Citations

Summary Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26/28) of patients ( P = 3.2x10 -5 ) and accurately identified 83% (10/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.

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 This study aimed to explore the effect of family history (FH) and polygenic risk scores (PRS) for multiple psychiatric disorders on lithium response in bipolar disorder (BD). Method The sample included patients from the Mayo Clinic BD Biobank. FH in first‐degree relatives was obtained via the patient questionnaire. Linear regression models tested the association of FH and PRS for BD, major depressive disorder (MDD), schizophrenia (SCZ), alcohol use disorder (AUD), anxiety disorder (ANX), and attention‐deficit/hyperactivity disorder (ADHD) with lithium response measured by the Alda A score adjusted for the Alda B sum score. Post hoc models additionally adjusted for clinical covariates (age at onset, rapid cycling, and BD subtype). Results 716 patients had Alda scores for lithium response (61.9% females, mean age = 43.4 years). FH‐BD ( β = −0.57, p = 0.015), AUD ( β = −0.44, p = 0.045), and ANX ( β = −0.61, p = 0.050) were associated with worse lithium response. After adjusting for clinical covariates, associations for FH‐BD and FH‐ANX were no longer significant. PRS‐BD was associated with better response ( β = 0.22, p = 0.041), while PRS‐MDD ( β = −0.28, p = 0.01) and PRS‐ADHD ( β = −0.24, p = 0.028) were associated with worse response, with effects largely unchanged after adjusting for clinical covariates. In the combined model considering all FHs simultaneously, only FH‐BD remained significantly associated with worse lithium response ( β = −0.71, p = 0.039). In the combined model for PRS, only PRS‐BD ( β = 0.31, p = 0.008; better response) and PRS‐MDD ( β = −0.29, p = 0.020; worse response) showed significant associations. Conclusions In this exploratory study, FH‐BD, AUD, and ANX were associated with poor response, though only FH‐AUD remained significant after adjusting for clinical factors. PRS‐BD predicted better response, while PRS‐MDD was associated with worse response. These findings suggest independent and potentially complementary roles of FH and PRS. Integrating both familial and genetic risk measures may improve personalized treatment strategies and outcomes for BD patients.