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Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a mainstay therapy for homologous recombination (HR)-deficient cancers; however, resistance remains a major clinical challenge. Previously, through a genome wide CRISPR screen, we identified ZNF251 haploinsufficiency as a novel driver of PARPi resistance. In BRCA1 -mutant ( BRCA1 mut ) cells, ZNF251 deficiency led to HR hyperactivation, conferring PARPi resistance that could be reversed by RAD51 inhibition. In this study, we further show that ZNF251 deficiency induces replication stress and a pseudo-senescence state, in which cells exhibit molecular and phenotypic markers of senescence while retaining proliferative capacity. Because senomorphic and senolytic therapies can target senescent cells, we tested whether these approaches could overcome PARPi resistance in ZNF251 -deficient breast cancer cells. Critically, targeting this senescence-like state with either senomorphic agents, such as cytokine inhibitors, or senolytic agents, such as BCL-2 and BCL-XL inhibitors, overcame PARPi resistance ex vivo and in vivo . Importantly, pseudo-senescence was also observed in other PARPi-resistant contexts driven by HR hyperactivation, including 53BP1 - and Shieldin -mutant cells, suggesting that it may represent a broader mechanism underlying PARPi resistance in breast cancer. Furthermore, in two olaparib-resistant, BRCA -mutant triple-negative breast cancer organoid models, treatment with DT2216, a BCL-XL–targeting PROTAC, sensitized both models to olaparib. Together, our work defines a novel pathway linking HR hyperactivation, replication stress, and pseudo-senescence, and positions both senomorphic and senolytic therapies as promising strategies to overcome PARPi resistance in BRCA1 mut breast cancer. Highlights ZNF251 deficiency drives PARP inhibitor resistance through HR hyperactivation, replication stress, and pseudo-senescence in BRCA1 -mutant breast cancer. Senomorphic and senolytic therapies overcome PARP inhibitor resistance in vitro , in vivo , and in patient-derived organoid models. Pseudo-senescence represents a shared vulnerability of HR-hyperactivated PARPi-resistant cancers and can be therapeutically targeted.

ABSTRACT Ciltacabtagene autoleucel (cilta‐cel) has demonstrated excellent efficacy and long‐term disease control in patients with relapsed/refractory multiple myeloma (RRMM). However, a proportion of patients experience early treatment failures. We investigated clinical factors associated with early progression or death (within 12 months) in patients with RRMM receiving standard‐of‐care cilta‐cel across the three Mayo clinic centers. Patients with a follow‐up of at least 12 months or progression or death within 12 months from infusion were included. Of the patients with early treatment failure ( n = 52), 69% had progressive disease and 31% had a non‐relapse mortality (NRM) event. In patients without early treatment failure ( n = 164), 13% of events were NRM. Among pretreatment factors, prior BCMA‐directed therapy, presence of extramedullary disease and a CAR‐HEMATOTOX score of ≥ 2 were independent predictors of early progression or death. The utilization of cilta‐cel in earlier lines of treatment (1–3 vs. 4 or more) demonstrated comparable PFS (12‐month PFS 73% vs. 77%, p = 0.94). Measurable residual disease positivity in the bone marrow at 3 months (11/197 patients) identified a small but high‐risk group with an increased risk of early treatment failure (OR 5.68; p = 0.012). Patients with less than a complete response on a FDG PET/CT at 3 months also had an increased risk of early treatment failure (OR 11.8; p < 0.0001). Our findings may help identify patients at high‐risk for early adverse outcomes despite receiving highly effective therapy, and support consideration of novel therapeutic strategies within a clinical trial setting.

