Citations

3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .

1056 Background: Resistance to HER2-directed therapies remains a major challenge in HER2-positiveMBC. In preclinical models, HER2+ tumors overexpress poly (ADP-ribose) polymerase (PARP), and PARP inhibition induces apoptosis through NF-κB suppression even in the absence of pathogenic mutations in BRCA 1/2 . We evaluated the safety, efficacy, and translational correlates of niraparib combined with trastuzumab in patients (pts) with refractory HER2+ MBC. Methods: This open-label Phase 1b/2 trial (NCT03368729) enrolled pts with HER2+ MBC (IHC 3+ and/or FISH amplified), measurable disease, LVEF ≥50%, and progression on ≥1 prior HER2-targeted therapy; stable CNS disease was allowed. Pts with germline BRCA1/2 mutations or prior PARP inhibitor exposure were excluded. Niraparib 300 mg orally was administered on Days 1–21 of a 21-day cycle with trastuzumab 6 mg/kg IV every 3 weeks (loading dose 8 mg/kg on cycle 1). The Phase 2 portion used a Gehan/Simon two-stage design with early stopping for futility (P0=24%); ≥1 response among the first 20 patients triggered expansion to 40 patients. ORR was assessed by RECIST v1.1, meeting the primary endpoint and allowing response rate estimation with <7% standard error and a two-sided 95% exact CI width of 0.28. Gene expression profiling of paired tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed using the NanoString nCounter Tumor Signaling 360 panel at pretreatment compared to cycle 2. Results: Forty-six pts were enrolled (9/2019–2/2025); 41 were evaluable for response. Pts were heavily pretreated (median 3 prior regimens), including trastuzumab deruxtecan in 22 pts; 33% had brain metastases. Treatment-related adverse events were predominantly grade 1–2 and manageable. Clinical benefit rate (CBR) was 44% (18/41) including 1 complete response, 2 partial responses, and 15 stable disease. Eleven patients achieved disease control ≥ 6 months; 1 patient remained on treatment at data cutoff. Tumor profiling revealed enrichment of a B-cell–driven tertiary lymphoid structure signature with reduced hypoxia signaling in responders. Matched PBMC analyses demonstrated coordinated downregulation of interferon signaling, DNA damage response, metabolic activation, angiogenesis, and resistance pathways in clinical responders, whereas non-responders retained signatures of chronic stress and immune exhaustion. Conclusions: Niraparib plus trastuzumab demonstrated a favorable safety profile and durable clinical benefit in heavily pretreated HER2+ MBC. Integrated tumor and blood-based analyses identify immune-organized tumor microenvironments and systemic immune normalization as key correlates of prolonged response, supporting further investigation of PARP inhibition strategies. Clinical trial information: NCT03368729 .

Personas and patient journey maps are poised to improve human-centered care delivery, and technology design. However, they remain largely underutilized in healthcare settings globally. A persona composite and a journey map inspired by narratives of medical students managing illness in addition to the rigors of academia is presented. This scoping review illustrates how journey mapping and personas are used in healthcare contexts to frame the experiences of patients; formal and informal caregivers; nurses; and physicians. The heterogeneous findings reveal that despite their promise the utility of these tools is largely unexplored in health informatics.

Background Patients with substance use disorder (SUD) have high rates of hospitalization, readmission, and prolonged lengths of stay. Objectives To conduct a systematic review and meta-analysis of the impact of addiction consult services in the inpatient setting for patients with SUD. Methods Five databases were systematically searched from their earliest available records through January 2025. Two authors independently screened articles, extracted data, and assessed the quality of each study with the Newcastle-Ottawa Scale for observational studies and the Cochrane risk-of-bias tool for randomized clinical trials. Pooled odds ratios (ORs) with 95% CIs were calculated for dichotomous outcomes, and mean differences were calculated for continuous outcomes. Results The search retrieved 20 studies that met inclusion criteria. The intervention for all studies was an addiction medicine consult, but the definition of this consult varied. The meta-analysis did not detect statistically significant differences in hospital length of stay, hospital readmission, or emergency department visits at 1 year among patients who received the consult compared with those who did not; however, many of these outcomes were likely underpowered. However, addiction medicine consults significantly improved the odds of inpatient initiation of medication for SUD (OR, 7.30; 95% CI, 3.30-16.13; P <.001) and postdischarge SUD treatment linkage and adherence (OR, 3.31; 95% CI, 2.06-5.32; P <.001). Conclusion Inpatient addiction consult services are associated with increased inpatient initiation of medication for SUD treatment and postdischarge treatment linkage and adherence. No clear association was identified between the consult and readmissions, emergency department utilization, or length of stay.

