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TPS1125 Background: Despite the many available treatments for patients (pts) with HR+, HER2– recurrent/metastatic breast cancer (MBC), optimal treatment after progression on CDK4/6 inhibitors (CDK4/6i) is unclear. One possible CDK4/6i resistance mechanism is increased expression of Aurora kinase A (AURKA), a key mitosis regulator associated with poor prognosis. Further implicated in CDK 4/6i resistance, high c-Myc or RB1 loss of function (LOF) are associated with transcriptional co-regulation or synthetic lethality, respectively, with AURKA. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor with antiproliferative activity in HR+ BC-derived cell lines and BC xenograft models. Models with elevated AURKA or c-Myc expression, or RB1 LOF show greater alisertib sensitivity. Alisertib had activity in phase 1 and 2 trials, including objective response rates (ORRs) of 19.6–20% and median progression-free survival (PFS) of 5.4–5.6 months alone or with fulvestrant in pts with HR+/HER2–, endocrine-resistant MBC. The most common treatment-related grade ≥3 adverse events (AEs) were neutropenia, anemia, and leukopenia. Methods: ALISCA-Breast1 (NCT06369285) is a randomized phase 2 study. Primary objective: to determine the optimal alisertib dose administered with endocrine therapy (ET) based on AEs and serious AEs per CTCAE v5.0 and efficacy (ORR, duration of response, disease-control rate, PFS, overall survival). Secondary objectives: to identify biomarkers of efficacy and alisertib pharmacokinetics (PK). Key inclusion criteria: ≥18 years; ECOG performance status 0 or 1; confirmed HR+, HER2–, recurrent/metastatic breast adenocarcinoma not amenable to curative therapy; available tumor tissue for biomarker analyses; progression on or after ≥2 prior ET lines in recurrent/metastatic setting; prior CDK4/6i with ET in recurrent/metastatic setting. Key exclusion criteria: prior chemotherapy in recurrent/metastatic setting; prior AURKA-specific or pan-Aurora-targeted agents; unstable brain metastases. Eligible pts will be randomized 1:1:1 to alisertib 30 mg, 40 mg, or 50 mg orally twice daily on days 1−3, 8–10, and 15–17 every 28 days, plus physician’s choice of anastrozole, letrozole, exemestane, fulvestrant, or tamoxifen not previously used in recurrent/metastatic setting or progressed upon in adjuvant setting; ≤50 pts will be enrolled per arm in the USA and Europe. All pts will undergo sparse PK sampling. Tumor tissue will be centrally assessed for biomarkers, including RB1, MYC, TP53, ESR1, PI3K/AKT pathway, HER2 and AURKA genomic alterations/expression levels. The study will determine the optimal alisertib dose to combine with ET and may identify biomarker(s) defining pts with the greatest benefit from alisertib-based therapy. Clinical trial information: NCT06369285 .

AbstractObstructive sleep apnea (OSA) is a widespread condition associated with an elevated risk of adverse outcomes. Continuous positive airway pressure (CPAP) is the gold standard treatment, particularly for moderate to severe OSA. However, in many instances, CPAP compliance falls short of expectations, necessitating physicians to consider additional interventions to alleviate patient symptoms. A comprehensive understanding of OSA endotypes and phenotypes can potentially enhance the confidence in selecting the appropriate combination or intervention to improve patient care. In this review, we will discuss various interventions and medications available to enhance the treatment of patients with OSA, following a precision medicine approach.

