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TPS277 Background: Recent advances in genomic sequencing have deepened our understanding of the molecular complexity of metastatic castration-resistant prostate cancer (mCRPC), revealing multiple actionable alterations that now inform biomarker-driven treatment strategies. Accordingly, germline and somatic tumor profiling is recommended for all patients with mCRPC. Beyond DNA aberrations, gene expression profiling can uncover additional therapeutic targets and pathway activations. The phase 2 PREDICT trial is leveraging both DNA and RNA alterations to guide rationally designed, biomarker-based therapeutic approaches for patients with mCRPC. Methods: This multi-center, multi-arm, biomarker-driven phase 2 umbrella trial is evaluating rationally selected therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint is objective response rate in patients with measurable disease, with secondary endpoints including radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative biomarker analyses. Eligible patients must have progressive mCRPC of any histology, prior treatment with an androgen receptor pathway inhibitor (ARPI), and either prior or declined taxane chemotherapy, with both measurable and non-measurable disease permitted. Enrollment requires standard-of-care next-generation DNA sequencing from tissue or circulating tumor DNA performed in a CLIA-certified laboratory, and RNA-based allocation will use the CLIA-certified Caris MI Tumor Seek assay (whole exome and whole transcriptome sequencing) on tissue obtained within 12 months of study entry, with a real-time molecular tumor board reviewing results to confirm arm assignment. Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician’s choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977). Clinical trial information: NCT06632977 .

BACKGROUND: Cerebral microbleeds (CMBs) are associated with dementia, but the impact of specific microbleed patterns (with distinct pathophysiologies) is unclear. Lobar CMBs commonly result from cerebral amyloid angiopathy (sometimes with cortical superficial siderosis [cSS]), while subcortical microbleeds indicate a hypertensive cause. This study investigates the association of CMB presence, patterns, and frequency with dementia risk. METHODS: Participants from the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study), a community-based longitudinal cohort, with a 3T research magnetic resonance imaging scan at visit 5 (2011–2013) and without prior intracerebral hemorrhage or dementia were included. CMB and cSS presence and location were evaluated using a T2* gradient-recalled echo sequence. Each individual’s pattern of CMBs was classified as no CMBs, subcortical only, mixed (subcortical and lobar±cSS), lobar±cSS only, or cSS. Dementia adjudication was determined by blinded review of cognitive testing, informant interviews, and hospital discharge codes or death certificates (from follow-up visits and ongoing surveillance). Cox proportional hazards models assessed associations between CMBs and incident dementia through 2020, adjusted for demographics, vascular risk factors, and white matter hyperintensities. RESULTS: Among 1583 participants (mean age, 76 years; 24.7% cumulative dementia incidence over a median of 23.6 follow-up years), 361 had CMBs. Compared with individuals without CMBs, those with mixed (hazard ratio, 1.99 [95% CI, 1.40–2.83]) or lobar±cSS (hazard ratio, 1.96 [95% CI, 1.30–2.97]) CMB patterns had increased dementia risk, whereas individuals with a subcortical-only pattern did not (hazard ratio, 1.04 [95% CI, 0.78–1.39]). cSS presence (n=21; versus absence) showed an increased risk of dementia (hazard ratio, 2.57 [95% CI, 1.36–4.89]). Greater numbers of microbleeds across all CMB subtypes exhibited an increased risk of dementia. CONCLUSIONS: Lobar and mixed CMB patterns and increasing numbers of CMBs are associated with incident dementia. Certain CMB patterns have differential associations with dementia, but severe enough disease burden, regardless of CMB distribution, is associated with increased dementia risk.

Abstract Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier versus later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier versus later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed-effects models to estimate how much earlier versus later each individual progresses on plasma phosphorylated tau (p-tau)217, amyloid PET, tau PET and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cut-off points, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R = 0.38–0.47) in the MCSA and stronger (R = 0.74–0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET Alzheimer’s disease biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14–28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.

