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703 Background: The association of circulating tumor DNA (ctDNA) reduction with treatment response has been investigated across multiple malignancies. This study aims to assess the impact of ctDNA response on survival outcomes in patients receiving enfortumab-pembrolizumab (EV-P). Methods: We identified 32 patients with advanced urothelial carcinoma who received EV-P and had ≥2 ctDNA assessments with ≥1 detectable level. Deep molecular response was defined as >2-log reduction from highest ctDNA detection. Radiographic progression was determined from radiology reports documenting progression by RECIST criteria. Kaplan Meier analyses were performed to compute Hazard Ratios (HR) with 95% confidence intervals (CI) for radiographic progression free survival (rPFS), defined as time from treatment start to radiographic progression or death and overall survival (OS) defined as time from treatment start to death were computed. Log-rank tests were performed to compare PFS and OS in patients with deep molecular response to those without response. A p-value <0.05 indicated a statistically significant association with response. Results: Thirty-two patients were included (median age 71 years; range 39–90). Median follow-up was 10.6 months. At cutoff (10/1/2025), 26 patients were alive and 6 had died. Seventeen (53%) achieved a ≥2-log ctDNA reduction (responders), while 15 (47%) did not (non-responders). Progression-free survival was significantly longer in responders (log-rank P < 0.001); median PFS was 5.9 months (95% CI 2.4–NR) in non-responders and not reached in responders (HR 0.09, 95% CI 0.02–0.44; P = 0.0026). Median overall survival was 12.7 months (95% CI 10.0–NR) in non-responders versus not reached in responders (log-rank P = 0.011; HR 0.11, 95% CI 0.01–0.88; P = 0.037). At cutoff, 94% of responders and 67% of non-responders were alive. Conclusions: Achieving a >2-log decrease in ctDNA during EV + Pembrolizumab therapy was significantly associated with improved progression free and overall survival. These findings support ctDNA kinetics as a potential early biomarker of response warranting prospective validation. Clinical outcomes by >2-log ctDNA reduction status. Endpoint > 2-log drop (n = 17 ≤ 2-log drop (n = 15) Log-rank p Median (mo) ≤ 2-log > 2-log HR (95% CI) P C-index PFS 2 events (12%) 10 events (67%) 0.0002 5.9 (2.4–NA) NR 0.09 (0.02–0.44) 0.0026 0.77 OS 1 event (6%) 6 events (40%) 0.011 12.7 (10.0–NA) NR 0.11 (0.01–0.88) 0.037 0.73

743 Background: Although patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) have several emerging therapeutic options, there remains a clinical unmet need to improve efficacy, durability of response, and tolerability while obviating the need for radical cystectomy. TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger the innate immune response, inflammation, and potential immunogenic cell death. Herein we present interim safety and efficacy data of TARA-002 from the BCG-unresponsive cohort of the ongoing ADVANCED-2 study (NCT05951179). Methods: ADVANCED-2 (Cohort B) is a Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in BCG-unresponsive adults ≥ 18 years with high-grade NMIBC CIS (± Ta/T1). Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; or concomitant prostatic or upper tract urothelial involvement. TARA-002 is delivered intravesically for 2 hours and includes induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Biopsy is mandated at Month 3. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. The primary endpoint is complete response (CR) at any time defined by the absence of any high-grade recurrence. The key secondary endpoint is duration of response. Results: As of 07-October-2025, 32 BCG-unresponsive participants have been enrolled. Majority of participants were White (84.4%, 27 of 32), non-Hispanic (93.8%, 30 of 32), and male (68.8%, 22 of 32). The median age was 74 years (range: 47 to 92). The majority of participants had a baseline diagnosis of CIS only ie, without concomitant Ta/T1 (75.0%, 24 of 32). TARA-002 demonstrated a 68.4% (13 of 19) CR at any time in evaluable participants. The 6-month CR was 75.0% (9 of 12), the 9-month CR was 50.0% (4 of 8), and the 12-month CR was 37.5% (3 of 8). The salvage rate was 75.0% (6 of 8) with reinduction therapy. Most treatment-emergent adverse events (TEAEs) were mild (CTCAE Grades 1-2) and transient; no participants experienced higher than Grade 3 TEAEs. No participants experienced drug-related serious adverse events (SAEs) or drug-related TEAEs leading to withdrawal or death. Conclusions: In participants with BCG-unresponsive high-risk NMIBC with CIS ± Ta/T1, TARA-002 appears to be well tolerated and demonstrated encouraging efficacy, supporting ongoing accrual of the ADVANCED-2 study. Further follow-up will inform durability of response, and data will be updated based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

