Citations

BACKGROUND: Elevated blood pressure (BP) is a major contributor to coronary artery disease. We explored the impact of life-course BP on later-life normalized stress myocardial blood flow (sMBF N ) and myocardial perfusion reserve by cardiovascular magnetic resonance (CMR). METHODS: MyoFit46 prospectively recruited ≈500 National Survey of Health and Development 1946 birth cohort participants, aged ≈77 years, to undergo stress perfusion and late gadolinium enhancement CMR. Systolic (SBPs) and diastolic BPs were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, the annual rates of BP change (steepness of BP increase) and area under the BP trajectory curve (cumulative life-course BP burden) were derived using mixed-effects models. The associations between BP measures and CMR metrics were tested using generalized linear and additive models, adjusted for antihypertensive use, demographics, lifestyle choices, and comorbidities. Cross-sectional associations between CMR metrics and major adverse cardiovascular events (myocardial infarction, stroke, and heart failure) were also tested. Mediation analyses explored the mechanistic pathways linking life-course BPs, myocardial perfusion, and myocardial fibrosis. RESULTS: Among 459 included MyoFit46 participants, each 10 mm Hg higher SBP at 36 to 69 years was associated with 3% to 6% lower sMBF N by CMR at 77 years. At 43 to 63 years, as SBPs rose from 120 to 140 mm Hg, sMBF N was 18% to 24% lower. Having a sustained higher SBP by 10 mm Hg from 36 to 77 years was associated with 11% (95% CI, 8–14) lower sMBF N at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, 53 to 63, and 63 to 69 years was associated with 2% to 6% lower sMBF N at 77 years, associations not conditional on baseline or final BPs in each age interval. Associations may be clinically relevant as each 1% lower sMBF N was associated with 3% higher odds of major adverse cardiovascular events. sMBF N mediated ≈20% to ≈40% of the associations between life-course SBPs and late gadolinium enhancement at 77 years. Results were similar for diastolic BP, myocardial perfusion reserve, or sMBF (not normalized). CONCLUSIONS: Higher life-course BPs, steeper increases, and greater cumulative BP burden associate with lower myocardial perfusion by CMR at 77 years, which can be linked with higher odds of major adverse cardiovascular events and greater myocardial fibrosis burden. This underscores the importance of early life BP screening and guiding hyperetension treatment based on longitudinal BP trajectories (rather than relying solely on cross-sectional BPs). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05455125.

Background: The PRO-CTCAE provides patient-reported data on symptomatic AEs. A summary metric—the ACS—reflecting total AE burden can be calculated by averaging AE-level composite scores at a given timepoint for each participant. This study investigated the psychometric properties and interpretability of this PRO-CTCAE ACS in patients with breast, lung, or head/neck cancers. Methods: We conducted a secondary analysis of a PRO-CTCAE validation dataset comprising 940 adults undergoing chemotherapy or radiation therapy (clinicaltrials.gov: NCT02158637). We focused on empirically recommended symptom terms for three cancer sites. Analyses included Spearman’s correlations, coefficient alpha, and eigenvalues from the correlation matrices, confirmatory factor analysis (CFA), and principal component analysis (PCA). Latent profile analysis (LPA) was used to assess ACS interpretability in the lung cohort. Results: Mean composite score inter-correlations were moderate (0.30–0.35), and coefficient alphas were high (0.81–0.91). Eigenvalue ratios and CFA supported retention of a single factor/component, with suitable model fit indices. ACS correlated highly with factor scores and the first principal component from the PCA. Reduced sets of terms produced reliable scores that closely approximated the full set scores and aligned with external criteria. LPA in the lung subgroup identified four latent classes; ACS differentiated high vs. low symptom burden groups but did not distinguish the two groups expressing distinct symptom profiles. Conclusion: The ACS demonstrated structural validity through adequately fitting linear factor models and effectively summarized symptomatic AE burden. However, similar ACS values may mask clinically distinct symptomatic AE profiles, underscoring the value of both summary metrics and profile-based approaches.

