Citations

ABSTRACT Aims To evaluate the real‐world associations between semaglutide 2.4 mg and cardiometabolic comorbidities, biomarkers and cardiovascular risk among adults with overweight or obesity. Methods This retrospective cohort study used US claims data and laboratory measurements from the Komodo Research Database (2016–2024). Adults with obesity or with overweight and ≥ 1 obesity‐related comorbidity were included. Patients on semaglutide 2.4 mg for ≥ 12 months were compared with non‐users (including users of other obesity medications) using propensity score weighting with residual imbalances adjusted in regression model. Outcomes included time to onset of cardiometabolic comorbidities, change in cardiometabolic biomarkers and changes in 10‐year ASCVD risk score at 12 months. Results 25 783 semaglutide 2.4 mg users and 8 948 913 non‐users were identified. Semaglutide 2.4 mg was associated with significantly lower risks for incident prediabetes or type 2 diabetes, type 2 diabetes only, hypertension, ASCVD, heart failure and CVD (HRs 0.45–0.75; all p < 0.05), as well as greater improvements in BMI (−4.1 kg/m 2 ), SBP (−6.2 mmHg), HbA1c (−0.4%), LDL cholesterol (−7.7 mg/dL), triglycerides (−28.6 mg/dL) and HDL cholesterol (+1.9 mg/dL; all p < 0.001). At 12 months, semaglutide 2.4 mg users ( N = 161) demonstrated a greater reduction in ASCVD risk score (−0.7% vs. +0.3%; between‐group difference −1.0%, p < 0.001), with a decrease in the proportion at intermediate‐high ASCVD risk (14.9%–9.3% vs. 17.7%–18.7%; OR 0.3 [95% CI: 0.1, 0.6], p < 0.001). Conclusions Semaglutide 2.4 mg was associated with lower risk of multiple cardiometabolic comorbidities, favourable changes in biomarkers, and lower estimated ASCVD risk in this population.

Importance Standard treatment for human papillomavirus (HPV)–associated oropharyngeal carcinoma (OPC) often includes 7 weeks of intensive chemoradiotherapy with substantial toxic effects. Lowering the radiation dose to gross disease may maintain cancer control with fewer toxic effects. Objective To evaluate long-term oncologic outcomes among patients with HPV-associated OPC treated with definitive deintensified (chemo)radiotherapy. Design, Setting, and Participants This cohort study evaluated consecutive patients treated with (chemo)radiotherapy between September 2014 and August 2022 at multiple institutions under one academic hospital system. Eligible patients had p16-positive OPC with a clinical stage from T0 to T3 and N0 to N2c (according to the American Joint Committee on Cancer [AJCC] Staging Manual, seventh edition ) and favorable smoking history. Data were analyzed between August 2023 and October 2025. Interventions Treatment was 60-Gy intensity-modulated radiotherapy with first-choice concurrent chemotherapy of weekly cisplatin, 30 mg/m 2 , or weekly cisplatin, 40 mg/m 2 . Patients with OPC with a clinical stage from T0 to T2 and N0 to N1 (according to AJCC, seventh edition ) were recommended 60-Gy radiotherapy alone. Main Outcomes and Measures Evaluation of locoregional recurrence was the primary outcome. Distant recurrence, progression-free survival (PFS), and overall survival (OS) were secondary outcomes. Results A total of 240 patients received definitive deintensified (chemo)radiotherapy (207 receiving prospective protocol-adherent treatment and 33 receiving non–protocol-adherent treatment). Mean (SD) patient age was 60.3 (9.9) years (range, 33.0-84.0 years); 206 (85.8%) were male, and 34 (14.2%) were female. The cohort included 139 never smokers (57.9%) and 101 former smokers (42.1%) (median smoking history, 9.0 pack-years [range, 0.25-50.0 pack-years]). Concurrent chemotherapy was prescribed for 205 patients (85.4%), with 185 (77.1%) receiving cisplatin, and 165 (68.8%) receiving weekly cisplatin, 30 mg/m 2 . Median follow-up for surviving patients was 6.5 years (range, 0.44-11.0 years; 208 of 210 [99.0%] with minimum 2-year follow-up). Outcomes were as follows: 2-year OS was 97.9% (95% CI, 96.1%-99.7%), and 5-year OS, 92.4% (95% CI, 89.0%-96.0%); 2-year PFS, 94.1% (95% CI, 91.2%-97.2%), and 5-year PFS, 86.5% (95% CI, 82.1%-91.0%); 2-year locoregional recurrence, 1.3% (95% CI, −0.2% to 2.7%), and 5-year locoregional recurrence, 3.4% (95% CI, 1.1%-5.8%); 2-year distant recurrence, 4.6% (95% CI, 1.9%-7.3%), and 5-year distant recurrence, 7.3% (95% CI, 3.9%-10.7%). The median time to progression events was 1.9 years (range, 0.3-5.1 years); 12 of 26 recurrences (46.2%) occurred after 2 years. Thirty-three patients with low-risk disease (clinical stage T0-T2, N0-N1, according to AJCC, seventh edition ) received radiotherapy alone, which resulted in a 5-year PFS of 93.8%, with no patients experiencing a locoregional recurrence. Conclusions and Relevance In this cohort study, modest dose deintensification of 60-Gy radiotherapy in patients with HPV-associated OPC shows favorable rates of locoregional control. These findings provide support for ongoing investigations of deintensified radiotherapy.

