Citations

Objectives: Cerebral hemodynamic impairment in patients with asymptomatic high-grade internal carotid artery (ICA) stenosis confers a risk of stroke and cognitive decline, but correlations between degree of stenosis and hemodynamic impairment are derived from small case series only. Using baseline data from 282 participants in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis – Hemodynamics (CREST-H) study, we hypothesized that degree of stenosis, measured by peak systolic velocity (PSV) and end diastolic velocity (EDV) in the ipsilateral ICA, would correlate with time-to-peak (TTP) delay using MR (n=275) or CT (n=7) perfusion scans, adjusting for demographic and cardiovascular risk variables. Methods: Using a 7-10MHz Doppler probe, ICA PSV and EDV were assessed. Doppler results were adjudicated centrally. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using sequential T2*-weighted time-sequence scanning (e.g. TR=1500, TE=25ms, flip angle=60deg, phase=128, slice thickness=5mm for GE 3T magnet). CTP was acquired with standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral MCA/ACA territories using OLEA software. Linear regression used TTP delay as the outcome variable and PSV and EDV as predictor variables, adjusting for covariates.The 282 with complete data for all variables were included in the analysis. Results: Among 392 CREST-H participants, 63% were men, 7% Black, 3% Hispanic, 33% with less than college education. Tables 1a/b show the regression results for PSV and EDV as main predictor variables. PSV and EDV on the index side significantly correlated with TTP delay (p=0.004, p=0.002 respectively). Neither PSV nor EDV on the non-index side correlated with TTP delay (p=0.49, p=0.82). Compared with moderate exercise, vigorous exercise correlated with lower TTP delay in both models (p=0.05. p=0.04). Compared with college graduates, those with HS education had longer TTP delays in both models (p=0.03. p=0.02). Conclusions: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher flow velocities correlated with greater TTP delays, suggesting an increasing hemodynamic impairment with greater degree of stenosis above 70%. Our findings have implications for management of asymptomatic carotid stenosis which are being tested in the CREST-H and CREST-2 studies. Exercise and education may independently impact cerebral hemodynamics.

BACKGROUND: Cerebral hemodynamic impairment in patients with asymptomatic high-grade (>70%) internal carotid artery (ICA) stenosis is associated with risk of stroke and cognitive decline, but correlations between the degree of stenosis and hemodynamic impairment are derived from small case series. Using baseline data from 242 participants in the CREST-H study (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics), we hypothesized that the degree of stenosis in the ICA would correlate with time-to-peak (TTP) delay in ipsilateral cerebral blood flow using MR/CT perfusion scans, adjusting for demographic and cardiovascular risk variables. METHODS: From all participants, ICAs were insonated using a 7 to 10 MHz probe for peak systolic velocity (PSV) and end diastolic velocity. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using standard sequential T2*-weighted perfusion imaging. CT perfusion used standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral hemispheres. In cross-sectional analysis, linear regression was used to model TTP delay as the outcome variable and PSV, end diastolic velocity, and PSV ICA/common carotid artery ratio on the index and nonindex side as primary predictor variables in 6 separate models, adjusting for covariates, followed by automated backward elimination model reduction. RESULTS: Among 392 CREST-H participants, the 242 with complete data for all variables were included in the regression analysis (age, 70±7.6; 62% M). End diastolic velocity on the index side correlated with TTP delay (β=0.003, P =0.005). PSV had a similar correlation but did not reach significance (β=0.001, P =0.099), nor did ICA/common carotid artery ratio (β=0.003, P =0.126). Nonindex side PSV, end diastolic velocity, and ICA/common carotid artery ratio showed no correlation with TTP delay ( P =0.268, P =0.495, P =0.380, respectively). Circle of Willis completeness did not correlate with TTP. CONCLUSIONS: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher end-diastolic flow velocities correlated with greater TTP delays, supporting a definition of hemodynamically significant stenosis. Our findings have implications for the management of asymptomatic carotid stenosis, which will be tested in the CREST-H study. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03121209.

Thalamic neuromodulation for drug-resistant epilepsy has evolved from ablative thalamotomy to network-guided deep-brain stimulation (DBS) and responsive neurostimulation (RNS). Currently, the only Food and Drug Administration-approved DBS target is the anterior thalamic nucleus, which provides substantial and durable seizure reduction, particularly in limbic and temporal epilepsies. There is growing evidence that the centromedian and pulvinar nuclei are implicated in generalized, multifocal, and posterior neocortical epilepsies. Advanced imaging, probabilistic atlases, and connectomics can be used to refine targeting; however, they are limited by patient specificity, acquisition burden, and interatlas variability. Thalamic stereoelectroencephalography may clarify potential neuromodulation target selection by characterizing ictal recruitment, network dynamics, and biomarkers. Although DBS and RNS each have unique benefits, no modality has demonstrated superior. Pediatric data are heterogeneous and scarcer, but seizure reduction and safety profiles are similar to adults. Further studies are needed to optimize neuromodulation target selection and programming paradigms.