BACKGROUND: While health systems have implemented resources to improve lipid management in people with atherosclerotic cardiovascular disease, the population-level effectiveness is unclear. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease between January 1, 2021, and December 31, 2023, across 16 US academic health systems were analyzed. Atherosclerotic cardiovascular disease (defined by diagnosis and procedure codes) was established on or before the index date defined as the date of the most recent LDL-C (low-density lipoprotein-cholesterol) or the last day of the study period for those without an LDL-C available. Systems were surveyed to identify lipid management programs (eg, prevention/lipid clinic, electronic health record–based tools, and lipid management algorithms). Sequential multilevel multivariable logistic regression modeling was used to (1) assess the system-level association between an LDL-C <70 mg/dL and the presence of lipid management programs, adjusting for patient-level demographic and clinical characteristics, and (2) whether system-level uptake of statin or nonstatin lipid-lowering therapy was associated with an LDL-C <70 mg/dL. RESULTS: We included 1 738 042 patients with atherosclerotic cardiovascular disease (median, 88 365 per system; range, 17 086–2 48 371). About 81% of the health systems had prevention or lipid clinics. The proportion of those on statins ranged from 31.0% to 60.4% across health systems (median, 46.3%). Lower proportions were observed in the use of high-intensity statins (16.2%–33.1%), nonstatins (2.6%–8.1%), and combination lipid-lowering therapy (1.7%–6.3%). Among those with an LDL-C level available (n=890 521), 42.5% had an LDL-C <70 mg/dL, ranging 35.8% to 49.4% across systems. There was no association between the odds of achieving LDL-C <70 mg/dL and health system lipid management algorithm, prevention clinics/lipid clinics, or electronic health record–based tools. Neither system-level high-intensity statin utilization nor nonstatin use was associated with an LDL-C <70 mg/dL. CONCLUSIONS: Despite variability in lipid management resources and lipid-lowering therapy use across systems, many did not reach an LDL-C <70 mg/dL, and there was low uptake of lipid-lowering therapy. Innovative implementation strategies are needed for system-level lipid management.

Abstract Few prospective benchmark studies exist to characterize the evolving contemporary real-world practice for peripheral T-cell lymphoma (PTCL). We report the patterns of first-line care and outcomes for 720 patients with systemic PTCL enrolled in 2 related prospective cohort studies, Lymphoma Epidemiology of Outcomes (LEO) from 2015 to 2020 and Molecular Epidemiology Resource (MER) from 2002 to 2015, both followed to 2024. The primary end points were event-free survival (EFS) and overall survival (OS) using Kaplan-Meier estimator and Cox regression model. Secondary end points included correlations of clinical and treatment factors with survival. The most common induction regimens were CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based (70%), given as CHOP (36%), CHOP plus etoposide (23%), or CHOP-like plus novel agents (11.5%, including 5% BV-CHP [brentuximab plus cyclophosphamide, doxorubicin, and prednisone]). Consolidative autologous stem cell transplant was performed in 102 patients (14%). Within nodal PTCL, EFS and OS were adversely associated with International Prognostic Index 2 to 5, prognostic index for T-cell lymphoma score 1 to 4, and non–anaplastic large-cell lymphoma (ALCL) subtypes. Within LEO, which captured increasing first-line etoposide and brentuximab vedotin, adding etoposide to CHOP was associated with better OS in anaplastic lymphoma kinase-negative ALCL. BV-CHP showed a trend toward OS improvement in ALCL. Patients failing EFS6 and EFS24 had 5-year subsequent OS of 12% and 17%, respectively. The inferior outcomes in non-ALCL subtypes and patients failing EFS6 and EFS24 highlight unmet needs with CHOP-based induction, where clinical trials with targeted therapy should be prioritized. This trial was registered at www.clinicaltrials.gov as NCT02736357.

