Citations

Background. Although solid organ transplant prolongs survival in end-stage disease, recipients face high symptom burden and complex decisions at multiple junctures. Palliative care (PC) may address these needs, but referrals in transplant programs are infrequent, often reactive, and the benefits remain unclear. Methods. We retrospectively studied 12 676 heart, liver, lung, and kidney transplants across 3 Mayo Clinic sites (2018–2024). PC encounters were classified as pretransplant (≤1 y before admission), peritransplant (during hospitalization), or posttransplant (≤1 y after discharge). Results. Only 8.3% engaged PC, with patterns varying by organ and timing. Heart programs demonstrated the highest overall engagement, primarily pre- and peritransplant, whereas lung and kidney referrals occurred more often after discharge. Earlier timing coincided with longer survival, whereas peri- and posttransplant encounters occurred closer to death. In heart transplantation, pre- and peritransplant PC were observed in recipients with lower procedural volume and fewer short-term readmissions. Liver and lung cohorts displayed variable patterns. Kidney referrals occurred infrequently and were concentrated among recipients with higher morbidity. Timing of inpatient consultation showed a strong positive correlation with hospital length of stay, and pretransplant PC coincided with higher rates of goals-of-care discussions and fewer hospital interventions. Adapting screening criteria to focus on high-risk recipients, PC was associated with fewer short-term readmissions for heart and lung recipients. Conclusions. PC among solid organ transplant was infrequent and varied. Referral timing often aligned with patient morbidity and mortality. Structured, prospective validation of screening methods may identify patients most likely to benefit from palliative involvement.

Abstract Exercise training improves cardiovascular health and reduces the risk for future cardiovascular events and mortality. However, emerging evidence suggests that Masters athletes may have a higher prevalence of cardiovascular abnormalities, such as atrial arrhythmias, coronary atherosclerosis, aortic dilatation, and myocardial fibrosis, compared to their less active peers. The clinical management of Masters athletes may be challenging as available guidelines for such conditions are generally based on data derived from symptomatic sedentary patients, limiting their applicability to highly trained individuals. Other unique challenges in the clinical assessment of Masters athletes include differences in symptomatic presentations compared to sedentary individuals, potential resistance to the initiation of pharmacologic treatment, and the increasing availability of consumer wearable health data that may provide relevant information on their cardiovascular health status. The purpose of this joint EAPC/ESC and ACC Clinical Consensus Statement is to provide an in-depth update on the current state of knowledge on abnormal cardiovascular findings in Masters athletes. We present an expert-based approach on the diagnostic assessment, management, and prognosis of (i) atrial fibrillation, (ii) bradyarrhythmias, (iii) ventricular arrhythmias, (iv) coronary atherosclerosis, (v) aortic dilatation, (vi) myocardial fibrosis, and (vii) exercise-induced arrhythmogenic cardiomyopathy. Clinical challenges, areas of ongoing controversy, and uncertainty and the potential underlying mechanisms are discussed. We also present future perspectives and research directives to further refine current best practice strategies. This includes the need for clinical outcome studies, dedicated randomized controlled trials in athletes, and international registries with diverse populations and longitudinal follow-up to evaluate the natural history of cardiac abnormalities and facilitate development of evidence-based approaches in the clinical management of Masters athletes with cardiovascular abnormalities.

Death or dysfunction of retinal pigment epithelium (RPE) cells occurs in age-related macular degeneration (AMD) and certain inherited retinal dystrophies (IRDs). Induced-pluripotent stem cell (iPSC) derived-RPE have been used in early-stage clinical trials to treat AMD and IRDs by injecting them as a cell suspension or monolayers. While RPE transplant shows therapeutic potential, issues ranging from failure to repopulate the entire treatment area, clumping and monolayer folding, and a foreign body response to the support have been reported. We’ve shown that RPE can be grown on high concentration (>30 mg/mL) degradable fibrin hydrogels, and that cell free fibrin hydrogels implanted in the subretinal space degrade without causing inflammation. Here we describe manufacture and surgical implantation of degradable fibrin hydrogels carrying iPSC-RPE into a porcine model of geographic atrophy (GA). Large (15.25 × 58.42 × 0.2 mm) fibrin gel blanks were produced by injection molding, and iPSC-RPE were grown on their surface. Using a mechanical punch, the blank was subdivided into 1.5 × 5.0 × 0.2 mm doses, which fit a custom tool used for storage and surgical placement. Following aseptic packaging, RPE and gels were stable at 37 °C for at least 7 weeks. When transplanted into a pig model of GA, the fibrin scaffold degraded in <1 month and the iPSC-RPE provided partial rescue from GA as assessed by preservation of photoreceptors and blood flow in the choriocapillaris. We conclude that iPSC-RPE delivered on degradable fibrin hydrogels represent a potentially safe and effective approach to RPE transplantation.