Abstract Disclosure: R. Castaneda: None. D. Bechenati: None. R.D. Rivera Gutierrez: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. P. Bennett: None. A. Acosta: Novo Nordisk, Gila Therapeutics, Amgen Inc, Regeneron Pharmaceuticals, Boehringer Ingelheim, Rhythm Pharmaceuticals, General Mills, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, MedAll, AiCME, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix. Introduction: Tirzepatide, a dual GIP and GLP-1 receptor agonist, is an FDA-approved medication demonstrating the highest efficacy for weight loss among currently available treatments. However, the influence of sex and age on weight loss outcomes with tirzepatide remains unclear. Objective: To investigate the influence of sex and age on weight loss outcomes in patients treated with tirzepatide. Methods: This retrospective study evaluated weight loss outcomes associated with tirzepatide across sex and age groups. Patients with active malignancy, prior bariatric surgery, or concurrent anti-obesity medication were excluded. The primary endpoint was total body weight loss percentage (TBWL%) at 15 months by sex and age. The influence of age was analyzed as a categorical (≤45, 46-59, ≥60 years) and continuous variable. Secondary outcomes included TBWL% at 3, 6, 9, and 12 months by sex and age. Data were analyzed using independent t-tests, one-way ANOVA, and multivariate regression; results are reported as mean ± standard deviation. Results: The study included 1033 patients (57.1% female; mean age 56 ± 11 years; mean BMI, 37.7 ± 8 kg/m2). By age category, 18.8% (196) were ≤45 years (35.7% males, 64.3% females), 45.9% (473) were 46-59 years (42.7% males, 57.3% females), and 35.3% (364) were ≥60 years (54.7% males, 45.3% females). At all timepoints, TBWL was significantly greater in females compared to males at all timepoints. At 15 months females had a higher TBWL than males: 15.3% ± 10, n=340, vs. 10.2% ± 8, n=244, (p < 0.001). Among females, premenopausal women achieved a higher TBWL than postmenopausal women: 16.9% ± 10 vs 14.4% ± 9, p = 0.04. Analysis by age groups revealed a trend toward higher TBWL in younger patients that did not reach statistical significance (p = 0.152): ≤45 years (14.7% ± 10%), 46-59 years (12.9% ± 10%), and ≥60 years (12.7% ± 9%). After adjusting for baseline age, BMI, and diabetes status, sex remained a strong predictor for weight loss outcomes (PE= 4.5, 95% CI [2.96, 5.97], p < 0.001), following type 2 diabetes status (PE= 4.8, 95% CI [3.0, 6.7], p < 0.001). Conclusion: Sex but not age was a strong predictor of weight loss with tirzepatide. Female sex was associated with greater weight loss than male sex. These results emphasize the importance of considering sex-specific factors in weight loss strategies and warrant further investigation into the underlying biological mechanisms. Differential weight loss by menopause, underscores the role of sex hormones. Presentation: Monday, July 14, 2025

