Citations

Endocrine therapy remains the cornerstone of treatment for estrogen receptor alpha (ERα)-positive breast cancer, yet the relationship between individual genetic background and molecular response to ERα-targeted therapy remains incompletely understood. Using a well-characterized panel of lymphoblastoid cell lines (LCLs), we performed genome-wide pharmacogenomic expression quantitative trait locus (PGx-eQTL) analysis to identify estradiol (E2)- and tamoxifen (TAM)-induced SNP-gene pairs. PGx-eQTL signals were integrated with previously published breast cancer genome-wide association study datasets to examine their association with clinically relevant breast cancer phenotypes. We identified two ER-mediated PGx-eQTL SNP-gene pairs associated with breast cancer prognosis post-treatment with E2 or TAM. Notable loci included E2-regulated MRPL15 and TAM-regulated SYCP3, which have effects in a genotype-dependent manner, with genotype-dependent survival outcomes, from worse to better relapse-free survival. Similar endocrine-therapy effects on patient survival and breast cancer risk were observed in SIK2, post TAM-treatment, and in LSM4 with E2-treatment. Moreover, qRT-PCR validation in an independent LCL panel confirmed the genotype-specificity of these signals. Overall, we identified ER-mediated PGx-eQTL SNP-gene pairs which represent potential pharmacogenomic tools for identifying patients likely to benefit from ERα-targeted endocrine therapy, offering a foundation for more genotype-informed individualized treatment decisions in breast cancer.

Abstract Introduction Distinct temperature patterns have long been recognized to correlate with fevers of differing etiologies. While the use of wearable sensors for high-frequency temperature monitoring (HFTM) on a near minute-by-minute basis has been shown to detect fevers earlier than standard-of-care nursing vital sign assessments in hospitalized patients, leveraging these high-resolution datasets to computationally identify unique digital signatures for real-time diagnosis of underlying fever etiology has not been widely explored. Diagnostic uncertainty is common in patients undergoing hematopoietic stem cell transplantation (HCT), with only 20–30% of febrile neutropenic episodes being microbiologically documented. We hypothesized that unique temperature patterns extracted from HFTM data collected during episodes of febrile neutropenia could be used to develop a supervised machine learning classifier capable of accurately predicting underlying fever etiology in HCT patients. Methods We analyzed 68 clinically independent fever episodes recorded in HCT patients (n=90) outfitted with an FDA-cleared wireless temperature sensor (TempTraq®, BlueSpark Technologies) that measured axillary temperature every 2 minutes throughout hospitalization. Time-series features were extracted from temperature traces spanning 1 hour before to 3 hours after fever onset and used to train a suite of machine-learning models to distinguish engraftment fevers from other fever etiologies. Model training and evaluation were performed using repeated stratified 5-fold patient-level cross-validation, yielding 100 train-test evaluations. Results Among all classification models, the logistic regression classifier provided the best overall performance and interpretability, achieving 94% specificity (95% CI, 0.84–1.0) for identifying engraftment fevers with a mean AUROC of 0.88 ± 0.10. Feature importance analysis demonstrated that both clinical variables and HFTM-derived temperature dynamics contributed to model performance, with a strong reliance on time-series features captured within the first 4 hours of fever onset. Conclusion Our study provides a demonstration that continuous temperature data collected from patients outfitted with wearable sensors can be leveraged not only for early fever detection but also for machine learning–based diagnosis of fever etiology. These findings suggest that dynamic temperature patterns contain clinically meaningful physiologic information that with further studies could support real-time diagnostic decision-making and guide safe de-escalation of empiric antibiotics during febrile neutropenia in patients undergoing intensive cancer therapy.

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Conventional cigarette smoking remains a leading preventable cause of morbidity and mortality despite declining prevalence, yet evidence-based treatments remain underused. This narrative review examines guideline-supported therapies and emerging approaches, including digital tools, neuromodulation, and harm-reduction strategies. Standard care typically combines FDA-approved pharmacotherapy with behavioral counseling. Digital interventions can extend access and support adherence, particularly when integrated with pharmacotherapy and follow-up. Repetitive transcranial magnetic stimulation (rTMS) can be considered as an adjunctive option for patients who do not respond to pharmacotherapy and is FDA-approved. For patients unable to quit, structured harm-reduction strategies may help reduce risk while supporting progression toward eventual abstinence. These approaches should be used alongside, not in place of, guideline-recommended pharmacotherapy and behavioral counseling, which remain the gold standard for care. This review outlines a pragmatic, primary care–oriented model that integrates stepped-care with harm-reduction strategies.

