A New Rapid-Acting Antidepressant.

The discovery of the strikingly rapid and robust antidepressant effects of r/s-ketamine for the treatment of antidepressant-resistant symptoms of depression has led to new insights into the biology of antidepressants and the FDA approval of its s-isomer, Esketamine (Spravato), the first mechanistically new treatment for depression in over 60 years. To view this Bench to Bedside, open or download the PDF.

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

Ovarian cancer mutational processes drive site-specific immune evasion.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFß signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

Determining the three-dimensional atomic structure of an amorphous solid.

Amorphous solids such as glass, plastics and amorphous thin films are ubiquitous in our daily life and have broad applications ranging from telecommunications to electronics and solar cells1-4. However, owing to the lack of long-range order, the three-dimensional (3D) atomic structure of amorphous solids has so far eluded direct experimental determination5-15. Here we develop an atomic electron tomography reconstruction method to experimentally determine the 3D atomic positions of an amorphous solid. Using a multi-component glass-forming alloy as proof of principle, we quantitatively characterize the short- and medium-range order of the 3D atomic arrangement. We observe that, although the 3D atomic packing of the short-range order is geometrically disordered, some short-range-order structures connect with each other to form crystal-like superclusters and give rise to medium-range order. We identify four types of crystal-like medium-range order-face-centred cubic, hexagonal close-packed, body-centred cubic and simple cubic-coexisting in the amorphous sample, showing translational but not orientational order. These observations provide direct experimental evidence to support the general framework of the efficient cluster packing model for metallic glasses10,12-14,16. We expect that this work will pave the way for the determination of the 3D structure of a wide range of amorphous solids, which could transform our fundamental understanding of non-crystalline materials and related phenomena.

Observing crystal nucleation in four dimensions using atomic electron tomography.

Nucleation plays a critical role in many physical and biological phenomena that range from crystallization, melting and evaporation to the formation of clouds and the initiation of neurodegenerative diseases1-3. However, nucleation is a challenging process to study experimentally, especially in its early stages, when several atoms or molecules start to form a new phase from a parent phase. A number of experimental and computational methods have been used to investigate nucleation processes4-17, but experimental determination of the three-dimensional atomic structure and the dynamics of early-stage nuclei has been unachievable. Here we use atomic electron tomography to study early-stage nucleation in four dimensions (that is, including time) at atomic resolution. Using FePt nanoparticles as a model system, we find that early-stage nuclei are irregularly shaped, each has a core of one to a few atoms with the maximum order parameter, and the order parameter gradient points from the core to the boundary of the nucleus. We capture the structure and dynamics of the same nuclei undergoing growth, fluctuation, dissolution, merging and/or division, which are regulated by the order parameter distribution and its gradient. These experimental observations are corroborated by molecular dynamics simulations of heterogeneous and homogeneous nucleation in liquid-solid phase transitions of Pt. Our experimental and molecular dynamics results indicate that a theory beyond classical nucleation theory1,2,18 is needed to describe early-stage nucleation at the atomic scale. We anticipate that the reported approach will open the door to the study of many fundamental problems in materials science, nanoscience, condensed matter physics and chemistry, such as phase transition, atomic diffusion, grain boundary dynamics, interface motion, defect dynamics and surface reconstruction with four-dimensional atomic resolution.

Ten facts about land systems for sustainability.

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits-"win-wins" are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use.

Screening for genetic variability in photosynthetic regulation provides insights into salt performance traits in forage sorghum under salt stress.