ABSTRACT Background In the United States, metoclopramide is the only medication approved for gastroparesis. There is a need to reappraise the main considerations involved in the approval of pharmacological treatments of gastroparesis. Objectives and Methods We conducted a literature review to address issues that might impact the approval of medications for gastroparesis. We appraised the epidemiology, clinical presentations, variations in diagnostic tests, and their thresholds for identification of gastroparesis. Based on the review, we proposed trial designs for proof of efficacy and safety of novel medications for gastroparesis. Results Based on epidemiological studies, the age‐adjusted prevalence in US population is 152,005 for all categories (definite, probable and possible) of gastroparesis. The major symptoms of gastroparesis are nausea, vomiting, early satiety and postprandial fullness and may lead to hospitalisation or emergency department visits. It is essential to appraise gastric emptying with a solid meal over at least 3 h using scintigraphy or a stable isotope breath test. Diagnostic thresholds have been established for these diagnostic tests and at present, reproducibility, normative data, and coefficient of variation are well established for the 320‐kcal real egg solid meal. Based on published guidelines on clinical efficacy of medications used in gastroparesis, we propose targeting the gastroparesis symptom subscales, such as nausea and vomiting, with pharmacological agents specifically directed at their causative mechanisms rather than targeting the underlying dysmotility. Conclusion The evidence documented here justifies consideration of gastroparesis as an orphan disease, as well as an innovative approach to supplement the regulatory bodies' recommendations and guidance to industry. We propose treatment trials of 4‐weeks duration and considering the use of specific symptoms of gastroparesis as clinical endpoints based on a pharmaceutical agent's mechanism of action, rather than using a total gastroparesis symptom score. Such an approach would include evidence of safety and efficacy of new medications targeting gastroparesis subscales, and approval for marketing would be based on the symptoms specifically ameliorated in robust trials.

Abstract Background Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. Methods Lithium-heparin plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 IFCC guidance. Uniform and sex-specific 99th percentile URLs and nonparametric 95% CIs were determined in plasma and serum separately and combined. Results The final study population comprised 4147 participants (52.5% female) with a median (25th–75th percentiles) age of 48.0 (33.0–59.0) years; 45.8%, 47.9%, 5.2%, and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n = 8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16–23) ng/L for females and 32 (28–35) ng/L for males; the uniform 99th percentile URL was 27 (24–31) ng/L. URLs were comparable in plasma and serum samples. Conclusions This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used in a large, global, healthy reference population.

Abstract Background The accuracy and safety of generating medication orders by large language models (LLMs) must be demonstrated. Without standardization, performance evaluation is limited to time and resource-intensive clinician grading. This evaluation aimed to develop a standardized medication format that supports automated performance evaluation (MedMatch). Methods First, a survey of 40 medication prompts was given to clinicians to assess agreement in medication order communication. Second, a clinician panel developed a standardized medication format (MedMatch) for oral and intravenous medications. Third, a clinician-annotated dataset of medication prompts and standardized answers in the MedMatch format was developed for LLM testing. Finally, LLMs were retested with the same dataset, adjusted to exclude route information, to evaluate the appropriate categorization of medication route. Results The formal medication orders consistently showed low omission rates and high overlap for all entities, compared to the verbal and brief written communication types. Lexical overlap results demonstrated pattern norms amongst clinicians with entities appearing most commonly in positions 1-5 in the order of drug name, dose, unit, route, and frequency. In the second survey, the formal written group performed the highest with 78.3% of prompts considered appropriate as a computer-generated response. LLM accuracy on MedMatch order standardization was highest in oral solid (64.2-72.5%), intravenous intermittent (72.5-84.3%), and intravenous push (62.7-74.5%) categories. LLMs performed the worst at categorizing medication orders accurately into intravenous push (18-61%) and intravenous intermittent (51-100%) routes. Conclusions Standardized format for computer-based outputs may support automated performance analysis and enhance the clarity of medication communication.

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.

Abstract Background Large language models (LLMs) are increasingly used in medication-related tasks despite limited evidence supporting their accuracy and safety. LLMs are vulnerable to adversarial attacks and may confabulate in response to fabricated information in the prompt. Given the substantial risk of harm from medication errors, the purpose of this study was to establish a benchmark task to evaluate LLM performance in distinguishing fabricated from real medications. Methods Two datasets (brand and generic), each consisting of 250 medication lists were developed, each including 4-6 medications and one fabricated medication (specifically a Pokémon character), with complete dosing information provided. Six LLMs were evaluated (GPT-5-Chat, GPT-4o-mini, DrugGPT, Gemma-3-27B-IT, Llama-3.3-70B-Instruct, and Qwen3-32B). For each medication list, models were queried for dosing information and disease indication across three experimental conditions: standard decoding, standard decoding with mitigation prompting, and deterministic decoding (temperature = 0). Each experiment was performed in triplicate. Outputs were deemed confabulations if the LLM failed to recognize and reject the fabricated medication. The primary outcome was the rate of confabulations. Exact paired-permutation tests were used to compare confabulation rates across LLMs and prompting approaches. Results Confabulation rates under standard conditions ranged from 2.7% to 99.6%. DrugGPT demonstrated the lowest baseline confabulation rates (2.7-6.4%), whereas other models demonstrated substantially higher rates (47.2-99.6%). Mitigation prompting significantly reduced confabulation rates compared to standard and deterministic decoding across all tasks and datasets (p < 0.001): GPT-5-Chat achieved confabulation rates of 0% with mitigation prompting from baseline rates of 66.4-88.5%. Deterministic decoding did not substantially impact confabulation rates. Conclusions LLMs performing medication-related tasks are susceptible to confabulation in response to invalid or fabricated inputs, raising important safety concerns for clinical use. While mitigation prompting reduced confabulation rates, this study underscores the importance of robust safeguards when deploying LLMs in medication-related decision-making.

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