Citations

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis. Barrett's esophagus (BE) is a critical precursor of EAC. Patients with BE undergo endoscopic surveillance to monitor disease progression although only a small fraction develop EAC. These procedures are invasive and have limited accuracy in predicting BE progression. We evaluated the utility of an 8-protein mass spectrometry panel in predicting progression in patients with BE. METHODS: Eighty untreated controls and 20 cases were selected from our institutional tissue registry. Quantitative mass-spectrometry was performed on microdissected tissue sections. Data were split into 80% training and 20% test sets. We used Least Absolute Shrinkage and Selection Operator-regularized regression to train a logistic classifier on training data. Classifier performance was evaluated in test data. RESULTS: Ninety-two samples had sufficient tissue for mass spectrometry analysis (18 progressors, 74 nonprogressors). The multivariable regression model produced a sensitivity of 100% and a specificity of 39% in the overall cohort, with AUCs of 0.75 and 0.89 in the overall and test cohorts, respectively. Cox proportional hazards time-to-progression (TTP) showed a hazard ratio of 66.1 (95% CI 7.79–561, P = 0.00012) for the model prediction. DISCUSSION: The promising performance of the model generated here suggests that the test may aid in selecting patients most likely to benefit from active BE surveillance. Moreover, the association of this model's prediction with time-to-progression may offer decision support for management of patients likely to progress quickly. These results support continued development of this proteomic panel as a risk stratification tool for patients with BE.

BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

Abstract Disclosure: A.A. Khan: Alexion Pharmaceuticals, Inc., Amgen Inc, Amolyt Pharma, Ascendis Pharma. B.L. Clarke: Amolyt Pharma, Ascendis Pharma, EnteraBio, Extend Bio, Takeda. M.R. Rubin: Ascendis Pharma, MBX Biosciences. P.E. Schwarz: Aventis Pharmaceuticals, Genmab, Novo Nordisk. D.M. Shoback: Ascendis Pharma. C. Gagnon: Amgen Inc, Ascendis Pharma, Novo Nordisk, Shire, Takeda. A. Palermo: None. L.G. Abbott: Abbott Laboratories, Ascendis Pharma, Clarus, Shire, Takeda. L. Kohlmeier: Amgen Inc, Ascendis Pharma, Radius Health, Inc. E. Tsourdi: Alexion Pharmaceuticals, Inc., Ascendis Pharma, Kyowa Kirin, Takeda, UCB. F. Cetani: None. R. Jain: Amgen Inc, Ascendis Pharma. C. Zhao: Ascendis Pharma. B. Lai: Ascendis Pharma. M.A. Makara: Ascendis Pharma. J. Ukena: Ascendis Pharma. C.T. Sibley: Ascendis Pharma. A.D. Shu: Ascendis Pharma. L. Rejnmark: Amolyt Pharma, Ascendis Pharma, BridgeBio, Kyowa Kirin, Takeda. Background: Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (PTH) and is associated with reduced quality of life and a high comorbidity burden. Conventional therapy for hypoparathyroidism (active vitamin D and elemental calcium) aims to alleviate hypocalcemia but does not address insufficient PTH and may increase the risk of renal complications. Palopegteriparatide is a prodrug of PTH(1-34), administered subcutaneously once daily, designed to provide active PTH within the physiological range for 24 hours/day. It is approved by the Food and Drug Administration, European Commission, and Medicines and Healthcare products Regulatory Agency. This analysis evaluated the long-term efficacy and safety of palopegteriparatide in adults with chronic hypoparathyroidism through week 156 of the PaTHway trial. Methods: PaTHway is a phase 3 trial with a 26-week randomized, double-blind, placebo-controlled period followed by an ongoing open-label extension period. Serum biochemistries were assessed at baseline and regular intervals. Renal function was assessed by estimated glomerular filtration rate (eGFR). Safety assessments included 24-hour urine calcium and treatment-emergent adverse events (TEAEs). Results: At week 156, 89% (73/82) of participants remained in the trial; of those, 96% were independent from conventional therapy (no active vitamin D and ≤600 mg/day elemental calcium) and 88% had normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL) with a mean (SD) of 8.9 (0.6) mg/dL. Mean (SD) serum phosphate (3.4 [0.6] mg/dL) and calcium x phosphate product (30.6 [5.4] mg2/dL2) levels remained within normal ranges through week 156. Mean (SD) eGFR at week 156 was 78.0 (14.5) mL/min/1.73 m2, reflecting a mean (SD) increase of 8.8 (11.9) mL/min/1.73 m2 from baseline (P&lt;0.0001); 59% and 43% of participants had an increase in eGFR of ≥5 mL/min/1.73 m2 and ≥10 mL/min/1.73 m2, respectively. Among participants with baseline eGFR &lt;60 mL/min/1.73 m2 (n=23), the mean (SD) increase in eGFR was 14.0 (8.9) mL/min/1.73 m2 from baseline to week 156. Mean (SD) 24-hour urine calcium levels normalized with palopegteriparatide treatment, remaining below the upper limit of normal (≤250 mg/day) through week 156 (162.1 [117.8] mg/day). TEAEs were mostly grade 1 or 2, with no new safety signals identified. Conclusion: Through year 3 of the PaTHway trial, retention rate was high and palopegteriparatide demonstrated consistent longer-term safety and efficacy, which included the maintenance of serum and urine biochemistries within normal levels and sustained improvement in renal function. Presentation: Saturday, July 12, 2025