BACKGROUND: Catheter ablation for atrial fibrillation is a widely used rhythm-control strategy, yet its role in reducing thromboembolic risk and enabling oral anticoagulation (OAC) discontinuation remains uncertain. This meta-analysis aims to comprehensively synthesize and evaluate randomized controlled trial evidence supporting long-term antithrombotic strategies in patients with atrial fibrillation undergoing catheter ablation. METHODS: A systematic literature search was performed in MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials evaluating antithrombotic strategies after catheter ablation for atrial fibrillation. The primary outcome was ischemic stroke. A frequentist network meta-analysis comparing reported treatment arms, along with a pooled incidence meta-analysis for outcomes of interest, was conducted. RESULTS: Four randomized controlled trials, including 3924 patients, met the inclusion criteria. Three trials compared long-term OAC continuation versus OAC discontinuation, and 1 compared OAC continuation with left atrial appendage occlusion after catheter ablation. No significant differences in stroke incidence were observed when comparing OAC or left atrial appendage occlusion with no antithrombotic therapy (incidence rate ratio, 0.90 [95% CI, 0.02–33.85]; P =0.95; incidence rate ratio, 0.79 [95% CI, 0.00–241.01]; P =0.94, respectively). Among patients who discontinued antithrombotic therapy without undergoing left atrial appendage occlusion (n=1161), with 2864 cumulative person-years of follow-up, the pooled incidence of stroke was 0.23 events per 100 person-years (95% CI, 0.02–2.43; I 2 =0%). CONCLUSIONS: This analysis reinforces that, across randomized data, the incidence of thromboembolic events in patients who discontinued OAC after successful ablation remained low. However, the evaluation of net clinical benefit is limited by the low number of events across all treatment arms, underscoring the need for larger studies with prolonged follow-up to further validate the safety of this strategy, particularly in higher-risk populations.