Abstract Introduction Sedation is routinely administered to facilitate comfort and tolerance of life support for critically ill adults dependent on invasive mechanical ventilation. Isoflurane, a widely used anesthetic during surgery, has properties that may also benefit ICU patients requiring continuous sedation. However, efficacy as a sedative and safety in this population is not well established. Methods We conducted two identically designed multicenter randomized trials, INSPIRE ICU1 and INSPIRE ICU2, at hospitals across the US. Ventilator-dependent adults were randomly assigned in a 1.5:1 ratio to receive either inhaled isoflurane or intravenous propofol as the first-line sedative for up to 48 ± 6 hours, targeting a sedation depth between Richmond agitation-sedation scale (RASS) -1 (drowsy) to -4 (responsive only to physical stimuli). Isoflurane was administered via an anesthetic conserving device (Sedaconda ACD-S). In both arms, opioids were permitted at the lowest dose required to achieve freedom from pain. The primary outcome was the percentage of time at target sedation level, assessed as a noninferiority outcome with pre-specified margin of 15%. Secondary outcomes included opioid exposure, wake-up time after end of treatment, time to extubation, and proportion of time with spontaneous breathing effort. Results A total of 470 combined participants were included in the two trials. In each trial, 142 patients were randomly assigned to isoflurane and 93 to propofol. In INSPIRE ICU1, percentage of time within target sedation depth was 77.1 [53.2, 89.9] % with isoflurane and 80.9 [58.2, 96.4] % with propofol (difference -1.5 [-8.9, &gt;99] %; p &lt; 0.01 for noninferiority). In INSPIRE ICU2, percentage of time within target sedation depth was 72.6 [66.4, 78.9] % with isoflurane and 74.5 [67.5, 81.5] % with propofol (difference -1.9 [-9.4, &gt;99] %; p &lt; 0.01 for noninferiority). In both trials, patients assigned to isoflurane received significantly less opioid, measured as fentanyl equivalents, during the treatment period. In INSPIRE ICU2, participants receiving isoflurane were significantly likelier to exhibit spontaneous breathing efforts, but this finding was not replicated in INSPIRE ICU1. There were no significant differences in time to wake-up or time to extubation between groups in either trial. No episodes of malignant hyperthermia or propofol infusion syndrome were reported. Adverse events were comparable in type and frequency between groups. Conclusions In two US multicenter trials, isoflurane was noninferior to propofol for maintaining target sedation depth in adults undergoing invasive ventilation, and was associated with significantly lower opioid exposure. (NCT05327296, NCT05312385) This abstract is funded by: Sedana Medical

Abstract Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1 R132H , PIK3CA E545K , Cic KO , Fubp1 KO and Cdkn2a KO as the optimal combination (termed Oligo Cdkn2a ) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. Oligo Cdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. Oligo Cdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.

Objectives To compare patients’ perception of their degree of subglottic stenosis to their endoscopic exam findings, Clinical Dyspnea Questionnaire, and peak flow results. Study Design Prospective Multi-Institutional. Setting Tertiary Care Clinic. Methods A study of 50 patients comparing patients’ perception of their degree of subglottic stenosis to their endoscopic exam findings. All patients filled out a Clinical Dyspnea Questionnaire and a 10-point scale reflecting their perceived degree of stenosis in 10% intervals. Surgeons filled out the same scale based on measurements from the patients’ exam. Accuracy was defined as +/-1 on a 10-point scale. Pulmonary function testing, number of dilation procedures undergone, cause of stenosis, and demographic information were collected. Results Data complete for 49/50 patients. 48 (98%) were female, 47 (97.9%) Caucasian, 44 (89.8%) had idiopathic subglottic stenosis, and 28 (58.3%) had Grade I subglottic stenosis on the Cotton-Meyer scale. Spearman correlation coefficient was 0.67 indicating moderate correlation overall but 0.88, or high correlation, for those with normal Body Mass Index. Increased Dyspnea Index scores and higher Body Mass Index were correlated with decreased accuracy. Number of previous procedures was not correlated with accuracy. Higher Body Mass Index was correlated with increased dyspnea and lower peak flow volume. Conclusion Patients with normal Body Mass Index have strong predictive accuracy regarding their degree of subglottic stenosis. Better dyspnea scores were correlated with improved accuracy. There is no standard consensus on subglottic stenosis patient follow up. Prior studies have looked at using peak flow meters and validated questionnaires to monitor symptoms.

