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Objectives To evaluate biochemical recurrence‐free survival (BRFS) and metastasis‐free survival (MFS) as potential intermediate clinical endpoints (ICEs) for overall survival (OS) in patients undergoing salvage radical prostatectomy (sRP). Patients and Methods Evaluable patients were selected from a retrospective dataset, resulting in a cohort of 879 patients with recurrent, non‐metastatic, hormone‐sensitive prostate cancer treated with sRP at 13 centres. ICE surrogacy was evaluated using a two‐stage approach: (i) at the individual‐patient level by fitting Clayton copula models and estimating Kendall's ( >0.7 indicating a strong association) and (ii) at the centre level, by fitting weighted linear regression of 5‐year OS on 3‐year BRFS and MFS. Results The two‐step analysis included 759 patients for BRFS (366 events) and 476 for MFS (137 events), with median follow‐up of 37 months (95% confidence interval [CI] 36–42 months) and 34 months (95% CI 31–37 months), respectively. At the individual‐patient level, MFS showed a strong association with OS (Kendall's 0.85, 95% CI 0.82–0.88), which was not observed for BRFS (Kendall's 0.63, 95% CI 0.56–0.69). At the centre level, neither 3‐year BRFS ( R 2 = 0.15; slope = 0.34, P = 0.2) nor 3‐year MFS ( R 2 = 0.21; slope = 0.26, P = 0.14) predicted 5‐year OS with sufficient explanatory power. Limitations include the fact that centre‐level analysis was based on single‐arm associations rather than on treatment‐effect surrogacy across arms, and retrospective data collection. Conclusions The BRFS should not be used as a surrogate endpoint in the sRP setting. MFS requires further validation in future prospective studies to confirm its association with OS. Patient‐reported outcomes, such as quality‐of‐life and treatment‐related toxicity, should be considered in parallel with OS.

Objective To evaluate the effects of mepolizumab therapy on the blood transcriptome in patients with severe eosinophilic asthma (SEA) and to determine whether changes in gene expression predict responsiveness to mepolizumab treatment. Methods Fourteen consecutive patients diagnosed with SEA were prospectively enrolled. Each patient had sequential blood samples obtained pre-initiation and at 4, 8, and 12 weeks post-initiation of mepolizumab. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples for bulk RNA sequencing. Paired differential expression (DE) gene analysis was performed comparing baseline gene expression versus all timepoints. Changes in gene expression were also compared between responders versus nonresponders to mepolizumab treatment. Finally, gene set enrichment analysis was evaluated across timepoints and its interaction with the response to mepolizumab treatment. Results Principal component analysis of all genes demonstrated a homogeneous distribution, which did not separate into distinct groups based on either timepoint or therapeutic response. At week 12, 149 genes had significant DE (FDR < 0.05) compared to baseline. When performing all-way timepoint comparisons, 74 genes (63 protein-coding) were found to be downregulated at weeks 4, 8 and 12 compared to baseline, but no differences were observed between post baseline timepoints. Twenty-eight genes (16 protein-coding) did change with progression of time and were associated with response to therapy, and 56 protein-coding genes distinguished responders and nonresponders. At week 12, nonresponders had a high enrichment of genes involved with signaling pathways, including cytokines, growth factors, cell differentiation markers, and protein kinases. Conclusion In this exploratory study, mepolizumab use was associated with limited global transcriptomic separation with some preliminary differential-expression and enrichment findings. No definitive mechanistic or predictive response signatures were identified due to the study limitations. Future studies, including larger cohorts followed for longer durations with interrogation of specific immune subsets, may offer additional insight into the pathophysiology of severe eosinophilic asthma and into predicting response to mepolizumab treatment.

Abstract Objective Invasive presurgical evaluation plays a key role in pediatric epilepsy surgery, particularly in magnetic resonance imaging (MRI)‐negative cases, by guiding resective, disconnective, or ablative procedures. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Taskforce study provides an updated global overview of current invasive evaluation practices. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) in 29 countries across six continents. Included were children and adolescents who underwent presurgical evaluation and epilepsy surgery in 2023. The study was designed to enable comparison with the similar ILAE survey conducted in 2004. Results A total of 2427 patients were included. Invasive evaluations were performed in 21.1% of cases, most frequently in North America (33.7%, higher than Europe: 18.0%, p = .003). Among invasive cases, 32.3% had no detectable MRI abnormalities. The main indication for invasive evaluation was seizure onset localization (88.1%), followed by motor or sensory mapping (17.2%) and language mapping (14.2%). Stereoelectroencephalography (SEEG) was the predominant technique (19.8% overall, 93.6% of invasive cases), more common in North America (30.0%, p = .021) and less common in South America (7.4%, p < .001). Subdural electrodes were used in only 3.2% of invasive cases, and combined depth and subdural approaches in 3.2%. SEEG‐guided radiofrequency thermocoagulation (RF‐TC) was performed in 40.9% of SEEG cases, most commonly in Asia (63.8%). In 16.2% of invasive evaluations, patients did not proceed to resection, disconnection, or ablation, with the highest rate in Europe (28.5%). Significance This global survey provides the first broad overview of invasive evaluation practices in pediatric epilepsy surgery across participating centers worldwide. It highlights the widespread adoption of SEEG, declining use of subdural electrodes, and increasing application of SEEG‐guided RF‐TC. The high proportion of MRI‐negative cases and the considerable proportion of patients not proceeding to resection, disconnection, or ablation underscore the complexity of contemporary surgical candidates and the need for further refinement of selection strategies.