Abstract INTRODUCTION Multicomponent non‐pharmacological interventions, such as the HABIT Healthy Action to Benefit Independence & Thinking® program, have shown promise for improving emotional well‐being, functioning, and self‐efficacy in both people with mild cognitive impairment (pwMCI) and their care partners. However, limited research has examined whether outcomes differ based on type of care partner who co‐enrolls with the pwMCI. METHODS We analyzed data from 875 pwMCI−care partner dyads who completed the HABIT program. Multivariate linear mixed‐effects regression models evaluated changes from baseline in outcomes by care partner type (spouse vs. non‐spouse) at post‐intervention, 6‐months, and 12‐ months. RESULTS At post‐intervention, pwMCI with spousal care partners demonstrated significant improvements across all outcomes from baseline, whereas those with non‐spousal partners improved in five out of seven outcomes. Across subsequent follow‐ups, pwMCI with spousal care partners showed sustained mean reductions in anxiety (post‐intervention: −2.0; 12‐month: −0.9) and increased compliance (post‐intervention: 5.7; 12‐month: 0.9). Everyday functioning in memory (post‐intervention: −0.9; 12‐months: 1.8) and executive functioning (post‐intervention: −0.7; 12‐months: 4.8) improved at post‐intervention but declined thereafter. Spousal care partners reported reduced anxiety (−1.2) and depression (−1.3) at post‐intervention, but by 12‐months they experienced increased burden, anxiety, and depression relative to baseline. Non‐spousal pwMCI–care partner dyads did not show significant change at 6 or 12‐months. DISCUSSION The HABIT intervention may have more favorable outcomes for pwMCI and care partners in spousal compared to non‐spousal dyads. These findings highlight the potential impact of care partner characteristics on both immediate and long‐term response to behavioral interventions for MCI. Highlights At post‐intervention, people with mild cognitive impairment (pwMCI) with spousal care partners showed significant improvements across all outcomes, while those with non‐spousal partners improved in five of seven outcomes. Gains attenuated over time for both spousal and non‐spousal dyads Spousal care partners reported reduced anxiety and depression at post‐intervention, but by 12 months they experienced increased burden, anxiety, and depression relative to baseline. Non‐spousal pwMCI–care partner dyads did not show significant change at 6 or 12 months.

Abstract Background: Most patients with estrogen receptor-positive (ER+), metastatic breast cancer (mBC) treated with endocrine therapy (ET) will ultimately develop resistance. A large unmet need exists especially when resistance occurs following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), which is potentially driven by a mutation in the ERα-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival (PFS, median 5.6 mos vs 3.7 mos; HR: 0.669 [95% CI, 0.445‒1.125], P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), with a favorable safety profile (Goetz MP et al. Ann Oncol 2023;34:1141‒51). The single-arm, ELAINE 2 trial showed that LAS combined with abemaciclib (Abema) was well tolerated with a median PFS of ∼13 mos, ORR of 56%, and CBR of 66% (Damodaran S et al. Ann Oncol 2023;34:1131‒40). The phase 3, registrational, ELAINE 3 trial was initiated based on these promising earlier-phase data. Recent results from postMONARCH confirmed superior efficacy of fulv/Abema over fulv/placebo (mPFS 6.0 mos vs 5.3 mos, HR 0.73 [0.57‒0.95], nominal P-value 0.017) in non-biomarker‒selected, mBC patients after progression on a prior CDK4/6i and aromatase inhibitor (AI), with similar HR in an ESR1-mutated cohort (Kalinsky K et al. J Clin Oncol 2025;43:1101‒12). Additionally, recent data from EMBER-3 demonstrated meaningful PFS with a novel ET combined with abemaciclib after progression on AI/CDK4/6i (Jhaveri KL et al. N Engl J Med 2025;392:1189‒202). The ELAINE 3, global trial will compare LAS/Abema with fulv/Abema in a post-CDK4/6i, ESR1-mutation‒selected, mBC population. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Patients are being enrolled at approximately 152 sites in 13 countries (Australia, Belgium, Canada, China, France, Italy, Israel, Poland, Romania, Spain, Taiwan, United Kingdom, United States). Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an AI plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM (days 1, 15, and 29, then once monthly) plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS per RESIST 1.1 by blinded independent central review (BICR); key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Safety, time to cytotoxic chemotherapy, and quality of life (including vaginal health) will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. Enrollment is currently ongoing to meet the target sample size of 500 patients. Citation Format: M. P. Goetz, S. A. Wander, T. Bachelot, G. Curigliano, A. de Nonneville, E. N. Gal-Yam, K. Jhaveri, S. L. Sammons, S. Shen, C. J. Twelves, G. Gasper, P. V. Plourde, D. J. Portman, S. Damodaran. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-30.