Abstract This study aimed to investigate the association between objective and subjective olfactory assessments in patients with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection undergoing endoscopic endonasal skull base surgery (EESBS). Retrospective cohort study. Academic medical center. Adult patients with and without recent SARS-CoV-2 infection who underwent EESBS for sellar and parasellar lesion resection between 2020 and 2024 at the Mayo Clinic in Florida, Jacksonville, FL. Pre- and postoperative self-reported olfactory dysfunction and University of Pennsylvania Smell Identification Test (UPSIT) scores were collected. Patients with recent SARS-CoV-2 infection had a similar rate of discrepant preoperative objective olfactory assessments (38.2%, 26/68) compared with SARS-CoV-2-negative patients (39.9%, 127/318). SARS-CoV-2-positive patients were twice as likely to report postoperative subjective olfactory dysfunction (46.2%, 12/26) compared with SARS-CoV-2-negative patients (18.1%, 23/127, p = 0.002). There was no statistically significant difference in the mean preoperative (p = 0.162) or postoperative (p = 0.724) UPSIT scores between both groups. Patients with recent SARS-CoV-2 infection and discrepant preoperative objective olfactory assessments were twice as likely to self-report olfactory dysfunction following EESBS compared with SARS-CoV-2-negative controls. This increase in self-reported olfactory dysfunction was not accompanied by changes in objective psychophysical testing. These findings suggest that SARS-CoV-2 infection may impact subjective olfactory recovery following EESBS.

AbstractNocturnal hypoxemia is a prevalent feature of various respiratory diseases, significantly impacting patient outcomes and therapeutic strategies. Oximetry, a noninvasive and widely accessible tool, enables the measurement of nocturnal hypoxemia through oxyhemoglobin saturation (SpO2)-derived metrics such as the oxygen desaturation index, percentage of sleep time with SpO2 below 90%, mean SpO2, and measures of the area under the desaturation curve (e.g., sleep apnea-specific hypoxic burden). While these metrics are well established in obstructive sleep apnea (OSA), their application in other respiratory conditions, including chronic obstructive pulmonary disease, pulmonary hypertension, obesity hypoventilation syndrome, heart failure, neuromuscular disorders, pregnancy, and high-altitude residents, remains an area of active investigation. This review explores the pathophysiology of hypoxemia in these conditions and evaluates the role of SpO2-derived metrics in risk stratification beyond OSA. We also discuss the challenges of interpreting SpO2 data, particularly the difficulty differentiating disease-related hypoxemia from comorbid OSA. Additionally, we examine the limitations of oximetry, including sensor inaccuracies, motion artifacts, and skin pigmentation. Finally, we emphasize the need for further research to standardize these metrics across diverse conditions and advocate for their integration into clinical practice to enhance patient management and outcomes.

Abstract The objective of this study was to estimate the average hospitalization cost (AHC) for deliveries affected by severe maternal morbidity (SMM) and analyze trends from 2014 to 2019. The study also aimed to explore cost stratification based on patient, delivery, and hospital characteristics. Using the National Inpatient Sample dataset, all delivery hospitalizations from 2014 to 2019 were identified. Deliveries affected by SMM were determined based on the Centers for Disease Control definition. Deliveries were categorized into three groups: no SMM (nSMM), any SMM (aSMM), and SMM excluding cases with blood transfusion as the only indicator (SMMeBTo). A regression model accounting for survey design and adjusting for variables including age, race/ethnicity, primary payer, income, delivery method, hospital location/teaching status, and hospital region was used to test the trends in incidence. Hospital charges were adjusted using cost-to-charge ratios and presented in 2022 U.S. dollars ($). A regression model adjusting for the same variables was used to assess costs. From 2014 to 2019, 4,444,957 deliveries were identified, with a weighted estimate of 22,224,775. The rates of aSMM and SMMeBTo were 1.9 and 0.7%, respectively. AHC was $5,218 (95% confidence intervals [CI]: $5,200–5,235) for nSMM, $11,101 (95% CI: $11,038–11,165) for aSMM, and $11,541 (95% CI: $114,330–11,650) for SMMeBTo. Hospitalization costs across all SMM categories rose annually from 2014 to 2017, decreased in 2018, and peaked in 2019. All races had significantly higher costs than non-Hispanic Whites across all SMM categories. SMM costs were higher for cesarean deliveries. The highest cost was in deliveries involving a temporary tracheostomy. Urban teaching hospitals and those in the Northeast had the highest SMM costs. Deliveries affected by SMM incur significantly higher costs, with these costs increasing over time. Understanding disparities across patient factors, delivery methods, and hospital characteristics can inform interventions aimed at addressing inequities.