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Abstract Background Black women are more likely to develop and die from early‐onset breast cancer. Hereditary breast cancer (HBC) is strongly associated with early age of onset. Accordingly, HBC characteristics in young Black women were evaluated. Methods Black women diagnosed with invasive breast cancer at age 50 years or younger between 2005 and 2018 were recruited through the state cancer registries in Florida and Tennessee. Participants were asked to complete a questionnaire, sign medical records releases, and donate a saliva sample for free genetic testing to identify HBC germline pathogenic or likely pathogenic variant (GPV). Women with sporadic versus hereditary breast cancer were compared, based on age distribution, clinical characteristics, and family cancer history. Results Among 686 participants with confirmed genetic testing, 15.3% had GPVs in breast and/or ovarian cancer predisposition genes, including BRCA1 (7.7%), BRCA2 (4.5%), PALB2 (0.9%), and ATM (0.7%), with 1.5% in other genes. Compared to the sporadic group, triple‐negative breast cancers were overrepresented among BRCA1 carriers (23.6% vs. 75.5%; p < .001), and family history of breast cancer was significantly more frequent among BRCA1 , BRCA2 , and PALB2 carriers (all p < .05). The majority of breast cancers occurred by age 40 years in BRCA1 carriers (52.8%), compared to other genes, where age was more evenly distributed. Conclusion Among unselected young Black women with breast cancer, our findings demonstrate that the highest frequency of HBC GPVs are in BRCA1 , BRCA2, and PALB2, with identification of distinct histopathologic and demographic characteristics across HBC genes, underscoring the critical need for genetic testing in all populations.

Importance Decentralized clinical trials (DCTs) aim to increase trial access for underrepresented populations (URP) and ensure study outcomes, conclusions, and policy-related decisions are applicable to diverse populations. Objective To assess trends in the percentage of accrued participants from more than 120 miles from the research site upon DCT program implementation. Design, Setting, and Participants This descriptive quality improvement study was conducted from January 2024 to March 2025 at Mayo Clinic, a US multiregional, academic medical center (AMC) comprising 3 sites and an affiliated, community-based health care system. All individuals who consented and/or accrued to an institutional review board–approved clinical trial were included. Exposure DCTs are defined as trials with at least 1 decentralized capability beyond remote consent. DCT program development began July 2022. By January 2024, remote consent, video telehealth visits, remote phlebotomy, and device services were implemented across all sites and departments. Remote monitoring and oral medication delivery were available on a limited basis. Prospective automated program and DCT participant data collection and quarterly reporting began in January 2024. Main Outcomes and Measures Percentage of all DCT accrued participants with a residential zip code more than 120 miles from 1 of 3 AMC sites. Results There were 7469 participants (median [IQR] age, 62 [51-70] years; 3594 [48.1%] female; 241 [3.2%] Asian, 391 [5.2%] Black or African American, and 6347 [85.0%] White individuals) accrued to 765 DCTs. During the study period, the percentage of DCT participants residing more than 120 miles from an AMC site ranged from 18.9% in the first quarter (Q1) of 2024 (383 of 2032 participants) to 29.6% in Q1 of 2025 (346 of 1170 participants). Of those accrued, 1147 (15.4%) were of a racial or ethnic URP, ranging from 12.5% in Q1 of 2024 (253 participants) to 17.4% in Q1 of 2025 (204 participants). There were 1554 (20.8%) participants from a rural location, ranging from 16.6% in Q1 of 2024 (338 participants) to 24.9% in Q1 of 2025 (291 participants). Additionally, by geospatial distance from an AMC site, the male-to-female ratio was nearly 50:50, and the age distribution appeared similar. Conclusions and Relevance In this quality improvement study of a DCT program implementation, DCT accruals trended favorably among those residing more than 120 miles from an AMC site and those of rural or URP populations. While these findings cannot be directly attributed to program implementation, they are reassuring that this strategy may address some barriers to clinical trial access. Future studies should assess the sustained effectiveness and scalability of DCT models in improving equitable trial access.

A 46-year-old female was admitted to the hospital for confusion, cognitive decline, and hallucinations with alcohol withdrawal. Her history was notable for Alcohol use disorder (AUD) and family history of Alzheimer's disease (AD). Comprehensive workup was unrevealing for metabolic encephalopathy, infection, or nutritional deficiencies. Phosphatidyl ethanol level was 1181, indicating severe alcohol misuse. Phospho-Tau 217 testing raised suspicion of AD and FDG-PET scan confirmed patterns consistent with early onset AD. AUD can precipitate earlier or more severe onset of AD. Phospho-Tau 217 can be a useful screening marker to identify people at risk of AD to prompt intensive treatment.