Background/Objectives: Traumatic spinal cord (SC) injury (SCI) is a debilitating neurological condition. Minimally invasive approaches to monitor in real time the functional state of the neuromotor apparatus in animal models of SCI (at rest and movement) to assess effectiveness of therapy are needed in preclinical studies. We aimed to develop such a bioethically acceptable platform for SCI studies on non-human primates (Rhesus macaques). Methods: Epidural and myographic electrode implantation (EI) (wireless and wired, connected via a head plug) was performed. After EI, motor responses caused by electrical stimulation of the SC at the level of the cervical and lumbar thickening were recorded; electromyography of the limb muscles was recorded during quadrupedal movement of the animal on a treadmill with simultaneous assessment of movements’ kinematic parameters. Five weeks after EI, three animals underwent lateral hemisection of the SC in the C4–C5 segment under the control of a surgical microscope and intraoperative recording of motor- and sensory-evoked potentials. Results: Within 30 days after SCI, during treadmill testing, a decrease in electromyographic activity of the limb muscles and the volume of angular movement in the joints on the side of the injury was detected. Electrical stimulation at the L2–S1 segments of the SC at a frequency of 30 Hz led to the appearance of a locomotor pattern in the muscles of the hind limbs and an increase in the range of motion. Conclusions: Our platform can be used for pathophysiological studies of various neuromodulation modes and as a basis for the development of control neurointerfaces.

TPS646 Background: SSTR-targeted RPT has transformed the treatment landscape for NETs, significantly improving clinical outcomes in phase 3 studies versus other targeted therapies. Nevertheless, disease progression and renal toxicity after treatment highlight the need for further improvement. Use of the α-emitter 225 Ac as the radioactive component has shown promising results in clinical studies: initial data from ACTION-1 suggest promising efficacy for RYZ101, a first-in-class, highly potent α-emitting RPT, in patients with SSTR+ GEP-NETs progressing after 2–4 cycles of 177 Lu-somatostatin analogs. RYZ401 is a cyclic 6-amino acid SSTR-targeting peptide agonist conjugated to a DOTA chelator bound to 225 Ac. Preclinical data have shown an improved therapeutic window versus DOTATATE. RYZ401 has the potential to deliver higher radiation doses to tumors, with improved renal clearance and lower kidney absorbed dose, potentially eliminating the need for amino acid infusion. Methods: RYZ401-101 is a global, multicenter, phase 1, first-in-human, dose-escalation/-expansion study designed to determine the recommended phase 2 dose (RP2D) and optimal treatment regimen, safety and tolerability, and preliminary efficacy of RYZ401 in patients with NETs and other selected solid tumors expressing SSTRs. Key eligibility criteria: histologically confirmed metastatic or unresectable well-differentiated NETs; WHO grade 1–3 (Ki-67 ≤55%); ≥1 SSTR PET-positive measurable lesion; and disease progression after ≥1 prior treatment line. In dose escalation, 6–18 patients will receive escalating doses of RYZ401 (2.0–11.1 MBq IV Q6W × 2–4 cycles); no amino acid co-infusion is planned. In dose expansion, approximately 80 patients will receive RYZ401 at the RP2D, 40 patients with well-differentiated GEP-NETs (cohort A) and 40 with other SSTR+ tumors including non-GEP-NETs (cohort B). Primary endpoints: dose-limiting toxicities in weeks 1–4 of treatment (dose escalation) and safety (dose expansion). Secondary endpoints: safety, pharmacokinetics, and efficacy outcomes (dose escalation and expansion). RYZ401 dosimetry will be evaluated in a sub-study of 10−16 patients. Enrollment is ongoing in the USA. Clinical trial information: NCT07165132 .

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .

162 Background: In preclinical studies, the tryptophan-metabolizing enzyme, Indoleamine 2, 3-dioxygenase 1 (IDO1), promotes resistance to radiation in colorectal cancer, and IDO1 inhibition with epacadostat improves tumor radiosensitivity. In a phase 1 trial, patients (pts) with locally advanced rectal cancer (LARC, n=17) were treated with epacadostat in combination with short course radiotherapy (SCRT) and CAPOX which was well-tolerated, and the recommended phase 2 dose (RP2D) of epacadostat was 400mg BID. Here we report efficacy and safety from the NCI-supported phase 2 (NCT03516708) multicenter, open-label trial (treatment cohort). Methods: Pts were treated with standard of care (SOC) SCRT, then SOC neoadjuvant chemotherapy (NAC) followed by SOC surgical resection or non-operative management (NOM). Epacadostat (400 mg BID) started with SCRT and continued until starting NAC (a minimum of 21 days). Eight pts were enrolled prior to discontinuation of epacadostat by Incyte in February/March 2025. The primary endpoint is Neoadjuvant Rectal (NAR) score. In patients who underwent NOM, we calculated MRI-based tumor regression grade (MR-TRG). Secondary endpoints are pathologic complete response (pCR) rate, complete clinical response (cCR) rate, and progression free survival (PFS). Results: Table 1 summarizes baseline characteristics and endpoints (primary and secondary). NOM was pursued in 7/8 (87.5%) pts, surgical resection was performed on 1/8 (12.5%). At median follow-up of 12 months, local tumor regrowth occurred in 1 pt initially treated with NOM (after tumor regrowth, he underwent salvage surgery and is currently on surveillance). Treatment with epacadostat was interrupted in 2/8 (25%) patients due to grade 3 maculopapular skin rash. Most frequent treatment-emergent adverse events (TEAEs) regardless of causality (all grades (G)/G3-4) were bloating (75%/0%), increased ALT (62.5%/0%), increased AST (50%/0%), nausea (50%/0%), and constipation (50%/0%). Grade 3 diarrhea and grade 3 non-cardiac chest pain occurred in 1 patient each (both unrelated to epacadostat). Conclusions: Epacadostat demonstrates promising efficacy and manageable safety in patients with LARC. The biomarker cohort and correlative studies are ongoing. Clinical trial information: NCT03516708 . Baseline characteristics and endpoints. Patient Age Sex Ethnicity Stage Surgery/NOM NAR MR-TRG cCR/pCR Recurrence 1 52 M Caucasian T3N1 NOM NA 2 Y/NA No 2 45 M Caucasian T3N1 NOM NA 3 Y/NA Local tumor regrowth 3 48 M Caucasian T3N2 NOM NA 3 Y/NA No 4 61 M Caucasian T4N2 NOM NA 3 Y/NA No 5 57 M Caucasian T3N0 NOM NA 1 Y/NA No 6 60 F Caucasian T3N1 Surgery 15 3 N/ypT3N0 No 7 67 M Caucasian T4N0 NOM NA 3 Y/NA No 8 51 M Caucasian T4N2 NOM NA P NA No

BACKGROUND High-flow nasal cannula (HFNC) therapy is widely used in infants hospitalized with moderate-to-severe bronchiolitis. Although bronchiolitis severity has been consistently associated with later asthma, it remains unclear whether HFNC contributes additional risk or instead represents a marker of severe illness. We examined the relationship between HFNC use during bronchiolitis hospitalization and the subsequent hazard of asthma diagnosis in early childhood. METHODS We conducted a retrospective cohort study of 4736 children aged younger than 2 years hospitalized with bronchiolitis from 2015 to 2023 across 2 tertiary children’s hospitals. Children were stratified by HFNC exposure. Cox proportional hazards models evaluated the association between HFNC use and subsequent asthma diagnosis. Secondary analyses assessed HFNC duration and frequency. RESULTS Forty-three percent of children received HFNC. Asthma was subsequently diagnosed in 37% of HFNC-treated children and 22% of non-HFNC children (P < .001). After adjustment for demographic and clinical variables, HFNC use was associated with a 40% increased hazard of subsequent asthma diagnosis (hazard ratio, 1.40; 95% CI, 1.24–1.57; P < .001). No dose-response pattern was observed by HFNC duration or frequency. CONCLUSION HFNC use was associated with an increased hazard of subsequent diagnosis of asthma in childhood, likely reflecting underlying disease severity rather than a treatment-related effect. Prospective studies are needed to differentiate severity-related risk from treatment-associated factors to optimize respiratory support strategies for infants with bronchiolitis.

ABSTRACT Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Abstract Background Colony stimulating factor 1 receptor–related disorder (CSF1R‐RD) is a rare, rapidly progressive neurodegenerative disease with significant clinical heterogeneity. Apolipoprotein E (ApoE) polymorphism, known to modulate microglial function and influence neurodegeneration, may act as a genetic modifier in CSF1R‐RD. Objectives The objectives were to evaluate the distribution of ApoE alleles in CSF1R‐RD and assess their association with clinical and neuropathological features. Methods ApoE genotyping was performed in 55 individuals with CSF1R‐RD. Clinical data from 25 deceased patients were analyzed based on ApoE genotype. Neuropathological evaluation was conducted on brain tissue from 14 patients, with semiquantitative scoring of white matter pathology and microglial burden. Statistical comparisons were made between carriers and noncarriers of the ApoE4 allele. Results ApoE allele frequencies in CSF1R‐RD mirrored those of the general population (ε2: 7.3%, ε3: 79.1%, ε4: 13.6%). However, ApoE4 carriers exhibited significantly earlier symptom onset (median: 37.9 vs. 50.3 years, p = 0.0123) and death (median: 41.1 vs. 55.2 years, p = 0.0072). Neuropathological analysis revealed more severe white matter involvement and reduced microglial preservation in ApoE4 carriers ( p = 0.034). Conclusions Although ApoE allele distribution does not differ from the general population, the presence of the ApoE4 allele may influence the clinical trajectory and white matter pathology in CSF1R‐RD. These findings suggest that ApoE polymorphism is a potential modifier of disease course and should be considered in therapeutic planning and future research. © 2026 International Parkinson and Movement Disorder Society.