Introduction Burnout among healthcare professionals remains a critical public health issue linked to impaired cognition, emotional exhaustion and diminished clinical performance. Structured breathing practices have demonstrated promise in improving autonomic regulation and cerebral oxygenation, yet their feasibility, acceptability and implementation in real-world healthcare settings remain underexplored. Objectives This single-arm pilot feasibility trial aims to evaluate the feasibility, acceptability and implementation appropriateness of a structured breathing-based intervention for healthcare professionals across community-based Mayo Clinic Health System (MCHS) sites. Secondary objectives include assessing usability and engagement with the mobile breathing platform, while exploratory analyses will describe magnitude of variability and feasibility of collecting psychological and cerebral haemodynamic measures. This study will commence in November 2025 and is expected to be completed by June 2026. Methods and analysis A total of 40 clinicians (MD/DO/MBBS/PA) and nurses reporting moderate or greater burnout will be enrolled across four MCHS sites. Participants will complete a 4-month structured breathing programme delivered primarily online, supported by a mobile application for practice tracking. Assessments will occur at baseline, 2 months and 4 months, with functional near-infrared spectroscopy (fNIRS) measures of cerebral oxygenation collected at baseline and 4 months in a population subset. Primary outcomes include (1) recruitment yield, retention and adherence rates; (2) acceptability and participant satisfaction (survey and qualitative feedback); and (3) implementation appropriateness measured by the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Secondary outcomes include digital engagement and usability through mobile analytics and the System Usability Scale. Exploratory outcomes are psychological indicators (burnout, depression, anxiety, perceived stress, sleep, fatigue, professional fulfilment and resilience) and physiological endpoints (fNIRS). Analyses will be descriptive, summarising feasibility metrics with 95% CIs. Progression criteria (recruitment≥75%, retention≥80%, adherence≥70%, AIM/IAM/FIM≥4.0) will determine readiness for a definitive hybrid effectiveness–implementation trial. Ethics and dissemination The study is approved by the Mayo Clinic Institutional Review Board (IRB # 25-009320). All participants will provide informed consent. Study procedures ensure confidentiality, cultural sensitivity and participant safety. Data will be securely stored in REDCap and disseminated through peer-reviewed publications and scientific conference Trial registration number NCT07218458 .

Background Effective leadership is critical to the success of complex multidisciplinary healthcare organisations. As the organisation emerged from the global pandemic, Mayo Clinic recognised a need to transform its traditional, linear care model into a dynamic, platform-based approach to support its strategy. This required a new leadership model that could support and equip leaders with the skills needed to drive patient-centred healthcare transformation from within. Objective To develop and validate a new leadership competency framework capable of supporting future-ready leadership. Methods A multiphase, evidence-based approach was employed: (1) a visionary interview, goal setting and literature review; (2) focus groups with 23 leaders from across the organisation; (3) iterative competency framework development; and (4) a validation study involving a stratified sample of 129 physician leaders who rated competencies on importance and differentiation, and a qualitative verification by key stakeholders. Results Five core competencies with 23 behaviours were identified. The validation analysis established all behaviours as important for differentiating leadership performance. Stakeholder review confirmed the competencies were actionable and applicable across leadership roles at all levels. Conclusion The Leads Self, Leads Others, Inspires Others, Forward Thinking and Engages Others (abbreviated LLIFE) competency model positions a healthcare organisation to advance leadership excellence in a rapidly evolving healthcare environment that requires comprehensive transformation. It aligns with strategic goals, embeds values-based behaviours and supports continuous development, establishing a model that other healthcare institutions may learn from and adapt.

