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Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Alcohol use disorder is linked to a multitude of diseases and disorders, many of which can be diagnosed with imaging techniques such as US, CT, and MRI, enabling early detection and potentially preventing further damage and improving outcomes.

Radiologists are integral members of the interdisciplinary team for patients with mucinous appendiceal neoplasms and can directly affect care by suggesting the diagnosis of pseudomyxoma peritonei, optimizing imaging protocols for evaluating peritoneal implants, and reporting the primary tumor and spilled tumor cells thoroughly.

5069 Background: Ra-223 improves the overall survival in patients with mCRPC to the bone. We assessed the safety of standard-of-care Ra-223 in combination with peposertib, a DNA-dependent protein kinase inhibitor, with or without avelumab, an anti-PD-L1 antibody. Methods: Patients with mCRPC and two or more skeletal metastases identified by bone scintigraphy with or without lymph node metastases up to 3 cm in size, but no visceral metastases, were eligible. Progression after progression after at least one androgen receptor pathway inhibitor or taxane was required. Phase 1 consisted of a two-step sequential safety lead-in using a 3+3 design. Step 1 combined 6 standard cycles of Ra-223 (55 kBq/kg), with increasing doses of peposertib: 50, 100, and 200 mg PO bid on days 3-26 of each cycle. Step 2 combined Ra-223 with the maximum tolerated dose of peposertib and added standard avelumab 800 mg IV every 14 days, starting at cycle 2 of Ra-223. Results: A total of 9 patients participated in Step 1, where the maximum tolerated peposertib dose of 200 mg PO bid with Ra-223 was deemed tolerable. A total of 6 patients participated in Step 2 and the combination of Ra-223, peposertib at 200 mg PO bid, and standard avelumab was deemed tolerable. Of the 15 patients in Phase 1, none experienced grade 4 or higher treatment-related toxicities, while 7 experienced grade 3 toxicities, including neutropenia (1), anemia (1), cardiac chest pain (1), fall (1), maculopapular rash (2), and lymphopenia (2). The median (Q1, Q3) PSA velocity from the beginning to the end of treatment was lower for Step 2 versus Step 1: 2.1 (-0.1, 4.6) versus 23.5 (18.6, 77.1) ng/mL/month (p = 0.0067). OS and PFS were calculated with the limitation that the Phase 1 was non-randomized. Median OS was not reached for Step 2, as only 1 of 6 patients had died, versus 15.2 months for Step 1, where 8 out of 9 patients had died (p = 0.0537). The patient who died in Step 2 discontinued therapy prematurely after 3 cycles due to progression and survived 15.2 months (the 5 alive completed all 6 cycles). The median radiographic PFS was 7 months for Step 2 versus 12.7 months for Step 1 (p = 0.8910). Conclusions: The combination of Ra-223 and peposertib, with or without avelumab was well tolerated. The triplet combination showed the most promising results at this early evaluation. We continue to accrue in the randomized Phase II portion of the trial. Clinical trial information: NCT04071236 .

