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With improvement in medical and surgical care, the number of adults with congenital heart disease (CHD) is soaring. Adults with CHD commonly have impairments in brain health. However, significant gaps in knowledge remain regarding the relevant types and prevalence of neurologic and psychiatric risk and their associated risk factors. We sought to review current evidence, identify gaps in knowledge, and develop key next steps to improve scientific understanding and clinical care. Three working groups—Genetics and Brain Health, Characterizing Neuropsychological and Psychological Outcomes, and Neuropsychological and Psychosocial Interventions—were composed of multidisciplinary experts in relevant clinical and research domains, as well as adults with CHD. Each group identified 5 key knowledge gaps and associated next investigations needed to address those gaps. For Genetics and Brain Health, 5 key knowledge gaps were identified: lack of a standardized neuroimaging protocol for adults with CHD, need to understand neuroradiological–pathological–neuropsychological correlates, role of gene–environment interactions, what can be learned from brain health risk models from other groups, and how existing multimodal approaches influence risk and neuroresilience. Adults with CHD can benefit from routine assessment of brain health, as well as increased clinical and basic research into the underlying factors that contribute to risk and neuroresilience for neurologic and psychiatric sequalae. Multidisciplinary collaborative efforts that incorporate adults with CHD across the research cycle are essential for all key next steps.

Objectives To comprehensively review the available literature on prehabilitation and rehabilitation exercise, nutrition, and psychological support interventions for patients with kidney cancer (KC), to summarise the clinically relevant efficacy and cost‐effectiveness of interventions, to expose key knowledge gaps, and to inform future investigations and initiatives. Methods This review was performed according to the per Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) Extension for Scoping Reviews Guidelines. We included randomised controlled trials (RCTs) assessing programmes of prehabilitation or rehabilitation, exercise, psychological support, or nutrition components in patients with KC or KC caregivers from January 2004 to March 2022. Statistically significant positive (SS+) and negative (SS−) results were summarised. Results The systematic search yielded 10 968 records including 18 RCTs, involving 2774 unique subjects, 706 of whom were KC patients/survivors. None included caregivers or assessed cost‐effectiveness. Two interventions were implemented before surgery, one was implemented prior to initiation of systemic therapy, eight were implemented during systemic or radiation therapy, three were implemented after treatment, while implementation time was not specified for four interventions. Conclusion Most (14/18) RCTs involving exercise, nutrition, psychological support, or prehabilitative or rehabilitative programmes for KC performed to date demonstrated SS+ results. The evidence was most robust regarding previously evaluated psychological support, especially mindfulness‐based interventions (9/10 studies demonstrating SS+ improvement in primary outcomes), followed by therapeutically valid exercise with/without psychological support (5/8 RCTs demonstrated efficacy), then nutrition or pharmacological interventions (2/5 demonstrated efficacy). Level 1 evidence supports counselling patients and referral to mindfulness‐based psychological therapy along with physical therapy or physical medicine and rehabilitation, as well as consideration of preoperative carbohydrate drinks. No studies have examined impact on caregivers, or cost‐effectiveness, which are both critical areas for future study.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.

Summary In adults with classic Hodgkin lymphoma (cHL), metabolic tumour volume (MTV) is valuable for risk stratification. This systematic review explored the role of volumetric parameters in children, adolescents and young adults (CAYA) with cHL. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) method. Five databases were searched on 16 October 2024. Eligible studies were peer‐reviewed manuscripts, written in English, published since database inception that included patients ≤21 years of age with a diagnosis of cHL treated with chemotherapy ± radiotherapy with a baseline 18 F‐Fluorodeoxyglucose (F‐FDG) PET/CT scan for MTV quantification. The search strategy identified 3669 studies, of which 35 were eligible for inclusion. Fifteen studies (43%) evaluated a cohort exclusively ≤21 years of age. All eight studies that explored the association of baseline PET parameters with known risk factors identified a significant correlation. Nine of 12 papers (75%) demonstrated a statistically significant correlation with disease response to therapy on PET/CT. Fifteen of 20 papers (75%) demonstrated an independent statistically significant correlation with clinical outcomes. In the CAYAHL population, volumetric PET parameters are valuable for risk stratification despite heterogeneity in results. Future harmonization of the segmentation approach will facilitate incorporation of MTV into clinical practice.

