Citations

Advanced-stage high grade serous ovarian cancer (HGSC) initially responds to platinum-based chemotherapy; however, most HGSC tumors recur and develop chemotherapy-resistance, making recurrent ovarian cancer (OC) a fatal disease. Ovarian cancer stem cells (OCSCs), a subpopulation of cells capable of surviving treatment and repopulating tumors, contribute to disease relapse, and understanding the mechanisms(s) responsible for OCSC survival is critical for developing strategies to overcome acquired resistance and prevent tumor recurrence. However, whether platinum-induced OCSC enrichment results from the selection of pre-existing OCSCs or chemotherapy-induced cellular plasticity, and the molecular mechanisms underlying these processes, remain poorly understood. Here, we demonstrated that cisplatin treatment not only enriched for OCSCs but promoted the conversion of ALDH- cells to ALDH+ cells, revealing chemotherapy-induced plasticity as a potential mechanism for OCSC expansion. This conversion was associated with nuclear receptor signaling pathways, vitamin D receptor signaling (VDR/RXR) and retinoic acid receptor signaling (RAR/RXR). Importantly, activation of VDR/RXR signaling with vitamin D reduced stemness phenotypes and the cisplatin induced conversion to ALDH+ cells. In addition, vitamin D combined with cisplatin decreased tumor volume in vivo compared to either treatment alone. In contrast, cisplatin treatment increased RAR/RXR signaling, supporting an associative role for ligand-dependent nuclear receptor signaling in OCSC plasticity. Together, these findings reveal that platinum chemotherapy can actively promote the acquisition of stem-like properties and identifies VDR/RXR signaling as a potential regulatory mechanism of OCSC plasticity. Targeting this pathway with vitamin D may provide a therapeutic strategy to target OCSCs and improve responses to platinum-based chemotherapy.

Abstract Patients with rare genetic disorders often wait years for a correct diagnosis, highlighting the urgent need for early and efficient triage for those at risk. Electronic health records (EHRs) are rich in useful information, yet the extent to which this data is sufficient to generate prediagnostic signals is uncertain. We trained machine learning models on billing codes and phenotypes extracted from clinical notes and applied these across eight conditions in a longitudinal cohort of roughly 3 million patient records from the Mayo Clinic, seeking early identification of conditions. The number of patients identified early varied by condition, ranging from 10% to 89% at 99% specificity. Median lead times exceeded one year prior to the first diagnostic billing code for most conditions, including Fabry disease (1,408 days), hereditary angioedema (2,755 days), neurofibromatosis type 1 (1,067 days), and hereditary hemorrhagic telangiectasia (2,320 days). We show that ML models trained on EHR data can prioritize patients for clinician review and confirmatory genetic testing and that the integration of diverse phenotypic data sources provides superior predictive value.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

Introduction: Limited research explores dermoscopy use among physician associates (PAs), outside of one prior study examining dermoscopy in PA student education. This study sought to investigate dermoscopy use among practicing PAs and its impact on their overall diagnostic confidence, including in darker skin tones, when differentiating between benign and malignant skin lesions. Methods: An anonymous survey was developed in 2023 with input from experts in dermoscopy and survey creation to assess PA confidence in skin lesion evaluation as well as PA dermoscopy knowledge and use, perceptions, barriers to use, and prior education. The dermoscopy survey was included as an optional module in the 2024 American Academy of Physician Associates (AAPA) Salary Survey. Results: Of 3,174 invited PAs, 995 (31.4%) responded. Most had never used dermoscopy in practice (81%) but knew or recognized the term (71%). A majority (53%) believed PAs should be trained in dermoscopy during PA school, and 26% reported no interest in future dermoscopy use. Dermatology PAs reported more frequent dermoscopy use and generally greater confidence in evaluating skin lesions, both overall and in darker skin tones, than PAs in other specialties. PAs in surgical (OR=0.2, 95% CI 0.1-0.6) and medical (OR=0.3, 95% CI 0.2-0.5) subspecialties were less likely to use dermoscopy at least annually compared with PAs in primary care. PAs in rural areas were more likely to feel confident in differentiating skin lesions than those in urban areas (OR 2.9, 95% CI 1.7-5.0). Conclusion: Dermoscopy use is associated with higher overall skin lesion assessment confidence. Wider adoption, especially outside dermatology, requires training, increased advocacy, and expanded education.