7543 Background: Delayed neurotoxicity (DNT) after ciltacabtagene autoleucel (cilta-cel) is associated with severe morbidity and mortality occurring in 10-15% of patients. A high post-infusion peak absolute lymphocyte count (ALCpeak ≥3x10 9 /L; ALC hi ) is correlated with an increased risk of DNT (25-30%). We previously examined prophylactic dexamethasone (PPX DEX) administered for 3 days when ALC hi was reached and found no reduction in ALC expansion, DNT incidence or severity. Here, we report the use of prophylactic cyclophosphamide (PPX CTX) on ALC kinetics and DNT. Methods: We conducted a retrospective analysis of patients (pts) treated with cilta-cel at Mayo Clinic (09-12/2025; n =60). Pts with ALC hi received CTX 500 mg IV/PO once (n = 22). Outcomes and ALC kinetics including ALCpeak, ALC D28 (ALC D28 ), and area under the curve D1-D28 (ALC AUC ) were compared with PPX DEX cohort (12/2024-08/2025; n =50) and a historical cohort without PPX (04/2022-11/2024; n =116). Results: Pre-lymphodepletion (LD) demographics were similar across historical ALC hi , PPX DEX, and PPX CTX groups. Pre-LD CRP was higher in the historical ALC hi cohort; however, baseline ferritin, CRS, and ICANS, and disease burden did not differ significantly between groups. There were no statistically significant differences in time to ALCpeak or ALC kinetics among the 3 cohorts. Among pts with ALC < 3×10⁹/L treated during the PPX CTX study period, 2 developed cranial nerve palsy (IEC-CNP; 2/38, 5%). Both presented with unilateral facial nerve palsy and were treated with corticosteroids. One pt resolved symptoms by one month, while the second had persistent symptoms at 2 weeks and remains on follow-up. Among ALC hi patients in the PPX CTX cohort, DNT occurred in 4/22 pts (18%), including 1 case of IEC-CNP (5%) and 3 with parkinsonism (IEC-PKS, 14%). Within the PPX CTX cohort, baseline characteristics and post-infusion CRS or laboratory parameters did not differ between patients with and without DNT. Among patients who developed DNT, ALC kinetics were similar across PPX CTX, PPX DEX, and historical cohorts. PPX CTX was well tolerated, with 2 cases of grade 1 nausea reported. The incidence of DNT did not differ significantly between the PPX DEX (14/61, 23%) and PPX CTX (4/22, 18%) cohorts. However, DNT presentations in the PPX CTX cohort appeared milder and were responsive to treatment. Two of three patients (67%) presented with mild symptoms (one with dynamic dysphasia; second with flat affect) that responded to DEX. A third patient presented with typical parkinsonian features (hypomimia, bradykinesia, rigidity) and demonstrated clinical improvement following high-dose CTX. Conclusions: PPX CTX was well tolerated. While it did not significantly impact ALC expansion kinetics or DNT rates, first few cases of IEC-PKS suggest that the presentation may be milder and amenable to less toxic treatment. Larger cohorts are needed to refine optimal prophylactic strategies.

An exhalation delivery system for fluticasone (EDS-FLU) is designed to deposit drug into sinonasal regions above the inferior turbinate, particularly sinus drainage pathways not reached by standard nasal steroid sprays. We evaluated the efficacy and safety of EDS-FLU for chronic rhinosinusitis (CRS). We reviewed four independent randomized controlled trials derived from three published articles identified through searches of PubMed, Embase, SCOPUS, Google Scholar, Web of Science, and the Cochrane Library up to April 2024. Outcomes included 22-item Sinonasal Outcome Test (SNOT-22) scores, nasal symptom scores, nasal polyp scores, patient global impression of change (PGIC), responder and surgical indication rates, and adverse events. Compared with EDS-placebo, EDS-FLU produced greater reductions in nasal polyp scores and SNOT-22 scores over 6 months. At 3 months, nasal congestion, facial pain, rhinorrhea, and olfactory dysfunction improved more with EDS-FLU, and PGIC responder and complete response rates were higher at 3 and 6 months. EDS-FLU reduced surgical indication and increased overall responder rates at 3 months but not at 6 months. Epistaxis and nasal septal erosion or ulceration occurred more frequently with EDS-FLU, whereas rates of headache, nasal congestion, nasopharyngitis, and upper respiratory infection were similar between groups. EDS-FLU provides clinically meaningful improvements in subjective and objective outcomes in CRS but is associated with an increased risk of local nasal adverse events, warranting individualized risk-benefit assessment.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P &amp;lt; .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P &amp;lt; .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P &amp;lt; .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P &amp;lt; .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Background: Hepatocellular carcinoma (HCC) has a poor long-term prognosis due to high recurrence and cirrhosis-related mortality, even after potentially curative treatments such as liver transplantation (LT), surgical resection, or ablation. This study aimed to identify factors associated with ≥10-year survival in HCC patients. Methods: A retrospective cohort study was conducted among HCC patients diagnosed between 2004 and 2022 using the National Cancer Database. Multivariable Cox regression was used to identify predictors of overall survival, and logistic regression was used to identify predictors of ≥10-year survival. Results: Among 249,600 HCC patients, 177,585 (71.2%) died within 5 years, 8613 (3.5%) died at 5–10 years, 54,988 (22.0%) were alive with <10 years of follow-up, and 8219 (3.3%) survived ≥10 years. LT, resection, and ablation were performed in 6.6%, 9.3%, and 11% of patients, respectively. Compared with ablation as the reference group, LT [adjusted odds ratio (aOR) 11.96, 95% confidence interval (CI): 11.27–13.29] and resection (aOR: 2.83, 95% CI: 2.57–3.08) increased the odds of ≥10-year survival, while non-curative treatments reduced the odds compared with ablation (aOR: 0.50, 95% CI: 0.47–0.55). Cox regression results were consistent with the logistic model, confirming the association. Decision tree analysis confirmed LT as the dominant determinant of long-term survival. Black individuals were associated with lower odds of ≥10-year survival (aOR: 0.88, 95% CI: 0.820–0.96) and decreased likelihood of receiving LT (aOR: 0.73, 95% CI: 0.55–0.96). Conclusions: LT offers the best chance of ≥10-year survival in HCC. Ensuring equitable access is essential, especially for Black patients who have lower transplant rates and worse outcomes.