Citations

Background Immune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs. Methods We carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6–8 weeks after ICI initiation. Findings were validated in two external cohorts. Results We identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8) , OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade ≥2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade ≥2 (OR 3.02; 95% CI 1.83 to 5.02; p<0.001), grade ≥3 (OR 3.59; 95% CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95% CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group. Conclusions Novel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

ABSTRACT Objectives This portion of the Geriatric Emergency Department (GED) Guidelines 2.0 focuses on delirium in the emergency department (ED). Methods A multidisciplinary group applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and develop recommendations related to older ED patients with possible delirium. Results The GED Guidelines 2.0 Delirium Work Group derived six evidence‐based recommendations for risk stratification, diagnosis, and brain imaging. To reduce universal screening, the Delirium Risk Score may be used to identify older adults at low risk for delirium, though the evidence certainty is very low. In adults over 65 admitted to ED observation units, Zucchelli's risk assessment tool (threshold ≥ 4) may stratify delirium risk, also with very low certainty. For adults over 75, the REDEEM Score may be used to identify low‐ or high‐risk individuals, again with very low certainty. For diagnosis, 4AT, bCAM, CAM‐ICU, mCAM, AMT‐4, or RASS may be used to rule delirium in or out, based on very low certainty. The Delirium Triage Screen (DTS) may be used to rule out, but not to rule in, delirium, also with very low certainty. For diagnostic imaging, there is very low certainty of evidence to recommend for or against obtaining a head CT as part of the evaluation for older ED patients with delirium. All recommendations are conditional, reflecting very low certainty of evidence due to the lack of high‐quality ED‐based studies and comparative effectiveness research. Conclusion Rigorous ED‐based research is needed to strengthen evidence and guide delirium care for older adults in geriatric emergency medicine.

ABSTRACT Background The impact of psychosocial health and socioeconomic status (SES) on long‐term lung transplant survival remains unclear. Methods We conducted a single‐center, retrospective 2:1 matched case‐control study of adult lung transplant recipients (1999–2019). Cases survived ≥6 years post‐transplant; controls survived <6 years. Matching was based on transplant year (±5 years) and indication. Psychosocial health and SES were assessed using the Psychosocial Assessment of Candidates for Transplant (PACT) score, Mayo Clinic Housing‐Based Socioeconomic Status (HOUSES) index, and Area Deprivation Index (ADI). Secondary covariates included insurance, marital status, employment, caregiver relationship, and proximity to the transplant center. Conditional logistic regression adjusted for age and gender was used. Results Among 189 patients (63 cases, 126 controls), PACT score, HOUSES index, and ADI were not significantly associated with long‐term survival. Patients with non‐family caregivers had lower odds of survival compared to those with a spouse or partner (OR = 0.16, p = 0.022). Regional residents had lower odds of long‐term survival compared to local recipients (OR = 0.55, p = 0.001). Conclusions Pre‐transplant psychosocial and SES measures were not significantly associated with long‐term survival. Caregiver relationships and geographic proximity may have a greater impact on outcomes, highlighting the importance of support systems and access to care.

Introduction Social media platforms, particularly X (formerly Twitter), play an influential role in professional networking and information dissemination. This study aimed to examine X usage trends among faculty in a single department of surgery at a large academic institution. Methods Faculty X accounts were analyzed from January to June 2022. Metrics such as follower count, number of accounts followed, and post (formerly: tweets) types (original/quoted reposts) were studied. Themes of posts were categorized as personal, promotional, educational, or related to academic events/conferences. Associations between faculty rank, division, gender, and post metrics were explored using Mann-Whitney U and Kruskal-Wallis tests. Results Of 133 faculty members, 53 (39.85%) had X accounts, with 3 excluded due to privacy settings. A total of 3476 posts were analyzed, averaging 0-34 posts/month per faculty. Categories included professional (63%, n = 2174), educational (19%, n = 653), and personal (13%, n = 436). No significant associations were found between faculty gender/division and posting rates. However, faculty rank correlated significantly with primary post categories ( P < 0.01). Associate professors, and professors posted more about academic events (2% and 1%) than instructors or assistant professors (1%). The most followed faculty actively promoted colleagues’ work through reposting. Conclusion Less than half the faculty in a single department of surgery engaged with X. Those active predominantly used it for promotion, followed by education and personal use. Adoption remains limited, highlighting opportunities for growth in utilizing X for academic dissemination.