Abstract Disclosure: R.D. Rivera Gutierrez: None. D. Bechenati: None. R. Castaneda: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. T.M. Taaffe: None. P.K. Bennett: None. A.J. Acosta: Novo Nordisk, Gila Therapeutics, Rhythm Pharmaceuticals, Amgen Inc, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, AiCME, MedAll, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix Sciences. Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular (CV) benefits. Tirzepatide (TZP), a dual GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist approved for weight management and glycemic control, currently lacks evidence on CV outcomes. This study evaluates TZP’s impact on cardiometabolic parameters and atherosclerotic cardiovascular disease (ASCVD) risk scores. Methods: We conducted a multicenter retrospective study of adults prescribed TZP from June 1, 2022, to November 1, 2024. Inclusion criteria included 12 months of TZP use and age >18 years. Exclusion criteria were pregnancy, active malignancy, concurrent FDA-approved antiobesity medications, and prior bariatric surgery. Endpoints included changes in blood pressure, lipid profiles, liver enzymes, glucose control parameters, medication use (statins, aspirin, antihypertensives), and ASCVD risk scores from baseline to 12 months, stratified by sex. Data were obtained from electronic medical records. We present data as mean differences [95% CI]. We used T-tests and multivariate regression analyses for analyses. Results: Among 831 participants (59.4% female; 91.2% White; mean age: 58 ± 12 years), 12-month weight loss was -12% [-13, -11], p<0.001. We observed significant improvement in systolic blood pressure (SBP) (-4 [-5, -3] mmHg, p<0.001), triglycerides (TG) (-38 [-52, -23] mg/dL, p<0.001), total cholesterol (TC) (-7 [-10, -4] mg/dL, p<0.001), LDL cholesterol (LDL) (-6 [-9, -4] mg/dL, p<0.001), fasting glucose (FG) (-39 [-48, -29] mg/dL, p<0.001), ALT (-10 [-15, -5] U/L, p<0.001), HbA1c (-1.3% [-1.5, -1.2], p<0.001), and HDL cholesterol (HDL) (+4 [+3, +5] mg/dL, p<0.001). The Lifetime and 10-year ASCVD scores did not significantly change after 12 months (p>0.05), underscoring TZP’s potential in mitigating the aging-associated increase in CV risk. Considering sex, females had greater weight loss (-13% [-14, -12] vs. -10% [-11, -9], p<0.001), and greater improvements in TC (-5% [-8, -2] vs -3% [-6, 0.1], p<0.001) and LDL (-10% [-14, -6] vs -4% [-8, 1], p<0.001). Males had a greater reduction in DBP (-2% [-4, -1] vs (-1% [-6, 3], p=0.006). Both males and females demonstrated similar improvements in FG and HbA1c. Conclusion: TZP significantly improved CV and metabolic parameters after 12 months, with greater benefits observed in females. These improvements effectively mitigated the age-related rise in ASCVD risk scores. Larger, prospective studies are warranted to confirm these findings and further investigate TZP’s long-term CV effects. Presentation: Monday, July 14, 2025

BACKGROUND AND OBJECTIVES: The Management of Myelomeningocele Study established a role for maternal-fetal surgery for myelomeningocele (MMC) but was limited to patients with a maternal body mass index (BMI) less than 35 kg/m 2 . However, as the rate of obesity has increased globally, some centers have extended the Management of Myelomeningocele Study criteria to include patients with a BMI of 35 to 40 kg/m 2 . We used the Fetal MMC Consortium registry to analyze the complications associated with maternal-fetal surgery in patients with a maternal BMI < 35 kg/m 2 compared with 35 to 40 kg/m 2 . METHODS: The prospective observational Fetal MMC Consortium registry sponsored by the North American Fetal Therapy Network was used to extract deidentified “maternal complication” and “fetal/neonatal complication” data sets, corresponding to patients with complete entries related to maternal or fetal/neonatal complications, respectively. Demographics, clinical characteristics, and complications were recorded. Propensity score matching was conducted with a 2:1 algorithm, and outcomes were compared between patients with BMI < 35 kg/m 2 and those with BMI 35 to 40 kg/m 2 . RESULTS: Propensity score matching resulted in 156 patients with BMI < 35 kg/m 2 and 78 patients with BMI 35 to 40 kg/m 2 in the “maternal complication” data set, and 130 patients with BMI < 35 kg/m 2 and 65 patients with BMI 35 to 40 kg/m 2 in the “fetal/neonatal complication” data set. No significant differences in the median number of maternal (2.0 vs 2.0; P = .257) or median number of fetal/neonatal (1.0 vs 1.0; P = .409) complications were observed between the 2 cohorts. Furthermore, prematurity rates did not differ significantly between the BMI < 35 and BMI 35 to 40 cohorts. CONCLUSION: Maternal-fetal surgery for open neural tube defect closure is not associated with increased risks among patients with a maternal BMI of 35 to 40 kg/m 2 . Extending the initial inclusion criteria for prenatal MMC closure has the potential to expand access to patients with a higher risk for open neural tube defects.