Abstract Motivation: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies—often severe and genetically complex—pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research. Results: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical ontology, and patient community advocates systematically reviewed and revised the epilepsy hierarchy in Mondo, aligning it with the International League Against Epilepsy (ILAE) classification system. These updates include reclassification of epilepsy subtypes, including syndromes, age-related epilepsies, and developmental epileptic encephalopathies, resulting in a more granular, standardized, and clinically relevant structure. Mondo now offers an enhanced framework for integrating epilepsy data across resources, enabling improved interoperability and facilitating rare disease research and data curation, with continued efforts underway to further refine and expand this integration.

Background/Objectives: Dizziness is a symptom of many disorders across a wide range of etiologies. If dizzy patients are seen for vestibular evaluation with an audiologist and no vestibular reason for the patient’s dizziness is found, the medical referral pathway can become convoluted. This can leave patients feeling discouraged and unable to manage their symptoms. Clinically symptomatic chronic respiratory alkalosis (CSCRA) is an acid–base disorder that typically presents with dizziness but is unfamiliar to practitioners in vestibular and balance care settings. Methods: In a retrospective chart review deemed exempt by the Mayo Clinic Institutional Review Board, 74 patients at Mayo Clinic Arizona were included. All had consultations with both Audiology and Aerospace Medicine to assess their dizzy symptoms. Results: After completing vestibular testing, arterial blood gas (ABG) testing, and a functional test developed at Mayo Clinic Arizona called the Capnic Challenge test, 40% of patients were found to have CSCRA contributing to their dizzy symptoms. Many of these patients also had common comorbidities of CSCRA, like postural orthostatic tachycardia syndrome (POTS), migraines, and sleep apnea. Fewer than one-fourth of these patients had measurable vestibulopathies causing their dizziness. Half of the patients referred by the vestibular audiologist to Aerospace Medicine had a diagnosis of CSCRA. Conclusions: Assessment for CSCRA should be considered as a next step for patients presenting with dizziness without a vestibular component. Being aware of the prevalence of CSCRA and its comorbidities may help balance providers offer quality interprofessional referrals and improve patient quality of life.

Abstract Background DPYD testing can identify patients at risk for severe toxicity when a standard fluoropyrimidine antineoplastic dose is prescribed. Sequencing-based methods detect rare variants, which require classification. Methods DPYD sequencing results over a 9-year period through to 2024 were analyzed. The dataset was filtered to calculate the positive test rate for different genotyping strategies, including targeted analysis of the Association for Molecular Pathology (AMP) Tier 1 and 2 recommended alleles, and as compared to sequencing. Variant classifications based on the laboratory’s clinical protocol were compared to ClinVar classifications and designations by the Clinical Pharmacogenetics Implementation Consortium (CPIC) expert panel. Results A DPYD variant was reported in 12.79% (896/7003) of those tested, with 2.53% (170/7003) of all reports including a variant of uncertain significance. Had only AMP Tier 1 or both Tier 1 and 2 been tested, 9.30% and 9.44% of patients would have received a positive report, respectively. Among the 281 unique, non-Tier 1/Tier 2 variants encountered during sequencing, >80% were not classified by the CPIC expert panel, while >48% were not reported in ClinVar. Variant classifications by our laboratory and those in ClinVar were generally concordant with the CPIC expert panel, despite the lack of a standardized classification system. Conclusions While AMP Tier 1 genotyping would have identified most patients at risk for fluoropyrimidine toxicity, sequencing is more comprehensive, identifying 26% more reportable variants compared to targeted genotyping. A standard framework for pharmacogenomic variant classification could facilitate consistent variant classification and a transition from targeted genotyping to sequencing.

