Citations

Importance Hospital-based shootings represent an extreme form of workplace violence, with notable consequences for staff, patients, and visitors. Despite growing concern, these events remain poorly understood. Objective To categorize hospital-based shootings from 2012 to 2024 and incorporate prior published events between 2000 and 2011 to examine trends in shootings over a 25-year span. Evidence Review Events in this systematic review of acute care hospital–based shootings in the US from January 1, 2012, through December 31, 2024, with subgroup analysis of previously published data trending shootings over 25 years (January 1, 2000, through December 31, 2024), were identified using EBSCO Regional Business News, ProQuest US Newsstream Collection, Gun Violence Archive, and Google News Search. Selected shooting events involved at least 1 injured person (a nonperpetrator or perpetrator) that occurred within or on the immediate property of the hospital. Findings A total of 327 news articles of unique hospital-based shooting events (5.2 per year per 1000 hospitals) were included from a review of 6658 articles, spanning 47 US states (94.0%). There was an overall incidence of 25.2 hospital-based shootings per year. Between 2012 and 2024, shootings increased by a mean (SD) of 1.7 (0.5) events per year, from 14 to 34 events (8.4% increase per year). Large hospitals accounted for the highest rate of shootings (258.1 events per 1000 hospitals). Events primarily occurred in urban settings (314 [96.0%]), and 161 (49.2%) occurred in the US South. Nearly one-third (105 [32.1%]) were potentially preventable by weapons screening. From 2000 to 2024, shootings increased by a mean (SD) of 1.1 (0.2) events per year, from 6 to 34 events (6.4% increase per year). A positive correlation was found in annual firearm fatalities in hospital settings and US firearms fatalities overall between 2012 and 2023 ( r = 0.42). Conclusions and Relevance This systematic review found that hospital-based shootings in the US have increased steadily over the past 25 years, representing an intersection between broader national trends in workplace and firearm violence. Large hospitals, those in the US South, and hospitals in urban communities are particularly at-risk settings. These findings underscore the need for hospital-specific prevention strategies, including consideration of weapons screening technology, alongside broader societal efforts to address rising firearm violence.

Abstract Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

PURPOSE 177Lu-PSMA-617 (LuPSMA) is an approved prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Older patients, particularly octogenarians, represent a substantial proportion of men with mCRPC but have been traditionally underrepresented in key registrational trials of LuPSMA. METHODS This retrospective multi-institutional study evaluated patients age 80 years and older with mCRPC after chemotherapy treated with ≥1 cycle of LuPSMA from August 2022 to December 2024. Clinical and demographic data were abstracted from electronic medical records. Outcomes included prostate specific antigen (PSA) response (PSA50 and PSA90), progression-free survival (PFS), overall survival (OS), and toxicities. Kaplan-Meier methods estimated PFS/OS; descriptive statistics summarized baseline and safety data. RESULTS Ninety-five patients (median age, 83 years) were included, of whom 36 (38%) and 21 (22%) had a history of cardiac disease or chronic kidney disease, respectively. Median follow-up was 24.1 months (IQR, 6.7-28.1). Patients received a median of five cycles of LuPSMA. Fifty-two (57%) and 21 (23%) patients achieved a PSA50 and PSA90, respectively. Median PFS and OS were 7.3 months (95% CI, 6.4 to 8.7) and 13.5 months (95% CI, 9.7 to 18.8), respectively. Grade ≥3 hematologic toxicities included anemia (n = 19; 20%) and thrombocytopenia (n = 4, 4%); grade ≥3 acute kidney injury occurred in one patient. Fourteen (15%) patients had dose delays, seven (7%) required reductions, and 10 (11%) discontinued therapy due to toxicity. Thirty-seven patients (39%) were hospitalized during therapy, with intensive care unit-level care required in two patients (2%), and there was one treatment-related death. CONCLUSION LuPSMA had comparable outcomes in octogenarians with mCRPC to patients on registrational trials, although 2/5 of patients required hospitalization during therapy. These findings support the feasibility and efficacy of LuPSMA in well-selected older men with mCRPC and suggest a role for closer monitoring of older patients.