Objectives: Current standard of care after a First-Time patellar instability event is non-operative management, with exceptions for patients with osteochondral fracture or loose body requiring immediate surgical intervention, patients with significant pathoanatomy, or contralateral patellar instability. For recurrent patellar instability, there is controversy as to when isolated medial patellofemoral ligament reconstruction (MPFL-R) is enough. The purpose of this study is to determine (1) the comparative outcomes of isolated MPFL-R after first-time patellar instability (FTPI) and recurrent patellar instability (RPI) and (2) the impact of osteochondral injury on outcomes after surgical treatment of FTPI. Methods: A prospective, multicenter cohort study (JUPITER: Justifying Patellar Instability Treatment by Results) database was queried for patients who underwent patellar stabilization surgery (PSS) between December 2016 and September 2022. Patients were included if they underwent a medial patellofemoral ligament reconstruction (MPFL-R) for FTPI or RPI. Those with less than 2 years of clinical follow-up, revision PSS, or concomitant bony procedures at the time of MPFL-R were excluded. Independent t-tests were performed to compare means for continuous variables, and chi-squared tests were performed to compare frequency for categorical variables, between groups. Results: A total of 739 patients met inclusion criteria with a mean age of 15.6 ± 3.3 years, and 59.9% female sex. FTPI occurred in 216 (27.2%) patients, and of these 104 (48.1%) sustained an operative chondral or osteochondral lesion. Those with FTPI had a significantly greater trochlear depth (2.9 mm vs. 2.6 mm; P = .048), but a significantly lower rate of pathological trochlear bump > 5 mm (52.3% vs. 67.8%; P = .008) than those with RPI (Table 1). Among the FTPI cohort, those with treatment of a chondral lesion were less likely to have patella alta (Caton-Deschamps Index > 1.3) (14.9% vs. 41.3%, P = .006), and less frequently had a mild or severe J-sign (25.0% vs. 42.7%, p = .016) than those without a chondral intervention (Table 2). Postoperatively, there were no differences with rates of recurrent instability (8.3% vs. 12.3%; P = .130) or return to sport (90.4% vs. 94.5%; P = .182) between FTPI and RPI, respectively (Table 3). There were no differences with rates of recurrent instability (7.6% vs. 9.1%; P = .807) or return to sport (89.1% vs. 91.7%; P = .755) between those with or without a chondral intervention, respectively (Table 4). Conclusions: This study demonstrates no difference in rates of recurrent post-operative instability between FTPI and RPI with rates consistent with the current literature. MPFL reconstruction remains as a durable surgical treatment option for patients presenting with either FTPI or RPI with relatively low rates of recurrent instability. In this patient population, patella alta was found to be protective of osteochondral injury which is also consistent with existing literature. Continued, long-term investigation is needed to understand outcomes for First-Time patellar instability and to better define the indications for surgical interventions in this population.

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. Here, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared to normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune reactive tumor microenvironment. Mutations in several SWI/SNF subunits were associated with higher rates of outlier retained introns across tumor types in TCGA data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention. Distinct protein-protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Further, SWI/SNF localized to genes which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFa and INFb in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to intron retention. Furthermore, T cell activation by novel peptides encoded by these tumor-specific splicing events suggests intron retention could be a source of tumor-associated antigens in SCCOHT. Citation Format: Elizabeth Raupach, Apurva Hegde, Krystine Garcia-Masnfield, Marice Alcantara, David Rose, Rebecca Halperin, Krystal Orlando, Jessica Lang, Ritin Sharma, Victoria David-Dirgo, Salvatore Facista, Rayvon Moore, Rochelle Kofman, Zoe Jensen, Victoria Zismann, Anthony Karnezis, Yemin Wang, Lynda Bennett, Timothy Whitsett, Marcin Kortylewski, William Hendricks, David Huntsman, Lorna Rodriguez-Rodriguez, Bernard Weissman, Jeffrey Trent, Patrick Pirrotte. Loss of SMARCA4 leads to intron retention and generation of tumor-associated antigens in small cell carcinoma of the ovary, hypercalcemic type [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B065.