BACKGROUND: Sorghum (Sorghum bicolor) is a promising opportunity crop for arid regions of Africa due to its high tolerance to drought and heat stresses. Screening for genetic variability in photosynthetic regulation under salt stress can help to identify target trait combinations essential for sorghum genetic improvement. The primary objective of this study was to identify reliable indicators of photosynthetic performance under salt stress for forage yield within a panel of 18 sorghum varieties from stage 1 (leaf 3) to stage 7 (late flowering to early silage maturity). We dissected the genetic diversity and variability in five stress-sensitive photosynthetic parameters: nonphotochemical chlorophyll fluorescence quenching (NPQ), the electron transport rate (ETR), the maximum potential quantum efficiency of photosystem II (FV/FM), the CO2 assimilation rate (A), and the photosynthetic performance based on absorption (PIABS). Further, we investigated potential genes for target phenotypes using a combined approach of bioinformatics, transcriptional analysis, and homologous overexpression. RESULTS: The panel revealed polymorphism, two admixed subpopulations, and significant molecular variability between and within population. During the investigated development stages, the PIABS varied dramatically and consistently amongst varieties. Under higher saline conditions, PIABS also showed a significant positive connection with A and dry matter gain. Because PIABS is a measure of plants' overall photosynthetic performance, it was applied to predict the salinity performance index (SPI). The SPI correlated positively with dry matter gain, demonstrating that PIABS could be used as a reliable salt stress performance marker for forage sorghum. Eight rubisco large subunit genes were identified in-silico and validated using qPCR with variable expression across the varieties under saline conditions. Overexpression of Rubisco Large Subunit 8 increased PIABS, altered the OJIP, and growth with an insignificant effect on A. CONCLUSIONS: These findings provide insights into strategies for enhancing the photosynthetic performance of sorghum under saline conditions for improved photosynthetic performance and potential dry matter yield. The integration of molecular approaches, guided by the identified genetic variability, holds promise for genetically breeding sorghum tailored to thrive in arid and saline environments, contributing to sustainable agricultural practices.

Modeling Temperature-Dependent Electron Thermal Diffuse Scattering via Machine-Learned Interatomic Potentials and Path-Integral Molecular Dynamics.

Electron thermal diffuse scattering is shown to be sensitive to subtle changes in atomic vibrations and shows promise in assessing lattice dynamics at nanometer resolution. Here, we demonstrate that machine-learned interatomic potentials (MLIPs) and path-integral molecular dynamics can accurately capture the potential energy landscape and lattice dynamics needed to describe electron thermal diffuse scattering. Using SrTiO_{3} as a test bed at cryogenic and room temperatures, we compare electron thermal diffuse scattering simulations using different approximations to incorporate thermal motion. Only when the simulations are based on quantum mechanically accurate MLIPs in combination with path-integral molecular dynamics that include nuclear quantum effects is there excellent agreement with experiments.

Search for Heavy Neutral Leptons in Electron-Positron and Neutral-Pion Final States with the MicroBooNE Detector.

We present the first search for heavy neutral leptons (HNLs) decaying into νe^{+}e^{-} or νπ^{0} final states in a liquid-argon time projection chamber using data collected with the MicroBooNE detector. The data were recorded synchronously with the NuMI neutrino beam from Fermilab's main injector corresponding to a total exposure of 7.01×10^{20} protons on target. We set upper limits at the 90% confidence level on the mixing parameter |U_{µ4}|^{2} in the mass ranges 10≤m_{HNL}≤150 MeV for the νe^{+}e^{-} channel and 150≤m_{HNL}≤245 MeV for the νπ^{0} channel, assuming |U_{e4}|^{2}=|U_{τ4}|^{2}=0. These limits represent the most stringent constraints in the mass range 35

First Search for Dark-Trident Processes Using the MicroBooNE Detector.

We present a first search for dark-trident scattering in a neutrino beam using a dataset corresponding to 7.2×10^{20} protons on target taken with the MicroBooNE detector at Fermilab. Proton interactions in the neutrino target at the main injector produce π^{0} and η mesons, which could decay into dark-matter (DM) particles mediated via a dark photon A^{'}. A convolutional neural network is trained to identify interactions of the DM particles in the liquid-argon time projection chamber (LArTPC) exploiting its imagelike reconstruction capability. In the absence of a DM signal, we provide limits at the 90% confidence level on the squared kinematic mixing parameter ϵ^{2} as a function of the dark-photon mass in the range 10≤M_{A^{'}}≤400 MeV. The limits cover previously unconstrained parameter space for the production of fermion or scalar DM particles χ for two benchmark models with mass ratios M_{χ}/M_{A^{'}}=0.6 and 2 and for dark fine-structure constants 0.1≤α_{D}≤1.