Abstract Background Knowing the prevalence of patent foramen ovale (PFO) and the increasing number of people who inject drugs (PWID) with right-sided infective endocarditis (RSIE), we aimed to better characterize the syndrome of injection drug use, RSIE, and PFO with systemic embolic events. Method A systematic search across multiple databases was independently screened using predefined criteria (from inception until September 2025). Published cases of adult PWID diagnosed with RSIE and ischemic stroke or other systemic embolic event were included, provided they had PFO assessment. Individuals were excluded if they had cardiac implantable electronic device (CIED) infections or any other conditions associated with systemic or paradoxical embolism. Results The review identified 13 studies with 14 young patients, mostly without comorbidities, predominantly infected with Staphylococcus aureus. In most cases, echocardiography revealed large tricuspid valve vegetations. Neuroimaging confirmed multiple ischemic infarcts, while 5 patients showed emboli outside the central nervous system (4 of them as the only systemic embolism). At least 11 (79%) patients had echocardiographic evidence of right-to-left shunting. Management included cardiac surgery in 6 cases that involved valve replacement or repair, percutaneous PFO closure in 2 cases, and percutaneous mechanical aspiration in 1 case. Three patients (21%) died during hospitalization, and only 27.3% patients had outpatient follow-up. Conclusions RSIE with systemic embolism in PWID with PFO has rarely been reported, affects younger patients without sex predominance, and was usually due to S. aureus with large tricuspid vegetations. Right-to-left shunting was characteristic, and outcomes were poor despite combined medical, surgical, and interventional therapies.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684 ). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (topo1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate topo1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined topo1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a topo1 inhibitor via DS-8201a may reduce systemic toxicity, while maintaining synergistic cytotoxic activity in combination with olaparib (PARPi). DS-8201a + olaparib was evaluated in the ongoing CTEP #10355 trial (NCT04585958). Results from Dose Escalation are presented. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ or ERBB2 amplification by NGS or ISH (local testing allowed). DS-8201a was given Q3W across all dose escalation regimens. Olaparib dosing in continuous (Module 1 D1-21) and intermittent schedules (Module 2 D8-14; Module 3 D3-9) were explored. A 3+3 dose escalation design was followed in Mod 1 & 2 and up to 6 pts in a safety cohort were planned for Mod 3. Primary endpoints included safety as graded by CTCAE v5 and determination of an RP2D. Results: As of Oct 26, 2025, 30 pts were enrolled and 28 pts were treated. 12 pts had uterine and 16 pts had ovarian cancer; mean age was 61.6 years, median number of prior therapies was 4 (range 1-10). HER2 expression by local testing was: 4 pts IHC 1+, 17 pts IHC 2+, 6 pts IHC 3+, 1 pt ERBB2 amplification (IHC not reported). 9/10 pts enrolled in Mod 1 (continuous olaparib) were DLT-evaluable: 1/7 pts at DL1 (DS-8201a 4.4mg/kg IV Q3W + olaparib 100mg BID D1-21) and 3/3 pts at DL2 (DS-8201a 5.4mg/kg IV Q3W + olaparib 100mg BID D1-21) experienced DLTs (G4 neutropenia, febrile neutropenia, WBC decrease, colitis), halting further Mod 1 enrollment. 12/16 pts enrolled to Mod 2 (intermittent olaparib) were DLT-evaluable and only 1 pt at the highest dose level (DL3, DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14) experienced a DLT (G3 colitis). Hematologic TRAEs were markedly attenuated in Mod 2 compared to Mod 1: 12% vs 30% G3 and 19% vs 50% G4 neutropenia; 25% vs 70% G3 anemia; 6% vs 20% G3 and 0% vs 20% G4 thrombocytopenia. 2/2 DLT-evaluable pts in Mod 3 (intermittent olaparib; DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D3-9) experienced DLTs (G3 diarrhea, G3 nausea & vomiting, G4 neutropenia), halting further Mod 3 enrollment. The Mod 2 DL3 regimen of DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14 was declared the RP2D and is under further investigation in an ongoing Dose Expansion cohort enrolling HER2 IHC 1+ platinum resistant ovarian cancer. Objective responses were observed across all modules and dose levels. Conclusions: In pts with HER2-expressing advanced solid tumors, DS-8201a in combination with intermittently-dosed olaparib was tolerable. DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14 was selected as the RP2D for further evaluation in Dose Expansion. Additional endpoints of clinical activity will be presented. Citation Format: Elizabeth K. Lee, Andrea Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Yinglu Zhou, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. CTEP #10355 A phase 1 trial of DS-8201a and olaparib in HER2-expressing malignancies: Results from dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT035.