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) placement is a common treatment for idiopathic normal pressure hydrocephalus (iNPH), but patients may require VPS revision. This study aims to evaluate the effectiveness of a standardized VPS placement protocol by comparing indications and rates of shunt revision compared with a historical institutional cohort. METHODS: All patients treated with VPS for “suspected” iNPH at a tertiary care center between January 2000 and January 2023 were retrospectively reviewed and divided into temporally distinct historical (before 2017) and standardized (after 2017) cohorts. Cumulative incidence and timing of VPS revision were compared using competing risks analyses. RESULTS: A total of 561 patients (median age 75.0 years) were identified with 324 (57.8%) in the historical and 237 (42.2%) in the standardized cohorts. Significant variations in surgical technique and shunt hardware were noted between the cohorts. With a median follow-up of 11.4 months for historical and 12.4 months for standardized cohort, shunt revisions occurred in 19.4% and 8.4% of patients in the historical and standardized cohorts, respectively ( P < .001). Revision indications also varied significantly with lower rates of overdrainage ( P < .001), infection ( P < .001), and proximal malfunction ( P = .042) but higher rate of distal malfunction ( P = .03) in the standardized cohort. Notably, no infections were noted in the standardized cohort. CONCLUSION: Risk of shunt revision among iNPH patients may be associated with modifiable factors related to surgical technique and shunt hardware selection. Importantly, no short-term complications such as hemorrhage, infection, or catheter malposition were observed with the standardized protocol. Development and refinement of standardized shunt protocols for iNPH patients should be commonplace to facilitate tracking, identification, and modification of modifiable technical risk factors.

Abstract Individuals who have serum elevations of anti-cyclic citrullinated protein (anti-CCP) antibodies are at risk for developing rheumatoid arthritis (RA), yet immunologic factors that lead to a transition from pre- to clinical RA remain unclear. Here, we used materials from anti-CCP antibody-positive individuals enrolled in a clinical trial that evaluated the efficacy of hydroxychloroquine to prevent clinical RA, and performed multi-modal single-cell profiling (transcriptome, surface proteins, T/B-cell receptor sequencing, and chromatin accessibility) on samples obtained at baseline and at RA onset in those who developed clinical RA (Converters) or follow-up point in matched Nonconverters. At both baseline and follow-up, Converters had expansions of peripheral helper T (Tph) cells and CD8 + T cells expressing GZMK and GZMB , along with elevated potentially autoreactive T-cell receptors in CD4 + T cells compared to Nonconverters. Induction of age-associated B cell signatures was observed in B cells of Converters prior to RA onset. Epigenetic profiling further identified chromatin accessibility changes in Converters over time, particularly within myeloid and NK cells. Lastly, predictive modeling using baseline immune features, including Tph cells, GZMK + XCL1 + CD8 + , and GZMB + CD57 + CD8 + T cells, together with clinical features such as anti-CCP3 levels, RF-positivity, and HLA shared epitope status, stratified RA risk and predicted time to onset. These findings define immune endotypes in pre-RA that could serve as targets for future preventive interventions and be used to stratify the risk of developing clinical RA in anti-CCP antibody-positive individuals.

Background Increased chronological age correlates with reduced relapse rates and increased disability in multiple sclerosis (MS). Biological age may better capture ageing’s impact on MS and might accelerate due to MS itself. Establishing accelerated biological ageing in adults is complicated by normal ageing and comorbidities. Telomere length, a well-recognised biological ageing marker, is shortened in adults with MS and associated with disability. Demonstrating accelerated biological ageing in paediatric-onset MS (POMS) would strengthen the hypothesis that MS drives premature biological ageing. This study aimed to determine if telomere length differs in POMS compared to age-similar healthy controls. Methods We performed a cross-sectional case-control study of whole blood samples and clinical data from The US Network of Pediatric MS Centers. Real-time quantitative PCR measured telomere length, expressed as a telomere to somatic DNA ratio (T/S ratio). T/S ratio was compared between cases and age-similar healthy controls using multivariate regression analysis adjusting for chronological age, sex, race, ethnicity, tobacco exposure, socioeconomic status and body mass index. Results We analysed 300 POMS cases and 200 controls. The unadjusted mean T/S ratios were 1.66 (SD 0.32) for cases and 1.71 (SD 0.29) for controls (mean difference –0.05, 95% CI –0.10 to 0.01, p=0.08). After adjusting for key covariables with face validity, POMS participants had a mean 0.086 shorter T/S ratio than controls (95% CI 0.015 to 0.157, p=0.018). Conclusions POMS participants demonstrated shorter telomeres than age-similar controls in a multivariable model adjusting for sociodemographic variables, suggesting that MS may contribute to accelerated biological ageing.