First Measurement of η Meson Production in Neutrino Interactions on Argon with MicroBooNE.

We present a measurement of η production from neutrino interactions on argon with the MicroBooNE detector. The modeling of resonant neutrino interactions on argon is a critical aspect of the neutrino oscillation physics program being carried out by the DUNE and Short Baseline Neutrino programs. η production in neutrino interactions provides a powerful new probe of resonant interactions, complementary to pion channels, and is particularly suited to the study of higher-order resonances beyond the Δ(1232). We measure a flux-integrated cross section for neutrino-induced η production on argon of 3.22±0.84(stat)±0.86(syst) 10^{-41} cm^{2}/nucleon. By demonstrating the successful reconstruction of the two photons resulting from η production, this analysis enables a novel calibration technique for electromagnetic showers in GeV accelerator neutrino experiments.

Trends in specific procedures performed at the time of cytoreduction for ovarian cancer: Is interval debulking surgery truly less radical? A Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVES: To evaluate procedures performed during primary debulking surgery (PDS) and interval debulking surgery (IDS) for ovarian cancer. METHODS: Patients surgically treated at our institution for newly diagnosed stage IIIC/IV epithelial ovarian cancer between 6/1/2015-12/31/2021 were identified using a prospectively collected database. Patients were triaged to PDS or neoadjuvant chemotherapy (NACT) followed by IDS using an institutional algorithm. Data on specific procedures performed, including consultants called, were collected from operative and pathology reports. Appropriate statistical analyses were applied. RESULTS: Overall, 467 patients underwent PDS and 434 underwent IDS; 76% (PDS) and 71% (IDS) of cases achieved complete gross resection. Comparing PDS vs IDS cohorts, median age was 63 years (range, 23-86) vs 67 years (range, 35-95), 79% vs 86% of patients had high-grade serous histology, and 38% vs 70% had stage IV disease. Most procedures (except ostomy, distal pancreatectomy) were more common during PDS (P < .05). Bowel surgery was performed during 65% of PDS and 33% of IDS, and upper abdominal surgery during 72% of PDS and 52% of IDS; both were more common during PDS (P < .001). Estimated blood loss (median, 500 mL [PDS] vs 300 mL [IDS]) and operative time (median, 362 min [PDS] vs 267 min [IDS]) were higher for PDS (P < .001). A consulting surgeon was utilized during 31% of PDS and 18% of IDS, with hepatopancreaticobiliary as the most commonly called service (61% and 65%, respectively). CONCLUSIONS: In our study of patients with advanced-stage ovarian cancer, while most procedures were more often performed during PDS, NACT did not obviate the need for radical surgical resection. Thus, advanced surgical skills remain essential.

ChatGPT compared to national guidelines for management of ovarian cancer: Did ChatGPT get it right? - A Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVES: We evaluated the performance of a chatbot compared to the National Comprehensive Cancer Network (NCCN) Guidelines for the management of ovarian cancer. METHODS: Using NCCN Guidelines, we generated 10 questions and answers regarding management of ovarian cancer at a single point in time. Questions were thematically divided into risk factors, surgical management, medical management, and surveillance. We asked ChatGPT (GPT-4) to provide responses without prompting (unprompted GPT) and with prompt engineering (prompted GPT). Responses were blinded and evaluated for accuracy and completeness by 5 gynecologic oncologists. A score of 0 was defined as inaccurate, 1 as accurate and incomplete, and 2 as accurate and complete. Evaluations were compared among NCCN, unprompted GPT, and prompted GPT answers. RESULTS: Overall, 48% of responses from NCCN, 64% from unprompted GPT, and 66% from prompted GPT were accurate and complete. The percentage of accurate but incomplete responses was higher for NCCN vs GPT-4. The percentage of accurate and complete scores for questions regarding risk factors, surgical management, and surveillance was higher for GPT-4 vs NCCN; however, for questions regarding medical management, the percentage was lower for GPT-4 vs NCCN. Overall, 14% of responses from unprompted GPT, 12% from prompted GPT, and 10% from NCCN were inaccurate. CONCLUSIONS: GPT-4 provided accurate and complete responses at a single point in time to a limited set of questions regarding ovarian cancer, with best performance in areas of risk factors, surgical management, and surveillance. Occasional inaccuracies, however, should limit unsupervised use of chatbots at this time.