PURPOSE The Lynch syndrome (LS) genes, MLH1 , MSH2 , MSH6 , and PMS2 , are considered to be some of the highest-priority genes to be tested for population genomic screening, with the aim to prevent and detect cancers early in those with a higher risk for such diagnoses. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1 , MSH2 , MSH6 , or PMS2 in the general population to build evidence-based guidelines for population genomic screening METHODS This retrospective case-control study uses Helix Research Network data from 230,159 participants across nine US health systems. Variant interpretation was performed following the American College of Medical Genetics and Association for Molecular Pathology guidelines. Clinical diagnoses were identified from electronic health records and claims data for 11 cancer types associated with LS, including colorectal and endometrial cancers. RESULTS Individuals with pathogenic variants in MLH1 , MSH2 , and MSH6 showed substantial risk for LS-related cancers compared with those without pathogenic variants. Conversely, individuals with pathogenic variants in PMS2 had no increase in risk for all 11 LS-associated cancers with hazard ratio (HR) of 1.0 (95% CI, 0.6 to 1.8) compared with those without a pathogenic variant. There was a small increase in risk when restricting the analysis to colorectal cancer with an HR of 3.5 (1.7-7.4). This increase in colorectal cancer risk was predominantly observed after age 60 years, 10 years after US Preventive Services Task Force guidelines recommend starting colonoscopies for the average population. Up to age 60 years, 2.6% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, closer to the general population (0.7%) than those with MLH1 (37.3%), MSH2 (28.9%), or MSH6 (6.7%) pathogenic variants. For 100,000 individuals screened for PMS2 , 854 additional colonoscopies would be performed, which would prevent or detect early 3.2 colorectal cancers. CONCLUSION This analysis across nine health systems highlights the clinical phenotypes of PMS2 pathogenic germline variants in the entire population.

Purpose: To determine the clinical utility of the assessment of preoperative orbital compliance in predicting the amount of postoperative proptosis reduction in patients with stable-phase thyroid eye disease who undergo orbital fat decompression surgery. Methods: A retrospective chart review was conducted of stable-phase thyroid eye disease patients who underwent orbital fat decompression by a single surgeon. Orbital compliance was measured preoperatively as axial globe displacement (in millimeters) using a Hertel exophthalmometer. Displacement ≥2.5 mm was classified as high compliance and <2.5 mm as low compliance. Radiographic thyroid eye disease type, preoperative proptosis, and intraoperative fat volume removed were recorded. Linear regression analysis determined whether orbital compliance independently predicted postoperative proptosis reduction. Levene’s test assessed variability between groups. Results: Forty-six orbits from 24 patients were included, 15 orbits with low compliance and 31 with high orbital compliance. Patients with high orbital compliance had a mean postoperative proptosis reduction of 3.19 mm (range 0.5–6.0 mm) while patients with low orbital compliance had a mean proptosis reduction of 2.67 mm (range 2.0–3.5 mm). On average, higher preoperative orbital compliance led to 0.959 mm greater proptosis reduction compared with low orbital compliance, when accounting for radiographic thyroid eye disease type and volume of fat removed intraoperatively ( p = 0.048). Variability in proptosis reduction was higher among the high orbital compliance group ( p = 0.00085). Conclusions: Higher preoperative orbital compliance results in greater proptosis reduction. However, patients with high orbital compliance have greater variability in proptosis reduction, suggesting that surgical outcomes are less predictable among these patients.