Citations

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Aptamers are short single-stranded DNA or RNA ligands that fold into defined three-dimensional structures and bind targets with antibody-like affinity and specificity, yet retain key advantages for central nervous system (CNS) applications including chemical synthesis, low immunogenicity, thermal stability, and facile modular engineering. This review summarizes recent advances positioning aptamers as “theranostic” platforms for CNS disorders, spanning discovery, optimization, delivery, and integrated sensing. We highlight the evolution of selection technologies from classical protein-‘Systematic Evolution of Ligands by Exponential Enrichment’ (SELEX) to Cell-SELEX and in vivo SELEX, now increasingly coupled with high-throughput sequencing, bioinformatics, molecular docking/molecular dynamics, and emerging artificial intelligence/machine learning (AI/ML) approaches that learn sequence–structure–function relationships and accelerate candidate prioritization and de novo design. We discuss chemical strategies that address nuclease degradation and rapid renal clearance, while noting trade-offs between stability and folding-dependent affinity. Since blood–brain barrier (BBB) transport remains the dominant translational barrier, we evaluate non-invasive intranasal delivery, receptor-mediated transcytosis via endothelial shuttles, intrathecal administration, and vector-enabled intracellular expression for sustained neuroimmune modulation. Finally, we discuss multifunctional conjugates and carriers and CNS-focused aptamer-based sensors for neurotransmitters and misfolded proteins, alongside multiplexed aptamer proteomics for biomarker discovery and monitoring. Collectively, converging advances in selection, computation, chemistry, and delivery are enabling aptamer-based closed-loop theranostics tailored to CNS disease biology.

ABSTRACT Pulmonary arterial hypertension (PAH) is associated with significant symptoms and impaired health‐related quality of life (HRQOL) and survival. Specialty palliative care (SPC), an intervention delivered by a multidisciplinary team, is focused on improving HRQOL. We performed a randomized controlled trial (RCT) of SPC among adults with PAH and impaired HRQOL to determine the impact of SPC on HRQOL as assessed by PAH‐SYMPACT. PAH‐SYMPACT is a validated PAH disease‐specific patient‐reported outcome measure that assesses HRQOL across four domains: cardiopulmonary symptoms, cardiovascular symptoms, physical impact, and cognitive/emotional impact. Sixty‐two patients were included (36 usual care, 26 SPC plus usual care), but only 58% of patients randomized to SPC completed their SPC visits. In the intention‐to‐treat analysis, SPC was associated with similar changes in total, symptom, and physical impact domain scores and increased cognitive/emotional impact scores, indicative of worse HRQOL. In the per‐protocol analysis, SPC was not associated with significant changes in total or individual domain scores. According to a survey of patients who completed SPC visits, most were satisfied with their visit and were likely to recommend SPC for other patients with PAH. In conclusion, limited SPC visits in this single‐center RCT were not associated with significant improvements in HRQOL among patients with PAH and impaired HRQOL, but the majority of patients who participated in a SPC intervention were satisfied and would recommend SPC to other PAH patients. Future studies of SPC in PAH are needed to determine the appropriate patient selection and timing for SPC. www.clinicaltrials.gov (NCT03905421).

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract INTRODUCTION Research into cognitive dispersion – a cognitive process score measuring the intra‐individual variability (IIV) across a single testing session – suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early‐onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition. METHODS A total of 309 participants (188 amyloid‐positive EOAD, 43 amyloid‐negative early‐onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion‐related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain‐specific cognitive trajectories, and its convergence with imaging biomarkers. RESULTS EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD‐specific biomarkers. Additionally, cognitive dispersion was associated with 12‐month reliable change across several cognitive domains. DISCUSSION These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.

Objective: To compare disease-specific quality of life (QOL) among patients with sporadic vestibular schwannoma (VS) by tumor management strategy using the recently developed and validated Mayo Clinic VSQOL Index relative to established minimal important difference (MID) thresholds. Study design: Cross-sectional cohort. Setting: Acoustic Neuroma Association and tertiary care center. Patients: Adults with sporadic VS. Interventions: Microsurgery, radiation, or observation. Main outcome measures: VSQOL Index scores were compared by tumor management strategy adjusting for age, sex, setting, tumor size at diagnosis, and duration of follow-up. Scores range from 0 to 100; higher scores indicate better QOL. Results: Of the 652 patients included, 333 (51%) were managed with microsurgery, 175 (27%) with radiation, and 144 (22%) with observation. The mean (SD) duration of follow-up was 6.2 (2.7) years. Global QOL adjusted mean scores (95% CI) differed significantly ( P <0.001) by management group: 70 (67-72) for microsurgery, 73 (70-77) for radiation, and 79 (75-83) for observation. Hearing Problems ( P <0.001), Dizziness and Imbalance ( P <0.001), Problems with Face or Eyes ( P <0.001), and Difficulty with Thinking and Memory ( P =0.03) domain scores also differed significantly by group. Pairwise comparisons that exceeded at least the lower bound of published MIDs included Global QOL scores (microsurgery versus observation) and Hearing Problems scores (microsurgery and radiation versus observation). Conclusions: At a mean follow-up of 6.2 years, several notable statistically and clinically significant differences in QOL were identified. These findings may be used to guide patient counseling regarding management options and require validation in future prospective studies.