INTRODUCTION: We conducted a retrospective cohort study comparing the safety of advanced therapies in patients with ulcerative colitis (UC). METHODS: Using an administrative claims database (OptumLabs Data Warehouse), we identified patients with UC who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents, anti-interleukin, Janus kinase inhibitors (JAK), or sphingosine-1 phosphate receptor modulators between 2016 and 2022 and had followed up for at least 1 year before and after treatment initiation. We compared the risk of serious infections, venous thromboembolism, and major adverse cardiovascular events through multinomial propensity score-based inverse probability weighting, with propensity scores estimated through generalized boosted models that accounted for disease characteristics, healthcare utilization, comorbidities, and previous and concomitant medications, and the competing risk of mortality. We calculated cause-specific hazard ratios (HR) and 95% confidence intervals for multiple treatment comparisons. RESULTS: We included 9,430 patients with UC treated with TNF antagonists (n = 4,111), anti-integrins (n = 3,165), anti-ILs (n = 1,342), JAK inhibitors (n = 701), or sphingosine-1 phosphate receptor modulators (n = 111), followed over median 27 months. After adjusting for confounding variables, anti-ILs were associated with a lower risk of serious infections compared with TNF antagonists (HR, 0.66 [95% confidence interval, 0.51–0.87]) and anti-integrins (HR, 0.75 [0.57–0.98]). JAK inhibitors were associated with a lower risk of serious infections compared with TNF antagonists (HR, 0.66 [0.46–0.94]). The incidence of venous thromboembolism (incidence rate, 1.4–2.0 per 100 py) and major adverse cardiovascular event (0.5–1.0 per 100 py) was very low, without any significant differences across agents. DISCUSSION: In a real-world cohort of patients with UC, anti-ILs and JAK inhibitors were associated with a lower risk of serious infections and may offer net benefit, especially in patients with previous TNF antagonist exposure.

Adolescents and young adults (AYA; ages 15–39) with acute leukemia have significant unmet supportive care needs. This pilot study integrated same-day palliative care (PC) into an AYA leukemia clinic, measuring symptom burden (SB) with validated symptom assessment tools at baseline, 3, and 6 months. Among 31 patients, moderate-severe symptoms included tiredness, anxiety, and poor appetite. AYAs experienced high SB and psychological distress, regardless of care phase or sociodemographics. With PC integration, tiredness and depression improved significantly; no symptoms worsened. Half of the PC visits led to management changes. Early integration of symptom-focused PC was feasible, value-adding, and well-received by patients.

Abstract As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau‐targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau‐targeting therapeutics, and interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials.

Stereotactic radiosurgery was associated with a higher obliteration rate compared with embolization in patients with eloquent brain arteriovenous malformations, whereas there was no evidence of a difference in functional outcomes or complications after adjustment.

ABSTRACT Femoroacetabular impingement (FAI) of the hip results from altered morphology of the proximal femur and/or acetabulum, creating abnormal contact between these structures during normal hip range of motion. The etiology of this structural phenotype is unknown. This study aimed to identify common single‐nucleotide variants (SNVs) among two families with seemingly heritable FAI. Additionally, this study examined biologic networks among proteins encoded by identified SNVs and surveyed the literature regarding the role of these proteins in musculoskeletal development. Methodologically, blood samples were collected from affected and unaffected members of two separate families with a pattern of heritable FAI. Exome sequencing identified SNVs, and a protein–protein interaction network assessment, in addition to a literature review, was performed to better understand the role of variant‐associated genes in musculoskeletal development. Results showed 33 and 43 variant‐associated genes affected in Family 1 and Family 2, respectively. Although no overlap in variant‐associated genes was found between families, network analysis showed that variant‐associated genes are functionally interconnected and are known to interact with each other. Furthermore, the variant‐associated genes are broadly associated with musculoskeletal development. Ultimately, genetic analysis of two families of multiple generations of FAI revealed variations in genes regulating musculoskeletal development, with several being critical local regulators of bone morphogenesis.