Pulmonary developmental disorders comprise a heterogeneous group of congenital abnormalities involving the airways, lung parenchyma, pulmonary vasculature, or overlapping developmental pathways. Although these conditions commonly present during infancy or childhood, many remain clinically silent until adulthood, when they are discovered incidentally or manifest with recurrent respiratory symptoms such as infection, hemoptysis, or progressive dyspnea. These abnormalities may be broadly categorized into airway, vascular, parenchymal, and mixed developmental anomalies. Airway abnormalities include congenital tracheobronchomegaly, branching anomalies of the tracheobronchial tree, bronchial atresia, bronchogenic cysts, congenital pulmonary airway malformations (CPAM), and bronchopulmonary sequestration (BPS). Vascular anomalies include pulmonary artery sling, proximal interruption of the pulmonary artery, Scimitar syndrome, and meandering pulmonary veins. Parenchymal disorders encompass congenital lobar overinflation and pulmonary hypoplasia. Increasing recognition of overlapping lesions, particularly combinations of CPAM, sequestration, and bronchial atresia, has challenged traditional compartmental classification systems and supports a developmental spectrum model. This review synthesizes contemporary concepts regarding embryologic mechanisms, pathogenesis, imaging findings, and management of these entities in adults. Particular emphasis is placed on imaging evaluation with CT and MRI, updated terminology, evolving molecular understanding of CPAMs, including lesions with malignant potential, and distinctions between congenital sequestration and pseudosequestration. Recognition of these disorders and their associated anomalies is essential for accurate diagnosis, appropriate management, and surgical planning in adult patients.

10578 Background: Multicancer detection (MCD) testing using cell-free DNA methylation patterns is a novel blood-based approach to cancer screening. In 2022, Mayo Clinic implemented offering MCD testing into routine clinical practice. Prior real-world reports have been limited to single-site experiences. We evaluated enterprise-wide implementation of MCD testing across all three Mayo Clinic sites using the Mayo Clinic Platform. Methods: We performed a retrospective analysis of de-identified clinical data from Mayo Clinic Platform Discover, including GRAIL Galleri tests performed at Mayo Clinic sites in Rochester, MN; Scottsdale, AZ; and Jacksonville, FL. This activity did not require IRB review per 45 CFR 46.102. Demographics, test results, cancer diagnoses, and prior cancer history were extracted using a privacy-preserving protocol, with data de-identified by expert determination. ICD-10 diagnostic codes were used to identify subsequent cancer diagnoses. Results: A total of 8,201 Galleri tests were performed in 7,300 patients; some patients underwent repeat testing. Fifty-seven tests (0.7%) were positive. Among MCD-positive patients, cancer diagnostic codes were identified in 32 patients, yielding a positive predictive value (PPV) of 58.7%. The most common cancers identified were oropharyngeal (34.4%), lymphoid and hematopoietic (34.4%), and gastrointestinal malignancies (18.8%).Among 8,144 MCD-negative tests (99.3% of all testing performed), 423 patients (5.2%) subsequently received a cancer diagnostic code, yielding a negative predictive value of 92.5%. The most commonly identified cancers in this group were male genital organs (36.6%), urinary tract (10.6%), and thyroid or other endocrine glands (7.3%). Overall, 10.1% of patients had a prior cancer history, which was more common in MCD-positive than MCD-negative patients (22.6% vs 10.0%). Patients with positive tests were older (mean age 68.4 vs 61.5 years) and more often male (67% vs 62%). Race distribution was similar. Conclusions: Enterprise-wide implementation of MCD testing across diverse clinical settings is feasible within routine workflows. Over half of positive tests were associated with cancer diagnostic codes, supporting the clinical promise of MCD testing. Limitations include incomplete capture of externally diagnosed cancers and lack of cancer signal-of-origin data. The Mayo Clinic Platform enables scalable, secure analytics to support future cancer interception strategies.