e15024 Background: Anetumab ravtansine (AR) is an antibody-drug conjugate (ADC) containing the microtubule inhibitor DM4. ADC drugs have high interpatient variability in pharmacokinetics and pharmacodynamics (PK/PD), which raises concerns whether current dosing based on body weight (mg/kg) is optimal. Thus, we evaluated the effects of patient characteristics, including novel biomarkers of the innate immune system (IIS), on the PK/PD of AR. Methods: Studies were performed in patients in three clinical trials of different cancers with AR as part of treatment: 1) platinum-resistant or refractory high-grade ovarian cancer treated with AR at 2.2mg/kg IV weekly plus bevacizumab(N = 19); 2) pleural mesothelioma treated with AR at 6.5 mg/kg IV every 3 weeks plus pembrolizumab(N = 28); and 3) mesothelin-positive advanced pancreatic adenocarcinoma treated with AR at 5.5-6.5 mg/kg IV every 3 weeks plus nivolumab (and ipilimumab or gemcitabine, N = 27). Intensive plasma PK sampling was performed after the first dose to calculate clearance (CL), volume of distribution (Vd), and area-under-the-plasma-concentration-time curve (AUC 0-inf ). The relationship between biomarkers of FcɣRs (CD64, CD32, CD16) on IIS blood cells, total body weight (TBW), body surface area (BSA), lean body mass (LBM), and sex with PK parameters and clinical outcomes were evaluated by pearson correlation, t-test and multivariate regression analysis. Population PK (popPK) methods further evaluated patient covariates and variability in PK. Results: Patients with higher IIS FcγR CD64 and/or higher TBW or higher BSA had higher AR ADC CL (p < 0.05). AR ADC CL was lower in females (0.030 ± 0.007 L/h) versus males (0.042 ± 0.006 L/h) (p < 0.05). Patients with stable disease and partial response had higher AR ADC AUC 0-inf versus patients with progressive disease AR ADC disposition was described by linear CL with two pathways for the release of the payload DM4, hydrolysis and the IIS. A time-varying drug-to-antibody ratio predicted the release of the DM4 payload. In the PopPK model, LBM and albumin were associated with CL of the AR ADC, LBM and IIS FcγR CD64 were associated with the Vd of the AR ADC, and LBM and age were associated with the CL of the released DM4. Conclusions: These results suggest that TBW-based dosing of AR ADC is not optimal, whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex may be more appropriate to reduce PK variability and improve response.

2030 Background: Brain metastases (BM) are common and arise in 30% of lung adenocarcinoma (LUAD) patients. Patients with LUAD that develop BM have significantly poorer outcomes, with a 10-16 month median overall survival. Unfortunately, current clinical practice for BM prediction is limited and so BM are typically detected after they develop and grow to cause neurological symptoms. Once BM are detected, currently neurosurgical tumor biopsies are performed to enable BM diagnosis via neuropathological evaluation. The aims of this study were to develop DNA methylation-based models that predict LUAD BM and non-invasively detect BM in blood to enable early diagnosis and treatment. Methods: DNA methylomes were acquired from 402 tumor tissue and plasma samples in a cohort of 346 LUAD and BM patients. Machine learning models were built using DNA methylation signatures that stratify BM risk in tissue and detect BM in plasma. Models were evaluated in independent validation datasets. A predictive nomogram was developed using the BM prediction model together with clinical factors to provide composite patient-specific scores reflecting BM risk. Results: The methylation-based BM predictor accurately stratified BM risk in a univariable Cox model using validation set data (HR = 5.65, 95%CI 1.85–17.2, p = 0.0023). Model utility was independent of the predictive value of clinical factors in a multivariable Cox model using validation set data (Table 1: HR = 8.92, 95%CI 1.97–40.5, p = 0.0046). The 5-year model accuracy was 0.81 and significantly higher than a similarly built cancer stage-based model (0.65), demonstrating utility over current practice. The combinatorial clinical-methylomic predictive nomogram had enhanced utility with an accuracy of 0.82 univariable Cox HR of 17.2 (95%CI 4.13–71.3, p < 0.0001), demonstrating comprehensive patient-specificity. The plasma-based model accurately classified BM from gliomas and lymphomas (AUROC=0.80), as typical clinical differential diagnoses, in validation set data. The models were validated further in additional external data. Conclusions: DNA methylation-based modeling of BM can accurately predict LUAD patients at risk for BM development and can non-invasively detect BM that develop. Future treatment approaches may tailor initial LUAD treatment and ongoing cancer surveillance to a patient’s BM risk, allowing for the potential to prevent and treat BM early. DNA methylation-based BM prediction is independent of clinical factors in a multivariable Cox proportional hazards model. Variable HR 95% CI p Methylome risk score 8.92 1.97–40.5 0.005 Age Years 0.96 0.92–1.02 0.177 Smoking Pack-years 0.99 0.95–1.03 0.496 EGFR Mutant vs wildtype 0.92 0.25–3.34 0.895 T T2 vs T1 1.58 0.41–6.04 0.505 T3−4 vs T1 1.49 0.28–7.98 0.642 N N1 vs N0 1.05 0.31–3.58 0.943 N2−3 vs N0 1.00 0.27–3.69 0.995 M M1 vs M0 145 12.2–1730 <0.001