BACKGROUND: The incidence of early-onset colorectal cancer is rising, yet survivorship care guidelines rarely address concerns unique to younger adults. Although treatment for colorectal cancer can have devastating consequences related to sexual function and fertility, these issues remain underrecognized and seldom addressed. OBJECTIVE: To better understand the impact of colorectal cancer diagnosis and treatment on sexual and reproductive health. DESIGN: Qualitative study of patients with early-onset colorectal cancer. SETTINGS: Semi-structured one-to-one Zoom interviews of patients recruited through convenience sampling from 7 academic institutions. PATIENTS: Sixty-three individuals diagnosed with colorectal cancer aged 50 years or younger were interviewed between March 2021 and August 2024. MAIN OUTCOME MEASURES: Patient perspectives regarding the sexual and reproductive health impacts of colorectal cancer diagnosis and treatment. Data were analyzed iteratively using directed and conventional qualitative content analysis. RESULTS: Participants discussed sexual and reproductive health side effects resulting from surgery, chemotherapy, and radiation. These side effects ranged in severity, with some experiencing almost none and others facing significant issues. They identified several domains, including surgical and treatment side effects, psychological impacts, effects on relationships, and unmet needs. Subdomains included sexual health, reproductive health, emotional distress, body image, communication challenges, impacts on dating, informational needs, financial support, and consultations. LIMITATIONS: Participants were recruited from academic medical centers only, and as such, responses may not reflect the experiences of those cared for in nonacademic settings. CONCLUSIONS: Sexual and reproductive health are critical but often overlooked concerns among younger patients with CRC, with significant impacts on physical functioning, partner relationships, and psychological well-being. Current survivorship guidelines fail to adequately address these needs. Our findings highlight the importance of pretreatment counseling and fertility preservation as well as the need for ongoing mental health support during and after cancer treatment. See Video Abstract . «NADIE ME LO DIJO»: ESTUDIO CUALITATIVO SOBRE LAS PREOCUPACIONES SEXUALES Y REPRODUCTIVAS TRAS EL TRATAMIENTO DEL CÁNCER COLORRECTAL DE APARICIÓN TEMPRANA ANTECEDENTES: La incidencia del cáncer colorrectal de aparición temprana está aumentando, pero las directrices sobre cuidados para supervivientes rara vez abordan las preocupaciones específicas de los adultos jóvenes. Aunque el tratamiento del cáncer colorrectal puede tener consecuencias devastadoras para la función sexual y la fertilidad, estas cuestiones siguen sin reconocerse lo suficiente y rara vez se abordan. OBJETIVO: Comprender mejor el impacto del diagnóstico y el tratamiento del cáncer colorrectal en la salud sexual y reproductiva. DISEÑO: Estudio cualitativo de pacientes con cáncer colorrectal de aparición temprana. ENTORNO: Entrevistas individuales semiestructuradas por Zoom a pacientes reclutados mediante muestreo por conveniencia en siete instituciones académicas. PACIENTES: Se entrevistó a 63 personas diagnosticadas con cáncer colorrectal antes de los 50 años entre marzo de 2021 y agosto de 2024. PRINCIPALES MEDIDAS DE RESULTADOS: Perspectivas de los pacientes sobre el impacto del diagnóstico y el tratamiento del cáncer colorrectal en la salud sexual y reproductiva. Los datos se analizaron de forma iterativa mediante un análisis de contenido cualitativo dirigido y convencional. RESULTADOS: Los participantes discutieron los efectos secundarios en la salud sexual y reproductiva derivados de la cirugía, la quimioterapia y la radiación. Estos efectos secundarios variaban en gravedad, ya que algunos no experimentaban casi ninguno y otros se enfrentaban a problemas importantes. Identificaron varios ámbitos, entre ellos los efectos secundarios de la cirugía y el tratamiento, las repercusiones psicológicas, los efectos en las relaciones y las necesidades no satisfechas. Los subámbitos incluían la salud sexual, la salud reproductiva, el malestar emocional, la imagen corporal, los problemas de comunicación, las repercusiones en las relaciones sentimentales, las necesidades de información, el apoyo financiero y las consultas. LIMITACIONES: Los participantes fueron reclutados únicamente en centros médicos académicos, por lo que es posible que las respuestas no reflejen las experiencias de las personas atendidas en entornos no académicos. CONCLUSIONES: La salud sexual y reproductiva son cuestiones fundamentales, pero a menudo se pasan por alto entre los pacientes jóvenes con CCR, con repercusiones significativas en el funcionamiento físico, las relaciones de pareja y el bienestar psicológico. Las directrices actuales para la supervivencia no abordan adecuadamente estas necesidades. Nuestros hallazgos ponen de relieve la importancia del asesoramiento previo al tratamiento y la preservación de la fertilidad, así como la necesidad de un apoyo continuo a la salud mental durante y después del tratamiento del cáncer. (AI-generated translation )

Abstract Glioblastomas exhibit low immunogenicity and a highly immunosuppressive tumor microenvironment (TME) mediated by both tumor cells and tumor associated microglia/macrophages (TAMs). However, biomarkers that allow for specific detection, monitoring and therapy response assessment of the TAM phenotype in glioblastoma are still lacking. To address this gap, we characterized the dynamics of TAM clusters in the TME of experimental SB28 glioblastoma using single-cell RNA sequencing, immunofluorescence, and molecular imaging and identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a dynamic TAM-specific target. Consequently, we investigated a novel 64 Cu-labeled TREM2 radiotracer with a blood-brain barrier transport vehicle for translational mapping of TAMs in the TME of glioblastoma. We found strong and highly myeloid cell-specific PET signals that followed the trajectory of TREM2 gene expression from early- towards late-stage tumors. Transient myeloid cell depletion via CSF1R inhibition showed a reduction of TREM2 PET signals compared to placebo and prolonged survival in SB28 glioblastoma mice, while TREM2 stimulation led to increased TREM2 PET signals. Translation into a pilot cohort of patients with glioblastoma revealed strong TREM2 PET signals predominantly at lesion edges and high heterogeneity across individuals, matching with immunohistochemistry. In summary, TREM2 PET imaging has strong potential as an immune cell-specific biomarker for personalized assessment of the TAM phenotype in the TME of patients with glioblastoma.

