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Abstract Background: Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain challenging to treat, particularly in older patients and those with a T-cell phenotype. Venetoclax (VEN), a selective BCL-2 inhibitor, has shown preclinical synergy with vincristine (VCR) in multiple preclinical ALL models. Following the previously reported establishment of the recommended Phase II dose (RP2D), we now report the results of the Phase II (Ph2) portion of EA9152 (VEN 600 mg daily with weekly L-VCR 2.25 mg/m² IV or VCR 1.5 mg/m2 IV capped at 2 mg), evaluating efficacy and safety in this high-risk population. Methods: This open-label, multicenter Phase II study enrolled adults (≥18 years) with R/R B- or T-cell ALL or LL. The phase II portion of this trial was a single-arm, open-label study evaluating the combination of VEN (600 mg po D1–28) with either L-VCR (2.25 mg/m² IV weekly x4) or vincristine sulfate (VCR) (1.4 mg/m² IV weekly x4). Following the market withdrawal of L-VCR in the United States in April 2022, no new patients were initiated on this formulation and patients already receiving L-VCR were transitioned to VCR at the start of their next treatment cycle or sooner if necessitated by drug availability. Prior VCR but not VEN exposure was permitted in Ph2. The primary endpoint was achievement of a complete response or complete response with incomplete count recovery CR + CRi rate by end of cycle 3. Secondary endpoints included measurable residual disease (MRD) response, progression free survival (PFS), overall survival (OS), and safety. The association of phenotype with response and time-to-event were evaluated using Fisher's exact test and the Cox proportional hazards model, respectively. Results: Twenty-one eligible patients were treated (B-cell ALL/LL: n=12; T-cell ALL/LL: n=9). The trial was terminated early after 22/56 patients were accrued on account of withdrawal of sponsor support. Median age was 50 years and 76.2% were male. Performance status was 0–1 in 85.7%. All patients had received prior chemotherapy; 47.6% had undergone prior transplant. Median number of treatment cycles was 1 (2 for B-cell, 1 for T-cell). By end of cycle 3, no patients in the B-cell cohort (0/12; 90% CI, 0.00–0.22) achieved CR or CRi, 8 had stable disease (SD). In the T-cell cohort, 1 of 9 patients (11.1%; 90% CI, 0.01–0.43) achieved CR, 1 achieved PR and 1 had SD. There was no statistically significant difference in CR + CRi rate between phenotypes (p=0.43). None of the patients achieved an MRD-negative CR/CRi by flow cytometry or molecular methods. At the time of this analysis, 16 of 21 patients had died. Median overall survival (OS) was 4.3 months (95% CI, 1.5–22.0) for B-cell and 10.2 months (95% CI, 2.0–16.4) for T-cell patients (HR 1.32, p=0.60). Median PFS was 2.9 months (95% CI, 1.7–3.7) for B-cell and 1.2 months (95% CI, 0.7–4.6) for T-cell cohorts (HR 2.18, p=0.18). Grade 3–5 treatment-related adverse events occurred in most patients. One T-cell patient experienced grade 5 respiratory failure. Among 16 patients enrolled under the revised protocol using VCR, only 1 experienced grade 3 peripheral motor neuropathy, and no peripheral sensory neuropathy was reported (combined AE rate 0.06; 90% CI, 0.00–0.26). Tumor lysis syndrome was not observed in this cohort. Conclusions: The combination of VEN at the established RP2D and L-VCR/VCR was feasible and had an acceptable safety profile in heavily pretreated patients with R/R ALL/LL. However, response rates, including CR/CRi and MRD negativity, were limited, particularly in the B-cell cohort. Median OS and PFS remain poor in both subtypes, highlighting the need for improved strategies in this high-risk population. Venetoclax, in combination with other chemotherapy regimens, has shown encouraging response rates warranting continued exploration of its benefit in ALL.