10512 Background: Polygenic risk scores (PRSs) combine information from single-nucleotide polymorphisms (SNPs) across the genome to explain substantial genetic breast cancer (BC) susceptibility. Previous studies have demonstrated that a multiple-ancestry PRS (MA-385) based on 56 ancestry-informative and 329 BC-associated SNPs is accurate for diverse populations and ranks among the most important known factors affecting the risk of BC development. However, medical guidelines call for more evidence before endorsing the clinical use of PRS, including studies to evaluate possible interactions of SNPs with environmental and hormonal risk factors. Here, we use longitudinal outcomes from the UK Biobank (UKB) to explore interactions of MA-385 and the five most informative individual BC-associated SNPs with the widely used Tyrer-Cuzick (TC) risk model and individual TC risk factors. Methods: The study cohort included 197,509 female UKB participants with no history of cancer at the time of study enrollment. We used Cox proportional hazards models to test associations of MA-385, individual BC SNPs, TC, and individual TC risk factors with BC outcomes. Effect modification of MA-385 and individual SNPs by clinical risk factors was evaluated by including interaction terms in the models. All models were adjusted for age at UKB enrollment and 10 principal components. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported per standard deviation, and significance tests were performed using two-sided p-values based on likelihood-ratio test statistics. Results: After a median follow-up of 11.8 years, 7,419 (3.8%) participants were diagnosed with BC.In a model including both MA-385 and TC, MA-385 was a significantly better predictor of BC development (HR = 1.56; 95% CI 1.53-1.60, p = 3.2 x 10 -329 ) over the TC model (HR = 1.21; 95% CI 1.18-1.23; p = 5.4 x 10 -69 ). We found no evidence of interaction between MA-385 and TC ( p = 0.31) , nor between individual SNPs and TC. After Bonferroni adjustment for multiple testing (102 tests), we found no evidence of interaction between MA-385 or individual SNPs with clinical TC factors. The strongest evidence for interaction was found between a BC SNP on chromosome 2 (rs13387042) and age at UKB enrollment (unadjusted p = 0.002; Bonferroni adjusted p = 0.23). Conclusions: In a longitudinal analysis of UKB, MA-385 was a highly significant predictor of BC risk and substantially improved prediction over TC. In contrast, interactions of MA-385, and individual BC SNPs, with TC and individual clinical factors in the TC model were not statistically significant. Clinical TC factors have minimal, if any, impact on the strength of the association between MA-385 and BC. These results may help to alleviate concerns expressed in guidelines that SNPs interact with environmental or hormonal risk factors.