Secondary cytoreductive surgery and oncologic outcomes in the era of targeted maintenance therapy for recurrent, platinum-sensitive ovarian cancer.

OBJECTIVES: To compare oncologic outcomes of secondary cytoreductive surgery (SCS) before and after FDA approval of Poly(ADP-ribose) polymerase inhibitor (PARPi) and bevacizumab maintenance therapies for platinum-sensitive recurrent ovarian cancer (PS-ROC). METHODS: Patients who underwent SCS for first recurrence of PS-ROC from 1/1/2013-1/1/2020 were identified. Exclusion criteria included prior chemotherapy for recurrence, bowel obstruction procedures, and palliative surgery. Data were dichotomized pre/post 1/2017, relative to FDA approval of PARPi and bevacizumab maintenance for ROC. Second progression-free survival (PFS2), the primary endpoint, was estimated using Kaplan-Meier method. RESULTS: Overall, 245 patients underwent SCS-131 (53%) pre- and 114 (47%) post-approval. Most patients had high-grade serous tumors (83% and 90%, respectively; p = 0.13). Deleterious BRCA1/2 alterations were identified in 27% (32/120) and 28% (32/113) of tested patients, respectively (p = 0.88). Disease-free intervals pre- and post-approval were: 6-12 months, 16% and 18%; 12-30 months, 56% and 59%; and >30 months, 28% and 24%, respectively (p = 0.73). Overall, 85% and 86% of patients, respectively, achieved complete gross resection (CGR; p > 0.99). PARPi maintenance use increased from 3.8% to 27% (p < 0.001) following approval, and bevacizumab from 1.5% to 12% (p < 0.001). Median PFS2 was 19 and 20.1 months, respectively. In the post group, 1-year PFS2 rate was 84.5% (95% CI, 75.7-90.4%) for patients with CGR vs 56.2% (95% CI, 29.5-76.2%) for those with residual disease; 3-year PFS2 rates were 31.3% (95% CI, 21.6-41.4%) and 12.5% (95% CI, 2.1-32.8%), respectively (p = 0.001). CONCLUSIONS: CGR during SCS is associated with improved PFS2 compared to suboptimal resection. Prospective randomized trials are warranted to elucidate the role of SCS as more therapeutics become available.

Mesonephric and mesonephric-like adenocarcinomas of gynecologic origin: A single-center experience with molecular characterization, treatment, and oncologic outcomes.

OBJECTIVES: Mesonephric (MA) and mesonephric-like (MLA) adenocarcinomas are rare cancers, and data on clinical behavior and response to therapy are limited. We sought to report molecular features, treatment, and outcomes of MA/MLA from a single institution. METHODS: Patients with MA (cervix) or MLA (uterus, ovary, other) treated at Memorial Sloan Kettering Cancer Center (MSK) from 1/2008-12/2021 underwent pathologic re-review. For patients with initial treatment at MSK, progression-free survival (PFS1) was calculated as time from initial surgery to progression or death; second PFS (PFS2) was calculated as time from start of treatment for recurrence to subsequent progression or death. Overall survival (OS) was calculated for all patients. Images were retrospectively reviewed to determine treatment response. Somatic genetic alterations were assessed by clinical tumor-normal sequencing (MSK-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]). RESULTS: Of 81 patients with confirmed gynecologic MA/MLA, 36 received initial treatment at MSK. Sites of origin included cervix (n = 9, 11%), uterus (n = 42, 52%), ovary (n = 28, 35%), and other (n = 2, 2%). Of the 36 patients who received initial treatment at MSK, 20 (56%) recurred; median PFS1 was 33 months (95% CI: 17-not evaluable), median PFS2 was 8.3 months (95% CI: 6.9-14), and median OS was 87 months (95% CI: 58.2-not evaluable). Twenty-six of the 36 patients underwent MSK-IMPACT testing, and 25 (96%) harbored MAPK pathway alterations. CONCLUSION: Most patients diagnosed with early-stage disease ultimately recurred. Somatic MAPK signaling pathway mutations appear to be highly prevalent in MA/MLA, and therapeutics that target this pathway are worthy of further study.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.