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD) whose genetic basis remains elusive, likely due to oligogenic complexity. To identify regulators of cardiomyocyte (CM) proliferation relevant to HLHS, we performed a genome-wide siRNA screen in human iPSC-derived CMs, revealing ribosomal protein (RP) genes as the most prominent effectors of CM proliferation. Whole-genome sequencing of 25 HLHS proband–parent trios similarly showed enrichment of rare RP gene variants, including a damaging RPS15A promoter variant shared in a familial CHD case. Cross-species functional analyses demonstrated that perturbation of RP genes impairs cardiac growth: knockdown of RPS15A, RPS17, RPL26L1, RPL39, or RPS15 reduced CM proliferation, caused cardiac malformations in Drosophila , and produced hypoplastic or dysfunctional hearts in zebrafish. Genetic interactions between RP genes and key cardiac transcription factors (TBX5 and NKX2–7) further support their developmental role. Importantly, p53 suppression or Hippo activation partially rescued RP deficiency phenotypes. Together, these findings implicate RP genes as critical regulators of cardiogenesis and candidate contributors to HLHS.

Abstract Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC- CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS and other CHDs.

Abstract Abdominally based free flaps are commonly utilized in the context of breast reconstruction. Historically, postoperative care of these patients involved liberal amounts of intravenous fluid administration; however, overadministration of fluids puts patients at risk of developing flap edema via fluid shifts, electrolyte imbalances, wound dehiscence, and other sequelae. The purpose of this study is to assess fluid administration trends in this cohort at the authors' institution and assess its impact on patient outcomes. A retrospective review was performed on patients who underwent free-flap breast reconstruction. Patient demographics and hospitalization data were collected, and type of abdominal flap and reconstruction timing was noted. Perioperative fluid administration volumes were tracked, and primary outcomes included complication rate and type (e.g., acute blood loss anemia [ABLA], partial/total flap loss, etc.). Multivariable logistic regression was performed to assess the impact of fluid volume on patient outcomes. A total of 115 patients (mean age of 51.3 ± 10.5 years) underwent 188 abdominally based free flaps. Deep inferior epigastric artery perforator flaps were performed most often (n = 91), followed by muscle-sparing transverse rectus abdominis flaps (n = 88). Multivariable logistic regression demonstrated that high perioperative fluid administration (≥9,000 mL) was associated with increased odds of medical complications (odds ratio [OR] = 21.7; confidence interval [CI]: 5.54–84.5; p < 0.001). Patients with high fluid administration volumes experienced an increased (but nonstatistically significant) flap complication rate (OR = 2.96; CI: 0.89–9.88; p = 0.08) and developed ABLA at a higher rate (OR = 15.86; CI: 5.30–46.4; p < 0.001). High-volume resuscitation (≥9,000 mL) was associated with increased odds of ABLA as well as a greater likelihood of medical and flap complications in patients undergoing abdominally based free flaps for breast reconstruction. These data should be used to guide the development of protocols within institutions, which perform free flaps for breast reconstruction.

Abstract The purpose of this study was to assess the long-term clinical and radiographic outcomes after distal ulna resection (Darrach procedure) in young adults. A retrospective chart review identified all adult patients who underwent Darrach resection at 40 years of age or younger and had a minimum of 5-year follow-up. Twenty-one patients (24 wrists) were available for final follow-up. Fifteen patients (16 wrists) returned for in-person evaluation, and seven patients (eight wrists) completed questionnaires by phone. Mean PRWE and QuickDASH scores were 32 and 34, respectively. The median visual analog scale at rest was 0 and 1 with activity. In 88% of cases, patients reported they would have the same surgery again. Of those who were employed preoperatively, 81% (13/16) returned to work, with all but one patient returning to their preoperative job. Radioulnar convergence occurred in all patients, but only three (23%) were symptomatic. The Darrach procedure may be a viable surgical option for DRUJ pathology in younger adults when other options are unavailable. Therapeutic IV.