Abstract Introduction Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy through enhancing T-cell-mediated immune responses but have also been associated with immune-related adverse events. Emerging literature suggests a potential association between ICI therapy and the development or reactivation of tuberculous mycobacterial infections. It is unclear whether ICI therapy is also linked to an increased risk of non-tuberculous mycobacterial (NTM) infections, though case reports are rapidly accumulating. We aim to better elucidate the potential association between ICIs and NTM infections through a case series. Case Series This series includes patients at Mayo Clinic who were diagnosed with active NTM infection during or after ICI use from January 1, 2012 to December 31, 2024. Data including demographics, malignancy details, ICI regimen and duration, timing and site of NTM infection, microbiologic findings, antimycobacterial therapy, and clinical outcomes were evaluated. There were seven patients with positive testing for NTM during or after ICI therapy. Two had one colony of M. gordonae on cultures which were determined by Infectious Disease to be contaminants. One case had a reported culture positive for M. franklinii at an outside hospital without further details available and thus was excluded from analysis. Chart review was performed for the remaining four patients with active NTM infection during or after ICI therapy. Two of the patients had underlying chronic obstructive pulmonary disease with a smoking history; these same two had primary lung malignancy. The other two patients had no known underlying lung disease or malignancy lung involvement (primary or metastatic). ICI therapies included PD-1, PD-L1, and CTLA-4 inhibitors. All four NTM infections predominant had lung involvement and were all different species; two were diagnosed while the patient was actively receiving ICI therapy and two were diagnosed several months after ICI discontinuation. Of the two receiving ICI therapy at the time of diagnosis, the ICI was held for 101 days for one patient and the other continued the ICI without interruption. Three received multi-agent therapy while the fourth declined treatment and died of malignancy complications soon after. The other three were alive at one year after NTM diagnosis and completed approximately one year of antimycobacterial therapy. Conclusions Tuberculous and non-tuberculous mycobacterial infections are increasingly seen after immune checkpoint inhibitor therapy. We present a series of four cases of NTM infections after or during ICI therapy for various types of malignancy with good outcomes after approximately one year of treatment. This abstract is funded by: None

ABSTRACT Aims We aimed to examine the association between GLP‐1 RA use and suicidal ideation or behaviours through a systematic review of observational studies. Materials and Methods A comprehensive search of MEDLINE, PubMed, EMBASE, CINAHL and PsycINFO was conducted from database inception through December 11, 2025. Observational studies investigating suicidal ideation, suicide attempts or complete suicide among adults using GLP‐1 RAs were included. Eligibility screening, data extraction and risk of bias assessments were performed independently and in duplicate, with disagreements resolved by a third reviewer. Results Forty‐three studies were included. Findings varied by study design. Some case reports suggested a temporal relationship between GLP‐1 RA use and suicidal ideation. Cross‐sectional studies and case–control studies identified a negative association between GLP‐1 RAs and suicide attempts. Pharmacovigilance and cohort studies showed more mixed results, with some studies identifying a positive association between semaglutide or liraglutide and suicidal ideation, while others paradoxically reported a negative association with suicidal behaviours (i.e., attempts and intentional self‐harm) or completed suicide. Conclusions While evidence does not support GLP ‐1 RAs as a causative agent for suicidality, due to multiple risk factors in this population, clinicians should routinely assess mental health status before and during GLP ‐1 RA treatment regardless of indication. Importantly, a history of concurrent mental health conditions should not preclude use of a GLP ‐1 RA ; rather, individual patient factors should be accounted for when making prescribing decisions.