Regionalizing ovarian cancer cytoreduction to high-volume centers and the impact on patient travel in New York State.

OBJECTIVE: To evaluate the theoretical impact of regionalizing cytoreductive surgery for ovarian cancer (OC) to high-volume facilities on patient travel. METHODS: We retrospectively identified patients with OC who underwent cytoreduction between 1/1/2004-12/31/2018 from the New York State Cancer Registry and Statewide Planning and Research Cooperative System. Hospitals were stratified by low-volume (<21 cytoreductive surgical procedures for OC annually) and high-volume centers (≥21 procedures annually). A simulation was performed; outcomes of interest were driving distance and time between the centroid of the patient's residence zip code and the treating facility zip code. RESULTS: Overall, 60,493 patients met inclusion criteria. Between 2004 and 2018, 210 facilities were performing cytoreductive surgery for OC in New York; 159 facilities (75.7%) met low-volume and 51 (24.3%) met high-volume criteria. Overall, 10,514 patients (17.4%) were treated at low-volume and 49,979 (82.6%) at high-volume facilities. In 2004, 78.2% of patients were treated at high-volume facilities, which increased to 84.6% in 2018 (P < .0001). Median travel distance and time for patients treated at high-volume centers was 12.2 miles (IQR, 5.6-25.5) and 23.0 min (IQR, 15.2-37.0), and 8.2 miles (IQR, 3.7-15.9) and 16.8 min (IQR, 12.4-26.0) for patients treated at low-volume centers. If cytoreductive surgery was centralized to high-volume centers, median distance and time traveled for patients originally treated at low-volume centers would be 11.2 miles (IQR, 3.8-32.3; P < .001) and 20.2 min (IQR, 13.6-43.0; P < .001). CONCLUSIONS: Centralizing cytoreductive surgery for OC to high-volume centers in New York would increase patient travel burden by negligible amounts of distance and time for most patients.

Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival.

OBJECTIVE: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC. METHODS: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset. RESULTS: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01). CONCLUSIONS: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.

Mainstreaming in parallel with ovarian cancer tumor testing to improve genetic testing uptake.

OBJECTIVES: Although genetic testing (GT) is universally recommended for patients with epithelial ovarian cancer (EOC), rates are low (34%). In 1/2019, we implemented mainstreaming-GT in parallel with tumor testing via MSK-IMPACT within oncology clinics. We sought to determine GT rates pre/post-mainstreaming and patient characteristics associated with GT. METHODS: Patients with newly diagnosed EOC seen at our institution from 7/1/2015-3/31/2022 were included. Clinical data were abstracted including social determinants of health (SDOH) variables, race/ethnicity, marital status, insurance, language, comorbidities, employment, and Yost index, a measure of socioeconomic status. GT rates were calculated overall and pre-/post-mainstreaming (1/2019). Logistic regression models were fit to identify variables associated with GT. RESULTS: Of 1742 patients with EOC, 1591 (91%) underwent GT. Rates of GT increased from 87% to 95% after mainstreaming (p < 0.001). Among 151 patients not undergoing GT, major reasons were lack of provider recommendation (n = 76, 50%) and logistical issues (n = 38, 25%) with few declining (n = 14, 9%) or having medical complications preventing GT (n = 7, 4.6%). High-grade serous histology, advanced stage (III/IV), and having a spouse/partner were associated with increased GT uptake (p < 0.01). Among SDOH variables, there were no differences by insurance, Yost score, language, comorbidities, employment, or race/ethnicity. In multivariable models, likelihood of GT increased with mainstreaming, even after adjustment for histology, stage, and marital status (OR 3.77; 95% CI: 2.56-5.66). CONCLUSIONS: Mainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non-high-grade serous histology, and early-stage disease, representing potential areas for future interventions.