Abstract Rural and low-socioeconomic status women face social determinants of health barriers leading to disproportionately low rates of breast cancer screening and markedly reduced participation in clinical trials. To address this gap, we developed the WeCARE (Women’s Engagement for Cancer Awareness, Resources, and Education) intervention using a community-engaged approach. This paper describes how Community Advisory Board feedback informed the development of Mayo Clinic Health System’s WeCARE intervention components. Their input was systematically analyzed using the Consolidated Framework for Implementation Research (CFIR 2.0) to identify determinants of acceptability, appropriateness, and feasibility and to guide actionable refinements to intervention content and delivery.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891

e14545 Background: Durable antitumor immunity depends on the maintenance of stem-like CD8⁺ T cells capable of sustaining long-term effector responses. Oncolytic viruses (OVs) are potent immunomodulatory agents that reshape the tumor microenvironment and augment antitumor immunity. We hypothesized that platinum-based chemotherapy alters tumor-intrinsic type I interferon (IFN-I) signaling in a manner that can be functionally restored by OV therapy, thereby promoting the generation and persistence of stem-like CD8⁺ T cells. Methods: Tumor cells treated with platinum chemotherapy were evaluated in vitro for changes in IFN-I pathway activity, OV replication, and markers of immunogenic cell death (ICD). Syngeneic mouse tumor models were used to assess antitumor efficacy and immune remodeling following combination therapy. Tumor-infiltrating lymphocytes were analyzed by single-cell RNA sequencing and multiparameter flow cytometry to define CD8⁺ T-cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Platinum chemotherapy significantly suppressed tumor-intrinsic IFN-I signaling, while OV therapy restored antiviral responses, enhanced viral replication, and increased ICD in vitro. In vivo, the combination strategy resulted in superior tumor control and profound remodeling of the tumor immune microenvironment. The most pronounced immunologic effect was observed within the stem-like CD8⁺ T-cell compartment. Combination therapy induced a distinct population of TCF7⁺ ISG15^high NFATC1^low AP-1^low CD8⁺ T cells, characterized by restrained activation, enhanced persistence, and reduced propensity toward terminal exhaustion. In IRF7-deficient tumors, this stem-like CD8⁺ T-cell population failed to emerge and antitumor efficacy was significantly diminished, indicating that moderate tumor-intrinsic IFN-I signaling is required for this immune state. Conclusions: Tumor-intrinsic type I interferon signaling is a critical determinant of synergy between platinum chemotherapy and oncolytic virotherapy, enabling the maintenance of durable stem-like CD8⁺ T-cell immunity. These findings establish a mechanistic rationale for combining platinum chemotherapy, oncolytic viruses, and immune checkpoint blockade and support ongoing clinical translation. Clinical trial information: ChiCTR2500107607.

4235 Background: Malignant portal vein tumor thrombus (PVTT) arising from hepatic metastases is associated with poor prognosis, rapid hepatic decompensation, and limited effective local treatment options despite systemic therapy. In real-world practice, local treatment intensity is frequently adapted to disease burden and treatment response. We evaluated outcomes of a risk-adapted, step-up local treatment strategy using microwave ablation (MWA) alone or in combination with iodine-125 (I-125) seed implantation for patients with malignant PVTT. Methods: We retrospectively reviewed patients with hepatic metastases treated with MWA with or without I-125 seed implantation between 2023 and July 2025. In clinical practice, MWA alone was preferentially used for patients with relatively limited disease burden, while MWA plus I-125 was employed as an escalation strategy for patients with more advanced PVTT or disease progression following MWA alone. The primary endpoint was PVTT-directed local outcome, defined as portal vein patency and/or local control of tumor thrombus on follow-up imaging. Secondary endpoints included progression-free survival (PFS), overall survival (OS), hepatic function changes, and treatment-related toxicity. Survival analyses were considered exploratory. Results: A total of 73 patients were included, of whom 50 were treated with MWA alone and 23 with MWA plus I-125 seed implantation. Patients receiving MWA plus I-125 demonstrated more advanced disease characteristics, including universal presence of PVTT and higher disease stage, consistent with treatment escalation by disease severity. Among patients with PVTT, MWA plus I-125 achieved portal vein patency and/or local control in 65% at first follow-up imaging. Treatment-related toxicities were manageable, with no unexpected grade ≥3 adverse events attributable to I-125 implantation. Median PFS was 11.5 months in patients treated with MWA alone and 9.9 months in patients treated with MWA plus I-125, consistent with greater baseline disease burden in the latter group. Conclusions: MWA alone and MWA plus I-125 function as complementary components of a risk-adapted, step-up local treatment strategy for malignant PVTT from hepatic metastases. Escalation to MWA plus I-125 appears feasible in patients with advanced or refractory PVTT and demonstrates a potential signal for improved PVTT-directed local control and portal vein patency. Prospective studies focused on PVTT-specific endpoints are warranted.