Abstract Purpose This analysis aims to provide a comprehensive overview of lung transplantation trends in the United States from January 1, 1988, through January 31, 2025. By examining key variables such as recipient ABO blood group, donor type (deceased or living), demographic factors, and geographic distribution, the goal is to highlight the evolution and current state of lung transplantation practices. Methods Data were obtained from the Organ Procurement and Transplantation Network (OPTN), encompassing all reported lung transplants during the specified time period. Relevant metrics included the number of transplants per year, recipient characteristics (blood type, race/ethnicity, gender, and age), donor type (deceased versus living), and state-level transplant volumes. Simple descriptive statistics (e.g., frequencies and percentages) were used to identify trends and capture the distribution of transplants among different demographic groups and geographic regions. Results A total of 55,435 lung transplants were performed in the United States between 1988 and early 2025. The vast majority (over 99%) utilized deceased donors, underscoring the limited role of living-donor lobar transplantation, with only 253 procedures reported nationally. Among recipients, ABO blood group O was the most common (∼45%), followed by group A (∼40%), group B (∼11%), and group AB (∼4%). Male recipients represented approximately 57% of transplants, while females accounted for 43%. Regarding race/ethnicity, White non-Hispanic patients constituted roughly 80% of all recipients, with Black non-Hispanic (8%) and Hispanic/Latino (8%) recipients forming smaller but significant proportions. Age distribution data revealed that individuals aged 50 to 64 years received nearly half of all lung transplants, and those over 65 years composed about a quarter of total recipients, reflecting a gradual shift in acceptance criteria favoring older adults. Geographically, California reported the highest volume of lung transplants, attributable to its large population and multiple high-volume transplant centers, while other states such as Florida, Ohio, North Carolina, and Missouri also demonstrated notable activity. Conclusion Lung transplantation in the United States has witnessed substantial expansion in both volume and scope since 1988, with the majority of procedures involving deceased donor lungs. A small number of living-donor lung transplants, while demonstrating innovative clinical possibilities, remains limited. The demographic profile of recipients continues to shift, evidenced by a growing proportion of older adults and a predominance of ABO type O and White, non-Hispanic recipients. Despite these advancements, persistent gaps in access, particularly among underrepresented racial and ethnic groups, highlight the need for further refinement in organ allocation policies and broader support services. This abstract is funded by: None

Abstract Rationale In the early post-lung transplant period, close surveillance is essential to detect allograft dysfunction, infection, or medication toxicity. This requires frequent in-person clinic visits and laboratory testing, creating substantial travel and time burdens for patients and caregivers. Remote patient monitoring (RPM), which uses devices to collect and transmit physiologic and symptom data to the care team, has the potential to reduce geographic barriers and enable earlier detection of changes in patient status. Understanding the feasibility, adherence, and clinical impact of RPM is essential before broader implementation. Methods The Chronic Lung Allograft Monitoring (CLAM) program was launched in August 2024 at our center. Participants were provided a tablet and devices (spirometer, pulse oximeter, scale, and blood pressure cuff) to submit daily physiologic and symptom data. Abnormal parameters triggered review by RPM nurses and escalation to transplant physicians according to protocol. After 12 months of monitoring, patients were transitioned to self-monitoring when clinically appropriate. Demographics, compliance, and escalation characteristics were summarized descriptively. An escalation was defined as any entry triggering an alert to the transplant team. Escalations were categorized by cause and reviewed to determine clinical impact. Results Among 105 enrolled patients, the median age was 64 (IQR 58-68) years, 66 (63%) were male. 70 (67%) remain enrolled, 22 (21%) graduated, and 13 (12%) discontinued monitoring prematurely. reasons for discontinuation included death (n = 7; 7%), patient preference (n = 3; 3%), and non-adherence (n = 3; 3%), yielding an overall dropout rate of 5.7%. Completion rates were 64% for vital sign and spirometry submissions and 91% for symptom questionnaires.There were 395 escalations, with a median of 3 per patient (IQR 1-6); 82 patients (78%) experienced at least one escalation. Causes of escalations are summarized in Figure 1. Of all escalations, 282 (71%) were managed with continued monitoring, while 113 (29%) resulted in changes in care. Seven escalations (1.8%) led to emergency department evaluation and 2 (0.5%) resulted in direct hospital admission. Among non-emergent escalations, 35 (8.8%) prompted expedited clinic visits; of the remainder, 42 (10.6%) led to diagnostic testing orders and 32 (8.0%) resulted in medication initiation or adjustment. Conclusions RPM after lung transplantation was feasible, well accepted, and frequently informed clinical decision-making. The CLAM program demonstrates high engagement and clinical utility, supporting further prospective evaluation of RPM in lung transplant care. This abstract is funded by: None