Abstract Context Preclinical studies demonstrate that treatment with calcitriol attenuates skeletal complications in mice with X-linked hypophosphatemia (XLH). Objective This work aimed to assess serum markers of mineral metabolism, nephrocalcinosis, skeletal microarchitecture, growth, and evidence of rickets following calcitriol monotherapy in children and adults with XLH. Methods A 1-year, prospective, single-arm, open-label study was conducted comparing baseline and 12-month outcomes. Participants were recruited from outpatient endocrinology clinics in the United States. Data were collected in a research unit. Eligible participants were aged 4 years or older, not pregnant, with baseline 25-hydroxyvitamin D of 20 ng/mL or greater and normal serum calcium. Participants were treated with calcitriol, with dose based on serum and urinary calcium concentrations, for 1 year. The primary end points were change in serum phosphate and nephrocalcinosis (all participants) and rickets severity score (children). Secondary end points included changes in additional markers of mineral metabolism, skeletal microarchitecture parameters via high-resolution peripheral quantitative computed tomography (all participants), and height z-scores (children). Results Serum phosphate did not change over 12 months of optimized calcitriol treatment. Rickets improved in 2 of 4 children with open epiphyses; height z-scores were unchanged. Nephrocalcinosis scores remained stable. Adults had increased cortical thickness at the radius diaphysis (P = .012). Serum alkaline phosphatase decreased in children (P = .021) and parathyroid hormone trended lower both in children (P = .065) and adults (P = .063). Four participants developed mild hypercalcemia and 2 developed hypercalciuria that resolved with calcitriol titration. Conclusion Calcitriol monotherapy is safe and well-tolerated in XLH, with modest benefits on laboratory indices of mineral metabolism and rickets.

Abstract Disclosure: N.M. Singh Ospina: None. Y. Chen: None. F. Du: None. J.P. Brito: None. H. Shao: None. Q. Liu: None. R.G. McCoy: None. T. Jiao: None. Background: The levothyroxine dose for patients with hypothyroidism is highly correlated with weight. In patients with hypothyroidism, TSH measurements are used to assess the adequacy of levothyroxine dosing.Since type 2 diabetes (T2D) and obesity are two common comorbidities for patients with hypothyroidism, and the significant weight loss associated with Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) therapy, the initiation of GLP-1 RA on levothyroxine users may significant increase the need for levothyroxine dose reduction potentially requiring additional TSH tests to assure control. Objectives: To evaluate the timing and frequency of TSH testing within one year of initiation of GLP-1, or sodium-glucose co-transporter 2 (SGLT-2) inhibitors, in patients with T2D on levothyroxine treatment. Methods: We identified a cohort of T2D patients using 15% of Medicare fee-for-service claims data from 2005 to 2020. Cohort entry was defined by the initiation of GLP-1 or SGLT2. Patients needed to continuously receive the same dose of levothyroxine for &gt;6 months and have at least 1 TSH measurement before the index date. We excluded patients with hyperthyroidism, thyroid cancer, end-stage renal disease, HIV/AIDs, organ transplant, or who received medications that affect thyroid levels before the index date. The primary outcome was the timing and frequency of TSH testing within one year after GLP-1 RA initiation. Demographics, comorbidities, and medication use were balanced using 1:1 propensity score matching based on the index date. Results: After matching, no significant demographic differences were observed among the 2,107 patients in GLP-1 RA and SGLT-2 groups, respectively. Overall, 32.1%, 32.3%, and 35.6% were aged 65-70, 70-74, and over 75, with 69.3% female and 87.9% white. In the year before the index date, the average number of TSH tests was higher in the GLP-1 RA (1.16 ± 1.27) compared to the SGLT2 (1.07 ± 1.18, p-value: 0.001). In the year after the index date, the average number of TSH tests declined to 0.93 ± 1.18 for GLP-1 and 0.89 ± 1.13 for SGLT2 (p-value: 0.03). Most patients (48.6 vs. 49.5%) had no TSH tests, 41.3 vs. 40.6% had 1-2 tests, and 10.1 vs. 9.9% had more than 2 tests in the GLP-1 RA and SGLT-2 group, respectively. Fewer patients (32.3 vs. 33.6%) were tested within 0-6 months while the majority (67.7 vs. 66.5%) waited longer than 6 months. The relative risk of TSH testing between the GLP-1 RA group and the SGLT2 group was 1.03 (95% CI: 0.98 to 1.08) 1-year before the index date and 1.00 (95% CI: 0.94 to 1.06) 1-year after the index date. Conclusions: Despite the potential impact of GLP-1 RA on levothyroxine dosing, on average, half of patients did not receive a TSH test after treatment initiation. There were no significant differences in TSH testing patterns between GLP-1 and SGLT2 groups, with similar test frequencies and timing observed. Presentation: Saturday, July 12, 2025