Background: Particulated juvenile articular cartilage (PJAC) implantation has demonstrated promising early results in the treatment of symptomatic articular cartilage defects of the patella. However, some uncertainty exists regarding the stability of this cell-based technique in lesions that are not well contained or shouldered. Purpose: To compare clinical and magnetic resonance imaging (MRI) outcomes of PJAC treatment in shouldered versus unshouldered full-thickness cartilage defects of the patella. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of prospectively collected data from an institutional knee registry was conducted to identify patients treated with PJAC for full-thickness symptomatic patellar cartilage lesion between January 2009 and August 2017. Cartilage defects were graded arthroscopically according to the Outerbridge classification and characterized as shouldered or unshouldered. For the primary outcome, postoperative MRI studies were read by a musculoskeletal fellowship-trained radiologist who characterized the percentage of fill based on both coronal and sagittal images. Patient-reported outcome measures (PROMs) were obtained at baseline and 2-year follow-up. MRI and PROM results were compared between the shouldered and unshouldered cohorts. Results: A total of 64 knees in 60 patients (mean age, 26.3 ± 7.6 years) were identified, of which 62 (97%) knees underwent a concomitant patellar stabilization or offloading procedure. There were 32 (50%) shouldered and 32 (50%) unshouldered defects. On postoperative MRI, 68.8% of shouldered lesions demonstrated 67% to 100% fill, compared with 59.4% of unshouldered lesions; 12.5% of shouldered lesions and 15.6% of unshouldered lesions demonstrated 34% to 66% fill; and 18.8% of shouldered lesions and 25.0% of unshouldered lesions demonstrated 0% to 33% fill ( P = .604). At 2 years, significant improvements were observed in Knee Injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) (23.1 to 65.3; P < .001), International Knee Documentation Committee (IKDC) (41.2 to 76.0; P < .001), KOOS Physical Function Shortform (PS) (34.8 to 13.9; P < .001), Kujala (52.0 to 87.5; P < .001), 12-Item Short Form Survey (SF-12) Physical Health (39.5 to 51.5; P < .001), Veterans Rand 12 Item Health Survey (VR-12) Physical Health (40.7 to 52.8; P < .001), Veterans Rand 6D (0.66 to 0.79; P < .001), SF-12 Mental Health (48.9 to 53.4; P = .015), and VR-12 Mental Health (49.4 to 54.0; P = .019) values. No significant change was observed in Pediatric Functional Activity Brief Scale score (9.1 to 10.3; P = .384). All PROMs were equivalent between shouldered and unshouldered defects at the 2-year follow-up ( P = .318-.980). There was a greater improvement in both KOOS PS (27.2 vs 10.7; P = .015) and Kujala (44.3 vs 26.9; P = .039) values from baseline to the 2-year follow-up in the shouldered group. Conclusion: PJAC implantation with concomitant patellar stabilization led to significantly improved PROMs for both shouldered and unshouldered patellar cartilage lesions over time. Additionally, minimal differences were observed between shouldered and unshouldered defects treated with PJAC at the 2-year follow-up.

Spousal caregivers of persons living with serious illnesses experience significant emotional and social challenges related to their caregiving role. The purpose of this study was to gain a deeper understanding of how spousal caregivers perceive current and anticipated losses associated with caring for a partner living with advanced cancer. Spousal caregiver participants engaged in semistructured interviews about their caregiving experiences and subsequent changes that occurred in their lives. Caregivers experienced social changes, emotional energy investment, and relationship changes as sources of grief. Social changes involved a loss of freedom and increased isolation, while emotional energy investment manifested as suppressed emotions and fears about the future. Relationship changes encompassed both positive and negative shifts in communication and roles. Targeted interventions, such as support groups and counseling, are essential to mitigate the negative impacts of caregiving and improve the well-being of older adult spousal caregivers.