Abstract Background: Zedoresertib (zedo) and lunresertib (lunre) are oral, highly selective WEE1 and PKMYT1 inhibitors, respectively. Inhibition of these targets leads to premature mitotic entry, and in the presence of high replication stress causes mitotic catastrophe. In preclinical models, the combination of the zedo and lunre is synthetically lethal, supporting this first-in-class trial combination (NCT04855656). Methods: In this Phase 1 trial, patients (pts) with advanced solid tumors with CCNE1 amplification (amp), or FBXW7 or PPP2R1A deleterious mutations (mut) were treated with zedo (daily dosing) plus lunre (3 days on/4 days off), guided by preclinical modelling of the pharmacological contributions of WEE1 and PKMYT1 inhibition in achieving tumor regression. Objectives included safety, tolerability, recommended doses (RD), pharmacokinetics (PK), pharmacodynamics (PDy), antitumor activity and molecular response rate (MRR; ≥50% decline in circulating tumor DNA). Results: As of 18 Nov 2025, 54 pts (55.6% female ; prior lines of therapy 1 - 9, main cancer types: ovarian (OC) (35.2%), colorectal (31.5%), pancreatic (7.4%) and breast (5.6%)) were treated at 5 dose levels (DL) from 150 mg to 260 mg of zedo plus 60 mg or 80 mg of lunre. The most common ≥G3 treatment related adverse events (TRAEs) were anemia (9.3%), neutropenia (7.4%) and Palmar Plantar Erythrodysesthesia (PPE) (7.4%). There were no G5 TRAEs. 4 (9.3%) of 54 pts had a dose-limiting toxicity (G3 pain in extremity and G1 rash in same pt (zedo 150 mg / lunre 60 mg), G3 rash (200 mg / 80 mg), G3 PPE (260 mg / 60 mg), G3 vomiting (260 mg / 60 mg)). PK/PDy analyses showed dose-dependent exposures for both zedo and lunre and target engagement in most pts, with reductions in pCDK1 Thr14 and Tyr15 and yH2AX induction. 24 (55.5%) of 44 RECIST v1.1 evaluable pts showed tumor shrinkage (3 cCR, 5 uPR, 15 SD and 1 PD). Of 16 evaluable pts with advanced OC (12 platinum resistant , 2 unknown and 2 platinum sensitive) with CCNE1 amp (13 pts) or FBXW7 mut (3 pts), 13 (81.3%) showed tumor shrinkage (3 cCR, 3 uPR and 7 SD); clinical benefit rate (pts with CR, PR or SD) was 93.8%; 7 (43.8%) OC pts were on treatment for at least 16 weeks; 4 (25%) OC pts achieved GCIG CA-125 responses. Of 23 pts with a post baseline ctDNA analysis, a MRR of 39% was seen across all DLs. Conclusion: We report the first disclosure of clinical data of the first-in-field synthetic lethal combination of WEE1 and PKMYT1 inhibitors in a molecularly defined pt population. The safety profile of zedo and lunre was expected and manageable. Promising antitumor activity was observed in pts with CCNE1 amp or FBXW7 mut solid tumors, especially pts with OC. Further dose optimization of this combination is ongoing. Citation Format: Timothy A. Yap, Rahul Aggarwal, Elisa Fontana, Martin Hojgaard, Benedito A. Carneiro, Linda Duska, Patricia LoRusso, Siddhartha Yadav, Stephanie Lheureux, Cara Mathews, Ryan H. Moy, Nehal Lakhani, Mia Weiss, Joan Tymon-Rosario, Gerardo Colon-Otero, Ignacio Garrido-Laguna, Elisabeth K. Lee, Esteban Rodrigo Imedio, Jonathan Wessen, Luke Piggott, Vito Dozio, Noemie Luong, Christophe Mas, Alison M. Schram. First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT022.

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.