Citations

Abstract Motivation Intratumor heterogeneity arises from ongoing somatic evolution and complicates cancer diagnosis, prognosis, and treatment. Reconstructing evolutionary dynamics typically requires spatiotemporal samples, which are often unavailable in clinical settings. Computational approaches that can infer tumor evolutionary history from single-timepoint bulk sequencing data remain limited. Results We present estimating evolutionary events through single-timepoint sequencing (TEATIME), a novel computational framework that models tumors as mixtures of two competing cell populations: an ancestral clone with baseline fitness and a derived subclone with elevated fitness. Using cross-sectional bulk sequencing data, TEATIME estimates mutation rates, timing of subclone emergence, relative fitness, and number of generations of growth. To quantify intratumor fitness asymmetries, we introduce a novel metric—fitness diversity—which captures the imbalance between competing cell populations and serves as a measure of functional intratumor heterogeneity. Applying TEATIME to 33 tumor types from The Cancer Genome Atlas, we revealed divergent as well as convergent evolutionary patterns. Notably, we found that immune-hot microenvironments constraint subclonal expansion and limit fitness diversity. Moreover, we detected temporal dependencies in mutation acquisition, where early driver mutations in ancestral clones epistatically shape the fitness landscape, predisposing specific subclones to selective advantages. These findings underscore the importance of intratumor competition and tumor-microenvironment interactions in shaping evolutionary trajectories, driving intratumor heterogeneity. Lastly, we demonstrate that TEATIME-derived evolutionary parameters and fitness diversity offer novel prognostic insights across multiple cancer types. Availability and implementation R implementation of TEATIME is available on GitHub (https://github.com/liliulab/TEATIME) and Zenodo (https://zenodo.org/records/17422174).

Objective: This post hoc analysis of the CHAMPION-NMOSD trial evaluated the safety and efficacy of ravulizumab in patients with aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) previously exposed or naïve to rituximab (RTX). Methods: Patients received weight-based intravenous ravulizumab with a loading dose followed by maintenance dosing every 8 weeks. Patients were stratified by prior RTX exposure: no RTX exposure (RTX-naïve) vs RTX exposure > 3 months before initiating ravulizumab (RTX-exposed). Key outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), relapse rates, and vaccination timing from the last RTX dose. Results: Of the 58 patients enrolled, 89.7% were female, with a mean age of 47.4 years, and 21/58 (36.2%) were RTX-exposed. Relapses occurred in 12/21 (57.1%) RTX-exposed patients between their first RTX dose and study entry. The safety profile of ravulizumab was generally similar between RTX-exposed and RTX-naïve groups. Common TEAEs included COVID-19, headache, urinary tract infection, and upper respiratory tract infection. UTIs were more frequent in RTX-exposed individuals. One patient in each group experienced a meningococcal infection. No adjudicated on-trial relapses were reported while on ravulizumab. Conclusions: Following initiation of ravulizumab, RTX-exposed and RTX-naïve patients with AQP4-Ab+ NMOSD achieved sustained disease control and demonstrated a manageable safety profile. Clinical Trial Information: The CHAMPION-NMOSD Trial; ClinicalTrials.gov identifier: NCT04201262 (registered October 06, 2020).

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

794 Background: HER2 protein, encoded by ERBB2 gene, is the target of emerging therapies for patients (pts) with advanced urothelial carcinoma (aUC). High HER2 IHC expression (IHC 3+) is present in ~15% of pts with aUC, while >50% of pts have HER2 IHC 1+/2+/3+ expression. EVP is the preferred 1 st line regimen for pts with aUC, but the impact of HER2 status on EVP outcomes is unclear. Methods: We identified pts from the UNITE study with tumor samples tested for HER2 by IHC and another cohort with next-generation sequencing (NGS) data available. Outcomes were compared by HER2 IHC status (HER2 IHC 0/1+ vs 2+/3+) and separately based on ERBB2 status (alteration vs wild-type). X 2 test was used to compare observed response rate (ORR) and logistic regression was used to compare disease control rate (DCR). Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) from EVP start were evaluated using log-rank test and Cox proportional hazards models. Multivariate analysis (MVA) included age, sex, race, ECOG PS, neutrophil:lymphocyte ratio, albumin, hemoglobin, primary tumor site, tumor histology, prior lines of treatment, and metastatic sites as covariates. Results: Among 521 pts treated with EVP from 16 sites, 112 had HER2 IHC data and 313 had NGS. Median age was 71, 74% were men, 84% Caucasian, 82% had ECOG PS 0-1, 65% pure urothelial histology, and 73% received frontline EVP. HER2 IHC distribution (n=112) was 27%/21%/37%/15% for 0/1+/2+/3+, respectively. ERBB2 alterations were present in 14% (44/313). Baseline characteristics were similar in HER2 0/1+ and 2+/3+ pts, except more primary bladder tumors in 2+/3+ pts (83% vs 63%, p=0.01). For the overall cohort (n=521), with a median follow up of 7.3 mos from EVP start, ORR was 54%, DCR 81%, median DOR (mDOR) 8.5 mos, median PFS (mPFS) 8.5 mos, and median OS (mOS) 19.8 mos. Pt outcomes by HER2 IHC status are shown (Table). In univariate analysis (UVA), pts with HER2 IHC 0/1+ had longer mOS compared to HER2 IHC 2+/3+, but this was not significant in MVA (HR: 0.5; CI: 0.2–1.3, p=0.17). No significant differences were observed in other outcomes. Evaluating clinical outcomes by ERRB2 status, no significant differences were seen for ERBB2 -altered vs wild-type pts. Conclusions: In this retrospective study, no significant differences were seen in EVP treatment outcomes based on HER2 IHC status or ERBB2 status. These findings are hypothesis-generating and require validation in larger and prospective cohorts. HER2 0/1+ (n=54)* HER2 2+/3+ (n=58) OR (95%CI, p) HR UVA (95%CI, p) HR MVA (95%CI, p) ORR 49% (23/47) 55% (27/49) 1.3 (0.6-2.9, p=0.5) - - DCR 79% (37/47) 88% (43/49) 1.9 (0.7-6.2, p=0.2) - - mDOR 11.7 mos 10.4 mos - 1.3 (0.7-2.4, p=0.4) 1.2 (0.4-3.3, p=0.8) mPFS 5.9 mos 7.1 mos - 0.8 (0.5-1.4, p=0.5) 1.1 (0.5-2.5, p=0.9) mOS 42.4 mos 18.7 mos - 2.3 (1.1-4.5, p=0.02) 2.0 (0.8-5.4, p=0.2) *HER2 0/1+ used as reference.