Abstract Background: The current standard of care for first-line (1L) treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) consists of induction chemotherapy combined with trastuzumab (TRAS) and pertuzumab (PERT) followed by maintenance therapy with TRAS + PERT. Although this regimen has been associated with sustained disease control, most patients eventually experience disease progression. The HER2CLIMB-05(NCT05132582) study is investigating the efficacy and safety of adding tucatinib to TRAS + PERT as maintenance therapy in patients with HER2+ MBC after completion of 1L chemotherapy-based induction therapy. Methods: Patients with centrally confirmed HER2+MBC without evidence of progression after 1L induction therapy with 4 to 8cycles of a taxane combined with TRAS + PERT, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no or asymptomatic brain metastases (BM) were enrolled in HER2CLIMB-05. Contrast-enhanced brain magnetic resonance imaging was performed at screening and regular intervals during the study. Patients were randomly assigned 1:1 to receive either tucatinib 300 mg or placebo twice daily, in combination with either TRAS (6 mg/kg IV or 600 mg SC) plus PERT (420 mg/kg IV) or a SC fixed-dose combination of TRAS, PERT, and hyaluronidase administered every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors. The primary endpoint is investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety. Results: Between March 2022 and July 2024, 654 patients were randomly assigned to receive tucatinib (n = 326) or placebo (n = 328) with1L maintenance therapy. All patients were female (median age: 54 years [range, 24-83]);45.0% were White, 35.2% were Asian, 2.9% were Black/African American, and 19.3%were Hispanic/Latino(a)/Spanish origin. Most patients had ECOG PS of 0 (64.1%)and de novo metastatic disease (69.3%). At baseline, 12.4% of patients had presence or history of BM and 52.6% had hormone receptor-positive MBC. As of September5, 2025, PFS was statistically significantly improved with the addition of tucatinib versus placebo to 1L maintenance therapy (hazard ratio [HR] = 0.641 [95%confidence interval (CI), 0.514-0.799]; 2-sided P &lt; 0.0001). All prespecified patient subgroups demonstrated a PFS benefit with tucatinib combination 1L maintenance therapy consistent with the overall population and regardless of presence or absence of BM at baseline or hormone-receptor status. OS is still immature (observed number of deaths = 51;tucatinib arm versus control arm HR = 0.539 [95% CI, 0.303-0.957; 2-sided P= 0.032]). In the safety analysis set, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm (n = 326) were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase:25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1% were, respectively, grade ≥ 3. In the tucatinib arm, 13.5% of patients discontinued tucatinib due to TEAEs. Conclusions: In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC. Citation Format: E. Hamilton, G. Curigliano, M. Martin, F. Lerebours, J. Tsurutani, M. Savard, K. Jerzak, X. Hu, L. Martins de Aquino Pimentel, C. O'Sullivan, E. Tokunaga, A. Okines, C. Huang, W. Jacot, J. Sohn, E. Cronemberger Silva, V. Mueller, S. Yang, G. Granata, Q. Shen, L. Santarpia, V. Dieras Her2climb-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-01.