7014 Background: Mosun is a CD20xCD3 bispecific antibody that can be administered in the outpatient setting for a fixed duration. Intravenous Mosun is approved for the treatment of relapsed/refractory FL after ≥2 prior lines of therapy. Mosun SC achieved high response rates with manageable safety in patients with 3L+ FL in a pivotal Phase II study (Bartlett et al. ASH 2024). We report the efficacy and safety of Mosun SC in patients with previously untreated high-tumor burden FL in the Phase II MorningSun study (NCT05207670). Methods: Patients with previously untreated high-tumor burden FL, per GELF criteria, were enrolled into this cohort. Mosun SC was administered with step-up dosing in Cycle (C)1 (Day [D]1, 5mg; D8, 45mg; D15, 45mg) then 45mg on D1 for up to 17 cycles (1 year; 21-day cycles). Patients with a partial or complete metabolic response (CMR) after C17 could receive additional Mosun maintenance therapy (45mg every 8 weeks for up to 1 year). Corticosteroid prophylaxis to reduce the risk of cytokine release syndrome (CRS) was mandatory in C1–2 and optional thereafter. The primary endpoint was progression-free survival (PFS) rate at 24 months. Key secondary endpoints included objective response rate (ORR), time to response (TTR), and safety. Results: As of May 29, 2024, 102 patients were enrolled; 55 patients had completed initial treatment (17 cycles), 31 had discontinued (most commonly due to progressive disease [n=19] and adverse events [AEs; n=4]), and 16 were ongoing initial treatment. Forty-two patients received maintenance treatment, and this was ongoing in 38 patients. Median age was 65 years (range: 24–86); 52.0% of patients were female. Most patients had Ann Arbor stage III/IV (91.2%) and a FLIPI score ≥2 (78.4%). Median duration of follow-up was 13.9 months. The 12-month PFS rate was 82.8% (95% confidence interval [CI]: 73.0–89.3). ORR was 87.3%; 60.8% of patients had a CMR. Among the 89 patients with a response, the median TTR was 2.7 months (range: 1.2–5.8). The most common AEs (≥30%) were injection-site reaction (57.8%), fatigue (42.2%), CRS (34.3%), headache (31.4%), and nausea (30.4%). Grade ≥3 AEs and serious AEs (SAEs) were reported in 44.1% and 29.4% of patients, respectively. CRS events were all Grade 1/2 and SAE of CRS occurred in 10.8% of patients (Table); all events resolved. Conclusions: Mosun SC demonstrated promising efficacy in patients with previously untreated high-tumor burden FL. The manageable safety profile, including rate of CRS, supports the administration of fixed duration Mosun SC in an outpatient setting. Additional data, including cytokine profiling and T/B/NK dynamics, will be presented. Clinical trial information: NCT05207670 . CRS events, n (%) PatientsN=102 Any grade 35 (34.3) Grade12 30 (29.4)5 (4.9) SAE 11 (10.8) ManagementSteroidsTocilizumabSteroids + tocilizumabFluidsICU admission 8 (7.8)6 (5.9)3 (2.9)3 (2.9)2 (2.0)

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

ABSTRACT Background Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra‐rare, acquired non‐malignant haematological disorder characterised by thrombosis risk, serious complications and debilitating symptoms in untreated patients. Objective This anchored indirect treatment comparison (ITC) evaluated efficacy data between proximal complement 3 inhibitor (C3i) pegcetacoplan and factor B inhibitor, iptacopan, in patients with PNH previously treated with complement 5 inhibitors (C5i; eculizumab, ravulizumab). Methods Respective pivotal studies provided patient‐level trial data for pegcetacoplan (16‐week PEGASUS [NCT03500549]) and published data for iptacopan (24‐week APPLY PNH [NCT04558918]). Differences in study design, duration and statistical methods between PEGASUS and APPLY PNH necessitated the comparative analyses to be conducted on secondary measures based on haemoglobin (Hb) levels, absolute reticulocyte count (ARC), lactate dehydrogenase (LDH) levels, and patient‐reported outcomes on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐Fatigue) scale scores. The availability of a common reference C5i treatment group in both PEGASUS and APPLY PNH studies allowed anchored ITC (Bucher method). Simulated treatment comparison (STC) assessed the robustness of the main analysis. Results Overall, baseline characteristics of the populations in the PEGASUS and APPLY PNH studies were broadly comparable. Anchored ITC showed comparable outcomes (mean difference, [95% CI]) on change‐from‐baseline to end of study for pegcetacoplan versus C5i, and iptacopan versus C5i, respectively, across endpoints: Hb level ( − 0.49 g/dL [ − 1.78, 0.80]); ARC ( – 34.41 × 10 9 /L [ − 90.02, 21.21]); LDH level ( − 115.16 U/L [ − 244.40, 14.01]); FACIT‐Fatigue score (3.57 [ − 5.60, 12.73]). Finally, the STC produced results consistent with the main Bucher analyses across all clinical endpoints and patient‐reported fatigue, providing similar point estimates and confidence intervals. Conclusion This anchored ITC, based on data from pivotal trials, did not indicate significant differences in clinical or patient‐reported outcomes between pegcetacoplan and iptacopan in PNH treatment. The findings suggest that PNH treatment decisions should also consider individualised disease‐ and patient‐related factors. Trial Registration: ClinicalTrials.gov identifier: NCT03500549.