566 Background: FGFR inhibitors (FGFRi) have an established role in treating FGFR2-altered (alt) cholangiocarcinoma (CCA). Tinengotinib, a novel FGFRi, has shown promising activity overcoming acquired resistance to prior FGFRi. We present biomarker analyses evaluating tinengotinib’s ability to overcome prior FGFRi resistance and to elucidate mechanism of resistance to tinengotinib. Methods: Eligible patients (pts) with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy were treated with tinengotinib 10 mg daily across 4 Cohorts: A1: FGFR2 fusion (fus) with primary progressive disease (PD) on prior FGFRi; A2: FGFR2 fus with PD after prior response to FGFRi; B: FGFR alt without FGFR2 fus; C: FGFR wild-type. Efficacy was assessed by RECIST v1.1. All pts underwent liquid biopsy for circulating tumor DNA (ctDNA) at baseline; additional timepoints include cycle 3 day 1 (C3D1), time of PD, and end of treatment (EOT). Samples were analyzed using FoundationOne Liquid panel. Results: 27 out of 55 enrolled pts had biomarker samples collected at baseline and C3D1. Among them, pts in A1 (n=10, 107 mutations (mut)), B (n=8, 90 mut) and C (n=5, 74 mut) showed a significant decrease in short variant allele frequencies (VAF) from baseline to C3D1 by a median relative VAF reduction of 100% (p<0.0001) for each of the three cohorts. Although a median relative VAF reduction of 33.3% was seen in A2 (n=4, 15 mut), this was not significant (p=0.6093) likely due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression free survival (p<0.0014). Additionally, 100% of median relative reductions in FGFR2 kinase domain (KD) mut were seen in A1 and B (p<0.0001, 95% CI 100-100% and p=0.0156, 95% CI 83.6-100%, respectively), with 92% and 57% clearance of initial FGFR2 KD mut by C3D1. In a subgroup of 10 pts with biomarker sampling at baseline and EOT, 3 pts in A1 with acquired resistance showed emergence of novel FGFR2 mut, loss of FGFR-sensitive mut and new mut in alternate pathways (e.g., AKT, EGFR, RAS/MAPK) while retaining the original FGFR2 fus. 1 pt from B developed resistance due to new FGFR2 rearrangements and FGFR2 mut. 4 FGFR wild-type pts from C developed resistance involving mut in TP53, KRAS, and other oncogenic drivers. Conclusions: These findings provide genomic evidence that tinengotinib may overcome resistance to prior FGFRi treatment in FGFR2 fus-positive CCA, as reflected by significantly reductions in ctDNA VAFs and frequent clearance of FGFR2 KD mutations. The emergence of resistance alterations including de novo FGFR2 mutations and bypass pathways activations indicates acquired resistance that may limit long-term benefit. These results support further investigation with expanded biomarker sampling to better characterize resistance evolution and guide therapy optimization in an ongoing Phase 3 trial. Clinical trial information: NCT04919642 .

Abstract Background Outpatient parenteral antimicrobial therapy (OPAT) allows patients to complete extended antimicrobial treatment at home, improving quality of life and reducing healthcare costs. National guidelines outline best practices for antimicrobial administration, vascular access management, monitoring, and recommend involving an infectious disease physician and a multidisciplinary team. Evaluating adherence to these practices can identify improvement opportunities and enhance outcomes. The primary objective of this study was to assess patient outcomes related to adherence to OPAT best practices at Mayo Clinic Health System – Southwest Wisconsin (MCHS–SWWI). Secondary objectives included evaluating adherence to key process metrics and identifying associations between baseline characteristics and outcomes. Methods This retrospective cohort study included adults discharged from MCHS–SWWI on home OPAT from November 2021 to July 2024. Patients were excluded if under 18 years old or if they received OPAT in non-home settings (e.g., skilled nursing, infusion center). Data on process metrics, outcomes, and safety were collected through manual chart review. These findings were evaluated against established best practices to assess the OPAT program's adherence and determine the impact of this adherence on patient outcomes. Statistical analysis used Pearson’s chi-square tests and Wilcoxon rank sum tests to measure associations of patient characteristics with outcomes. Results A total of 164 patients were included. The MCHS-SWWI OPAT program demonstrated high adherence ( &gt; 85%) to majority of established best practices. Successful OPAT completion occurred in 92.7% of patients, and overall incidence of adverse events and poor outcomes was generally low. Adherence to best practices was below 85% for vascular access selection (81.7%) and completion of weekly labs and vascular access care throughout the OPAT course (∼69%). Conclusion High adherence to OPAT best practices led to a generally low incidence of adverse events, treatment failures, and other unfavorable patient outcomes. The results of this study provide valuable insights to guide institutional quality improvement initiatives aimed at optimizing patient outcomes in OPAT therapy through targeted interventions. Disclosures All Authors: No reported disclosures