Abstract Introduction: CD19-directed CAR T-cell (CAR-T) therapy has substantially improved clinical outcomes for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, notable toxicities are associated with CAR-T, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Variable practice patterns have emerged regarding the use of CRS/ICANS prophylaxis (ppx) via corticosteroids and/or other pharmacologic agents, but the utility of these approaches on reducing CRS or ICANS following CAR-T in B-ALL remains unknown. Thus, we utilized the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) database to evaluate associations between ppx and the development and severity of CRS or ICANS following brexucabtagene autoleucel (brexu-cel) for B-ALL. Methods: Adult patients (pts) who received standard-of-care brexu-cel for relapsed/refractory B-ALL across 40+ US centers were included. Primary endpoints were the incidence of CRS and ICANS within 28 days of CAR-T infusion. Secondary endpoints included timing of CRS and ICANS onset, progression-free survival (PFS) and overall survival (OS). Univariable and multivariable logistic regression evaluated associations between ppx and incidence of CRS/ICANS; KM and log-rank methods were used for survival analyses. Results: A total of 378 pts were included: 53 pts (14.0%) received CRS/ICANS ppx and 325 (86.0%) received no ppx. Ppx agents included steroids only (26.4%), steroid and anakinra (52.8%), anakinra only (15.1%), and steroid and tocilizumab (5.7%). Pts in the ppx group had a higher proportion of Hispanic pts (64% vs 34%), Ph-like (36% vs 19%) and a lower proportion had 0-5% bone marrow blasts at apheresis (38% vs 53%). The ppx and no ppx groups were similar in age, prior therapies, CAR-T indication, and marrow blasts >50%. Cumulative incidence of any grade (gr) CRS was 94% with ppx and 86% with no ppx (p=0.025), of any gr ICANS was 53% with ppx and 51% with no ppx (0= 0.85). Cumulative incidence of gr 3-4 CRS was 9% in the ppx group and 10% in the no ppx group (p=1.00), of gr 3-4 ICANS was 26% in the ppx group and 29% in the no ppx group (p=0.71). Median time to onset for any gr CRS or any gr ICANS was identical in the ppx and no ppx cohorts (CRS: 5 days, range ppx 1-9 days, no ppx 0-14 days; ICANS: 7 days, ppx 1-20 days, no ppx 0-16 days). Univariate logistic regression analyses showed no significant association between ppx and the incidence of gr 2-4 CRS (OR 1.34, 95% CI: 0.75-2.40, p=0.326) or gr 3-4 ICANS (OR 0.88, 95% CI: 0.46-1.70, p=0.708). Multivariate analysis adjusting for ethnicity, leukemia genetic sub-type, and pre-apheresis disease burden similarly found no significant associations between ppx and gr 2-4 CRS (adjusted OR 1.06, 95% CI: 0.55-2.01, p=0.870) or gr 3-4 ICANS (OR 1.23, 95% CI: 0.59-2.55, p=0.584). When comparing steroid-only ppx (N=14) to steroid combinations or other drug ppx (N=39), there was no significant differences in gr 2-4 CRS (57% vs 44%, p=0.345) or gr 3-4 ICANS (43% vs 21%, p=0.115). Comparing cumulative incidence of dexamethasone (dex) exposure, pts in the ppx group had numerically greater dex exposure than pts in the no ppx group, with median (range) dosing of 182 mg (10-1386mg) and 100mg (1-4000mg), respectively. Finally, we found no significant differences in PFS or OS based on ppx. Median PFS was 9.6 months in the ppx group vs 13.3 months in the no ppx group (p=0.646) and median OS was 17.2 months in the ppx group vs 34.4 months in the no ppx group (p=0.170). Conclusions: In this large cohort of adult patients with R/R ALL receiving brexu-cel CAR-T therapy, prophylaxis intended to prevent CRS/ICANS was ineffective at reducing CRS/ICANS incidence, time to onset, or overall steroid exposure. Furthermore, PFS and OS were comparable between patients who received prophylaxis and those who did not. In the absence of prospective trials in B-ALL, these data suggest that current strategies of CRS/ICANS prophylaxis has limited benefit.