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor characterized by invasive growth, genetic heterogeneity and resistance to therapy. Alterations in the epithelial growth factor receptor (EGFR) are frequently detected in GBM, including gene amplifications, mutations and exon deletions, exemplified by the expression of EGFR variant III (EGFRvIII). To target both wild-type and EGFRvIII, we generated the humanized antibody A10, which reacts with the 287-302 loop that is fully exposed on the extracellular domain of EGFRvIII and conditionally exposed on cells expressing gene-amplified EGFR. However, A10 showed little or no reactivity for cells expressing normal levels of wild type EGFR. We engrafted antibody fragments derived from A10 on to ARTEMIS® Cell Receptor Platform, which introduces two separate receptors into engineered T cells to provide activation and co-stimulatory signals. Specifically, the A10 antigen-binding fragment (Fab) was fused to the N-terminus of a γδTCR-signaling domains (A10-AbTCR) while the A10 single chain variable fragment (scFv) was fused to a costimulatory signaling receptor (A10-CSR). The resulting A10 ARTEMIS® T cells were cytotoxic for tumor cell lines displaying amplified or overexpressed EGFR and EGFRvIII. Further, glioblastoma PDXs were sensitive to A10 ARTEMIS® T cell killing. This prompted an in vivo evaluation in EGFR-driven cancers. GBM39 PDX tumors (expressing amplified EGFRvIII) were implanted into the brains of NSG mice. Mice received one or two infusions. Treatment with one infusion of A10 ARTEMIS® cells resulted in prolonged survival of tumor bearing mice with 40 % of mice were long-term survivors (74 days) compared to a median survival of 32 days (control) or 52 days (mock T-cells). For mice receiving two A10 ARTEMIS® T cell infusions, there was 100% survival of mice beyond 60 days, while all control and mock treated mice were dead by 28 days. Further, treatments of EGFR-amplified MDA-MB-468 tumors resulted in complete tumor regression with one treatment of A10 ARTEMIS® cells. Thus, this new format of A10 engineered T-cells appears to be a particularly promising for treating cancers with high levels of EGFR or EGFRvIII including GBM. Citation Format: Antonella Antignani, Danielle Burgenske, Guangyan Xiong, Hongbing Zhang, Cheng Liu, Jann Sarkaria, David FitzGerald. Engineered T-cells, targeting overexpressed EGFR and EGFRvIII, produce complete remissions in a PDX model of human glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B056.

Introduction The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer’s disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient’s trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. Thus, we aim to conduct a systematic review assessing the efficacy of palliative care screening in the ED by assessing inpatient length of stay as the primary outcome and quality of life, percentage of hospitalisation and cost of care as secondary outcomes. Methods This study will use Ovid MEDLINE, Embase, EBSCO CINAHL, Web of Science and Cochrane as databases. The study population comprises adults aged 60 years and older, with no focus on any specific clinical specialty or disease. Patients who have not received palliative care screening will serve as the comparator. Only studies with an applicable comparator will be considered. Studies published from 1 January 2000 to 1 July 2025 will be included. All articles will be reviewed independently and in duplicate, and every author will participate in the review, data abstraction and conflict resolution process. Ethics and dissemination Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO registration number CRD42024562389.

Abstract Background Sickle cell disease (SCD) is a hemoglobinopathy with limited treatment options. Genetic modification of the patient's own hematopoietic stem cells (HSCs) offers an avenue to curative therapy using the patient's own cells. Many challenges exist in collecting sufficient numbers of starting material for manufacturing, beginning with the pre‐mobilization optimization of the patient to the mobilization, collection, and post‐collection phases. Study Design and Methods A working group within the Cellular Therapy Subcommittee of the American Society for Apheresis Clinical Applications Committee describes the challenges associated with apheresis collection of the starting material for gene therapy (GT) product manufacturing for patients with SCD and discusses potential strategies for overcoming these challenges. Results and Discussion Patients must undergo automated red blood cell exchange (RCE) to lower hemoglobin S in a relatively short window of time before apheresis collection of HSCs. The risks and benefits of transfusion as well as the logistics of providing adequate and appropriate blood products must be considered. Limited agents are available for mobilization of HSCs into the peripheral blood for collection and the timing of administration is short. Each collection cycle consists of RCE followed by at least three mobilization and apheresis collection events in addition to collecting backup cells. More than one cycle is typically needed to collect enough cells for GT drug product manufacturing. Optimization of patient factors and apheresis instrument parameters leads to better collection yields. Early and frequent ongoing coordination with all stakeholders involved is critical to developing personalized treatment plans for patients.