Abstract Rationale Transthoracic echocardiography (TTE) is a very useful measure of cardiac function in patients with pulmonary hypertension (PH), along with right heart catheterization, which is considered to be the gold standard of measurement. It is non-invasive, quick and a good screening tool to assess the function of a failing right ventricle against elevated pulmonary pressures. Portopulmonary hypertension (POPH) is defined as PH associated with portal hypertension. The Tricuspid Annular Plane Systolic Excursion to Systolic Pulmonary Artery Pressure (TAPSE/SPAP) ratio has been found to be an effective prognosticator in different subtypes of PH. This study focuses on the role of TAPSE/SPAP ratio in prognosis of patients with POPH undergoing liver transplantation. Methods This was a single-center retrospective study of POPH patients undergoing liver transplantation at Mayo Clinic Florida from June 2003 to December 2023. It included patients with POPH with a mean pulmonary pressure >20 mm Hg undergoing liver transplantation. Patients with incomplete TTE data, coexisting renal failure on dialysis and requiring liver retransplant were excluded. This study included 27 patients. The last TTE report before liver transplantation was used for data analysis. The TAPSE/SPAP ratio was investigated as predictor of all-cause mortality following liver transplant using Cox regression and area under ROC curve. (Brackets contain 95% C.I.) Time to death after liver transplantation was considered. Patients were followed till August 1, 2024. (The correlation of this ratio-TAPSE/SPAP with some catheterization measured pulmonary pressures and indices have been included in Table 1.) Results Among 27 patients, 13 were female, 14 male. The most common causes of liver failure in these patients were non alcoholic fatty liver disease (NASH) and alcoholic liver disease. Rarely, some etiologies like sarcoidosis, autoimmune hepatitis, primary sclerosing cholangitis and hepatitis B/C were present. There were 7 deaths among total of 27 patients. The hazard ratio (HR) of TAPSE/SPAP for overall mortality by Cox regression was 0.01 (0.00-0.58), p = 0.03. The area under ROC curve was 0.76 (0.55-0.96), p = 0.01 [Also for TAPSE alone, the area under ROC curve was 0.74 (0.51-0.97), p = 0.05] Conclusion This study infers that TAPSE/SPAP ratio seems to be a good predictor of survival in POPH patients undergoing liver transplant, with a higher ratio associated with decreased all-cause mortality. It suggests that TAPSE alone might also be a good predictor with higher TAPSE associated with decreased mortality. This abstract is funded by: None

Abstract Study Objectives Narcolepsy is a chronic condition affecting the sleep/wake cycle that is challenging to diagnose. Epidemiological data from large US-focused studies remain limited, with no validated claims-based case selection definitions for narcolepsy. We estimated the prevalence/incidence of diagnosed narcolepsy (type 1 [NT1], type 2 [NT2], overall) in an insured US population using validated, claims-based narcolepsy case definitions. Materials and Methods This observational study used HealthVerity administrative claims-linked electronic medical records to develop case definitions identifying individuals with NT1, NT2, and overall narcolepsy from diagnosis, medication, and procedure codes. Claims-based case definition performance (NT1, NT2, overall narcolepsy) was assessed using positive predictive values (PPVs). Prevalence (per 100 000 persons, on December 31, 2023) and annual incidence (per 100 000 person-years [PY], 2020 − 2023) were calculated/adjusted using PPVs for each case definition. Results Unadjusted point prevalence among individuals with ≥12 months of continuous enrollment were 15.5/100 000 (NT1), 51.1/100 000 (NT2), and 67.0/100 000 (overall narcolepsy). Unadjusted incidence rates were stable from 2020 − 2023 for NT1 (range, 2.0 − 2.3/100 000 PY) but declined across years for NT2 (9.1 − 7.6/100 000 PY) and overall narcolepsy (11.3 − 9.6/100 000 PY). PPVs (95% confidence interval) of NT1, NT2, and overall narcolepsy were 0.81 (0.72 − 0.88), 0.84 (0.75 − 0.91), and 0.80 (0.71 − 0.87), contributing to epidemiologic estimates being reduced by ~20% after PPV adjustment. Prevalence and incidence were higher in females than males. Individuals with NT1 were ~ 4 years younger versus NT2. Conclusions Validated definitions for narcolepsy can reduce potential misclassification. Our findings highlight a relatively low NT1 prevalence in the US. In contrast, NT2 prevalence estimates were > 3 times higher than NT1.