Abstract SWOG 1318 evaluated the feasibility of combining the tyrosine kinase inhibitor (TKI) dasatinib with prednisone and blinatumomab in older patients (pts) with Philadelphia chromosome positive (Ph+) B-acute lymphoblastic leukemia (ALL). Here, we present longer follow up (median follow up 5.6 years) with outcomes, predictors of response, and translational medicine studies. Methods: This trial was activated through the NCTN in January 2014 and closed to accrual in April 2021. Pt eligibility included: age > 65 years, Ph+ ALL, no evidence of central nervous system (CNS) disease, and adequate organ function. Treatment has been previously described (Blood Adv 2023; 7(7): 1279-85). Statistics: Categorical and quantitative endpoints comparisons used Fisher's exact and Wilcoxon tests. Survival endpoints used the Kaplan-Meier method and Cox regression models and were landmarked for post-baseline events as needed (i.e., number of cycles). Translational medicine studies: Single cell ATAC seq (10x genomics) was performed on 9 archived cryopreserved diagnostic samples from patients with > 500,000 cells. All samples successfully completed library preparation, sequencing, and demonstrated adequate blast clusters for analysis. Briefly, cryopreserved cells were thawed, and transposases were introduced into nuclei in single cell suspension and used to generate GEM beads. ATAC seq libraries were prepared per manufacture instructions. Libraries were then sequenced on a 25B flow cell on Novaseq X plus (Illumina). The data were analyzed with cloupe (version 9.0.0). Results: Twenty-four eligible patients were enrolled. The median age was 73 years (range 65-87). All pts had newly diagnosed Ph+ ALL. Seventy-nine percent of pts had additional cytogenetic abnormalities. Twenty-two pts (92%) achieved a complete remission (CR) during dasatinib and prednisone induction therapy. Most sites also monitored patient's blood or bone marrow with real-time quantitative PCR to quantify the BCR-ABL1 transcript for molecular response. Of 19 patients analyzed 17 (89%) were in a major or complete molecular remission at some point after treatment, with at least 12 of these patients achieving complete molecular remission. Three patients remain on maintenance. The median follow up for patients who are alive is 5.6 years (range 4.4-8.3). Five- year OS and DFS estimates are 63% (95% CI: 40-78%) and 64% (95% CI: 40-80%). Two patients relapsed in the CNS. One pt proceeded to allogeneic hematopoietic stem cell transplant (HSCT) and 1 to autologous HSCT. Increased age was associated with a decreased chance of achieving CR as best response (median age in responder group 73.2 years [range 65-82.9]; median age in non-responder group 85.5 [range 83.8-87.3]; p=0.02). Patients with extramedullary disease had shorter DFS (HR 0.22, 95% CI 0.04-1.15, p=0.07). Increased number of cycles of blinatumomab received was associated with a trend towards improved OS (HR 0.66, 95% CI 0.41-1.08, p=0.10). Translational medicine studies for chromatin accessibility in the blast clusters demonstrated improved OS in patients with homogeneous blast clusters (HR 0.42, 95% CI 0.06-3.04, p=0.39), high DUX4 differential accessibility (HR 0.26, 95% CI 0.03-2.55, p=0.25), and ATAC seq data corresponding to decreased chromatin accessibility in HOXA2 (HR 0.09, 95% CI 0.01-1.05. p=0.06). Conclusions: Despite an elderly population, this trial demonstrated impressive outcomes with longer follow-up for patients with Ph+ ALL. The number of cycles of blinatumomab and the presence of extramedullary disease may be important factors in outcome. Translational studies suggest additional markers may be predictors of overall survival, and these will need to be studied on larger scale studies. Decreased chromatin accessibility to HOXA2 was associated with a trend towards improved OS. Additional translational medicine will also be presented at the meeting.

Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

ABSTRACT Background We recently published the first real‐world multicenter and multi‐institutional study of cisplatin, gemcitabine, and durvalumab in patients with advanced biliary tract cancer (BTC). Here we present an expanded patient cohort with an increased sample size and longer median follow‐up. Methods The study population included patients with advanced BTC, who received cisplatin/gemcitabine plus durvalumab at 55 centers across 12 countries in Europe, the United States, and Asia. The primary endpoints of the study were progression‐free survival (PFS) and overall survival (OS). Secondary endpoints were overall response rate (ORR) and safety. Results Overall, 1358 patients were enrolled. Median PFS was 7.6 months (95% CI: 7.2–8.1), and median OS was 15.6 months (95% CI: 14.8–16.5). ORR was 35.6%, and DCR was 82.7%. Any grade AEs occurred in 1213 patients (89.3%). Grade 3–4 AEs occurred in 597 patients (43.2%). The rate of immune‐related AEs (irAE) was 20.3%. Grade 3–4 irAE occurred in 3.0% of patients. At the multivariate analysis for OS, normal albumin level (HR 0.68, 95% CI 0.57–0.81, p < 0.0001), CEA levels within normal ranges (HR 0.68, 95% CI 0.57–0.82, p < 0.0001), NLR < 3 (HR 0.62, 95% CI 0.52–0.74, p < 0.0001), ECOG PS 0 (HR 0.51, 95% CI 0.42–0.61, p < 0.0001), and prior surgery (HR 0.80, 95% CI 0.65–0.99, p = 0.036) were positive prognostic factors. Conclusion The updated findings, derived from an expanded cohort, further support the adoption of durvalumab in combination with gemcitabine and cisplatin in routine clinical practice, reinforcing the efficacy and safety outcomes demonstrated in the phase III TOPAZ‐1 trial.

Abstract BACKGROUND Craniopharyngiomas are a rare tumor along the pituitary-hypothalamic axis. Genetic analysis revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We previously reported that BRAF/MEK inhibition was associated with significant anti-tumor activity in newly-diagnosed PCP patients (Brastianos et al. NEJM 2023). We have now evaluated the efficacy of vemurafenib/cobimetinib in a separate cohort of patients with recurrent PCP whose tumors progressed after prior radiation. METHODS In this multicenter, NCI-sponsored cooperative group trial, patients with histologically confirmed BRAF-positive PCP who progressed after radiation were treated with vemurafenib/cobimetinib. The primary endpoint of response rate (RR) based on centrally determined imaging data was to be evaluated in 16 patients, where a partial response was defined as ≥20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR ≥ 30% (vs. null 5%; α=0.04). In this design, 3 or more observed responses in 16 evaluable patients would be considered evidence of promising activity. RESULTS Of the planned 16 patients, a total of 5 patients enrolled before the study was closed due to slow accrual. Median follow-up was 50 months (95% CI: 32 to not yet reached). Based on volumetric response criteria, all 5 patients had a response to treatment (100%; 95% CI: 47.8% to 100%). To date, 2 patients progressed, one of whom died 22 months after study entry. This cohort met the criteria for efficacy under the original design with &gt;3 responders. No grade 4 or 5 toxicities were observed. CONCLUSIONS Vemurafenib/cobimetinib resulted in an objective response in all patients with previously treated PCP. The study met primary endpoint, similar to that reported for previously untreated PCP. Thus, BRAF/MEK inhibitors could be an effective tool for previously treated PCP and warrants further evaluation. SUPPORT U10CA180821; U10CA180882; Genentech, https://acknowledgments.alliancefound.org;ClinicalTrials.gov: NCT03224767

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (&amp;lt;5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (&amp;gt;70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P &amp;lt; .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.