INTRODUCTION: High-quality colonoscopy requires accurate risk stratification for surveillance per the 2020 US Multi-Society Task Force guidelines and adherence to 2024 American College of Gastroenterology/American Society for Gastrointestinal Endoscopy quality benchmarks. Both are operationally challenging in clinical practice. We developed and validated Colon-Pilot, a large language model—powered clinical decision support system using GPT-4o to automate and standardize both functions. METHODS: The system was evaluated in 2 operational modes: (i) a human-in-the-loop clinical decision support validation of surveillance recommendations for 596 colonoscopies, comparing concordance with 2020 US Multi-Society Task Force guidelines against expert consensus, and (ii) an automated administrative audit applying Colon-Pilot to 42,632 colonoscopies across the Mayo Clinic Health System to calculate 2024 American College of Gastroenterology/American Society for Gastrointestinal Endoscopy priority quality indicators. Recommendations were autogenerated unless predefined safety criteria triggered manual review. RESULTS: Colon-Pilot issued recommendations for 522 of 596 cases (87.6%) and flagged 12.4% for manual review. For automated cases, guideline-concordant accuracy was 97.5% (Cohen κ = 0.970) versus 69.7% (κ = 0.781) for original endoscopist recommendations. Discordant artificial intelligence (AI) cases (n = 13) most often recommended longer-than-appropriate intervals (62%). Applied to the enterprise data set, Colon-Pilot calculated performance exceeding 2024 targets: adenoma detection rate 49.8% (≥35%), sessile serrated lesion detection rate 17.7% (≥6%), bowel preparation adequacy 91.8% (≥90%), and cecal intubation rate 97.4% (≥95%). DISCUSSION: Colon-Pilot demonstrated high fidelity in applying surveillance guidelines and automated quality benchmarking, outperforming unassisted endoscopists in guideline adherence. By combining safety protocols with large-scale automated reporting, it offers a scalable solution for improving both efficiency and quality in colorectal cancer prevention.

Abstract Background Coronary flow augmentation occurs through the simultaneous interaction and regulation of both endothelium-dependent and endothelium-independent mechanisms. A decrease in coronary flow reserve (CFR) secondary to either mechanism is associated with poor prognosis. However, at the individual level, the integrated impact of these two mechanisms has not been thoroughly investigated. Purpose This study investigated the prognostic implications of an integrated metric, CFRsum, combining endothelium-dependent and -independent CFR. Methods A total of 1441 patients with angina with non-obstructive coronary artery (ANOCA) undergoing coronary reactivity testing were studied. Endothelium-independent CFR was measured during adenosine-induced hyperemia, and endothelium-dependent CFR during intracoronary acetylcholine infusion. CFRsum was calculated by summing these components. Cardiovascular event was defined as composite of cardiovascular death, myocardial infarction, heart failure, and cerebral infarction. Results Our patients had a median age of 51.7 years, 69.0% of whom were female, and their CFRsum was 4.57 [3.88, 5.37]. Patients were divided into three tertile-based groups, and Cox proportional hazards analysis demonstrated that all CFR classes were independent predictors of prognosis, with CFRsum providing the best model fit (Likelihood ratio: 54.62, degrees of freedom: 7, P &lt; 0.001). The Kaplan-Meier curve (Figure) demonstrated a stepwise deterioration in prognosis across CFRsum tertile groups, with lower CFRsum being associated with progressively worse outcomes (p &lt; 0.001). Stratification by follow-up duration (3 years) revealed that patients with middle-range CFRsum exhibited comparable outcomes to those with the highest CFRsum during the early phase (&lt;3y) but significantly worse outcomes in the late phase (≥3y) (P = 0.459 and P &lt; 0.001, respectively). Conclusion CFRsum showed superior prognostic value over traditional CFR metrics in patients with ANOCA, identifying a compensated group with time-varying outcomes. This novel metric improves the assessment of microvascular function and supports better clinical management.