Brugada Syndrome (BrS) is a rare but clinically significant inherited arrhythmia disorder characterized by a type 1 ECG pattern and an increased risk of sudden cardiac death (SCD). Since its first description in 1992, BrS has been the subject of intensive investigation, yet risk stratification remains one of its greatest challenges. While survivors of cardiac arrest and patients with documented ventricular fibrillation (VF) are clear candidates for implantable cardioverter-defibrillators (ICDs), predicting risk in asymptomatic or intermediate-risk individuals is less straightforward. Over the past two decades, multiple risk scores have been developed—including the Sieira, Shanghai, BRUGADA-RISK, and PAT—each integrating combinations of clinical, ECG, electrophysiological study (EPS), and genetic data. Performance metrics vary, with C-statistics ranging from 0.70 to 0.82 in derivation cohorts, but external validation has often been limited. Importantly, current ESC and AHA/ACC guidelines only endorse syncope and EPS inducibility as validated predictors, reflecting the cautious stance of expert panels in the face of heterogeneous data. Nonetheless, the emergence of structured risk models has improved our ability to stratify intermediate-risk patients and stimulated further innovation. Looking ahead, opportunities lie in integrating artificial intelligence applied to raw ECG waveforms, wearable technology for dynamic monitoring, advanced cardiac imaging biomarkers, and polygenic risk scores. Multinational collaboration and federated learning will be essential to overcome statistical fragility and ensure global applicability. Ultimately, BrS risk scores should be considered decision-support tools that enrich but do not replace clinical judgment. Shared decision-making remains central, particularly in asymptomatic patients where ICD implantation is not a clear-cut choice.

ABSTRACT Background Li Fraumeni syndrome (LFS) is a hereditary multi‐cancer syndrome caused by alterations in TP53 (MIM# 151623). Next generation sequencing (NGS) allows for the detection of TP53 variants at lower variant allele frequencies (VAFs). A TP53 variant with a VAF < 50% may represent mosaic LFS, aberrant clonal expansion (ACE), or possible circulating tumor DNA. Differentiation among these conditions is important for optimal patient management. Methods Genetic testing was performed using a custom gene panel, with an average read depth of 350× (range 166–553×). DNA extracted from four different tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced. Results Here, we describe an adult female patient with a history of an adrenocortical neoplasm and osteosarcoma, diagnosed at 2 and 16 years of age, respectively. Testing of peripheral blood identified a pathogenic TP53 variant, c.733G>A, p.(Gly245Ser) (NM_000546.6); however, subsequent in vitro fertilization with preimplantation genetic testing for monogenic disorders (PGT‐M) did not identify this TP53 variant in any of nine embryos tested. Testing for possible mosaicism in the proband was performed on four different specimens, revealing variable VAFs of the TP53 variant (saliva: 44%; blood: 31%; cultured skin fibroblasts: 18%; and colon tissue: 9%). These results suggest a post‐zygotic event, consistent with mosaic LFS rather than ACE. Conclusion This case highlights the complexity of interpreting mosaic variants in the TP53 gene, and we propose a testing algorithm to aid in the delineation of this phenomenon when relaying cancer and reproductive risk information in the context of mosaicism.

Neoadjuvant immune checkpoint inhibition (Neo-ICI) in melanoma is an emerging therapeutic strategy that induces pathologic responses with significant prognostic implications for survival. Tumor burden in nonresectable melanoma has a major impact on immunotherapy efficacy, yet little is known on its impact in the Neo-ICI setting. We evaluated the association between tumor burden, measured by the sum of diameters (SoD), and pathological response in melanoma patients treated with Neo-ICI. A meta-analysis of published trials in resectable stage III/IV melanoma was conducted, extracting data on patient characteristics, treatment regimens, pathological response, and survival outcomes. A total of 451 patients were included in the meta-analysis. The pooled pathological complete response (pCR) rate was 47% (95% confidence interval: 35–58%; P < 0.001). Meta-regression demonstrated a significant association between SoD and pCR (moderator = −0.36; P = 0.032), with greater tumor burden associated with lower pCR rates. No significant association was observed between SoD and recurrence-free survival (RFS). This study identifies higher tumor burden as a potential risk factor for lower pathologic response rates to neoadjuvant therapy, underscoring the need to incorporate tumor burden into future clinical research and potentially clinical decision-making.