Introduction: Diastolic dysfunction is a hallmark of heart failure with preserved ejection fraction, yet echocardiographic grading is challenging in patients with hypertrophic or amyloid cardiomyopathies due to variable structural and functional remodeling. Consequently, there is a need for additional diagnostic tools to identify patients at increased risk of diastolic dysfunction and enhanced filling pressure. Research Question: What is the accuracy of an artificial intelligence (AI)-enabled electrocardiogram (ECG) model to predict diastolic dysfunction in hypertrophic and amyloid cardiomyopathy? Methods: We included patients with diverse phenotypes of hypertrophic cardiomyopathy (HCM) and cardiac amyloidosis and validated Mayo Clinic's AI-enabled ECG model to grade diastolic function (normal: grade 0/1; abnormal: grade 2/3). Echocardiographic analysis of systolic (LVEF) and diastolic function was performed within 14 days of ECG recording. Diastolic function was graded based on E/e’ (>14), left atrial volume index (>34 mL/m2), pulmonary venous atrial reversal flow duration (≥30 ms), and peak tricuspid regurgitation velocity (>2.8 m/s). Filling pressure was considered increased if ≥3 parameters were abnormal, inconclusive if 2 were abnomal, and normal if ≥3 were normal. Echocardiograms with severe mitral regurgitation were excluded. Results: We identified and matched 840 ECGs from non-obstructive HCM patients (n=125, age 58±19y, 70% male), 145 ECGs from obstructive HCM patients (n=29, age 56±18y, 66% male), 225 ECGs from apical HCM patients (n=33, age 66±14y, 61% male), and 382 ECGs from cardiac amyloidosis patients (n=49, age 70±13y, 57% male). The AI-enabled ECG model predicted diastolic dysfunction with an accuracy of 65% (non-obstructive HCM), 67% (obstructive HCM), 65% (apical HCM), and 75% (cardiac amyloidosis), with sensitivities of 94% and 97% for obstructive HCM and cardiac amyloidosis, respectively, and high positive and negative predictive values for cardiac amyloidosis. Systolic dysfunction (LVEF≤40%) was more common in cardiac amyloidosis (29%) than in all HCM patients (5%). Conclusion: The AI-enabled ECG model demonstrates moderate accuracy but high sensitivity for detecting diastolic dysfunction and increased filling pressure, especially in obstructive HCM and cardiac amyloidosis. The AI-enabled ECG is a useful, widely scalable, and low cost tool to identify patients at increased risk for diastolic dysfunction.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Background Antibiotic use may alter gut microbiota, which could be associated with various diseases, including cardiovascular disease (CVD). Accordingly, further epidemiological evidence is needed to clarify the potential risk of CVD associated with antibiotic exposure. We evaluated the association between long‐term antibiotic exposure and CVD risk in South Korea. Methods and Results This nationwide retrospective cohort study used data from the Korean National Health Insurance Service database. A total of 2 159 965 individuals aged 40 to 79 years who had no history of antibiotic prescriptions from 2004 to 2005 were included and followed through December 31, 2021. Antibiotic exposure was defined as the cumulative days of antibiotic prescriptions from 2006 to 2010. The primary end point was incident CVD with 2 or more days of hospitalization from 2011 to 2021. Adjusted hazard ratios (aHR) and 95% CIs for CVD according to antibiotic exposure were estimated using multivariable Cox proportional hazards models, adjusting for a range of covariates. Longer cumulative antibiotic prescription days were associated with an increased risk of CVD. The aHRs for CVD associated with 1 to 14, 15 to 90, 91 to 180, 181 to 364, and ≥365 days of antibiotic exposure were 0.98 (95% CI, 0.96–1.01), 1.01 (95% CI, 0.99–1.03), 1.05 (95% CI, 1.03–1.08), 1.06 (95% CI, 1.04–1.09), and 1.10 (95% CI, 1.07–1.13) compared with those with no antibiotic prescriptions. Conclusions In this large population‐based cohort study of Korean adults, long‐term antibiotic exposure may be associated with a higher risk of CVD. Further research is warranted to establish causality and elucidate the underlying mechanisms for this association.