: NCI, NCI, Department of Defense Richard G. MooreHonoraria: Fujirebio DiagnosticsConsulting or Advisory Role: Abcodia, Fujirebio DiagnosticsResearch Funding: Angle Steven E. WaggonerConsulting or Advisory Role: Regeneron Melissa A. GellerResearch Funding: Tesaro, Genentech, FATE Therapeutics, Morphotek, Bayer Keiichi FujiwaraHonoraria: Kyowa Hakko Kirin, Zeria Pharmaceutical, Nippon Kayaku, Chugai Pharma, Eisai, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, TakedaConsulting or Advisory Role: MSD, Taiho Pharmaceutical, Eisai, Takeda, Genmab, NanoCarrierResearch Funding: Eisai (Inst), Kaken Pharmaceutical (Inst), Chugai Pharma (Inst), Immunogen (Inst), Oncotherapeutics (Inst), AstraZeneca (Inst), Zeria Pharmaceutical (Inst), Ono Pharmaceutical (Inst), MSD (Inst), Regeneron (Inst), Merck KGaA (Inst), Ono Pharmaceutical (Inst), Genmab (Inst), Seattle Genetics (Inst)Travel, Accommodations, Expenses: MSD Angeles Alvarez SecordHonoraria: Myriad GeneticsResearch Funding: Tesaro (Inst), AstraZeneca (Inst), Genentech (Inst), Boehringer Ingelheim (Inst), AbbVie (Inst), Merck (Inst), PharmaMar (Inst), Clovis Oncology (Inst), Eisai (Inst), Seattle Genetics (Inst), Immutep (Inst), GlaxoSmithKline (Inst), VBL Therapeutics (Inst), OncoQuest Pharmaceuticals (Inst)Travel, Accommodations, Expenses: GlaxoSmithKlineUncompensated Relationships: Roche/Genentech, VBL Therapeutics, GOG Foundation, OncoQuest Pharmaceuticals, Regeneron, Aravive Katherine M. MoxleyConsulting or Advisory Role: Tessa Therapeutics (Inst), Clovis Oncology (Inst), GlaxoSmithKline Michael A. BookmanEmployment: The Permanente Medical GroupConsulting or Advisory Role: AstraZeneca, AbbVie, Immunogen, Merck Sharp & Dohme, Genentech/Roche, Seattle Genetics, AraviveNo other potential conflicts of interest were reported.