Citations

Background Radionuclide SPECT/computed tomography (CT) is standard for diagnosing transthyretin cardiac amyloidosis (ATTR-CM), but the prognostic value of quantitative metrics remains incompletely defined. We investigated their prognostic utility and additive value beyond existing staging systems. Methods Retrospective study of patients undergoing technetium-99m-pyrophosphate (PYP) SPECT/CT, including consecutive clinically referred patients (October 2023 to 2024) and trial participants with positive scans from January 2022. Myocardial PYP was quantified using standardized uptake values (SUV mean and SUV max ) and volumetric measures [percent injected dose (%ID), cardiac amyloid activity (CAA)]. Major adverse cardiovascular events (MACEs) comprised heart failure hospitalization or death. Cox and Kaplan–Meier analyses assessed associations; likelihood ratio testing and change in area under the curve (AUC) evaluated the additive prognostic value to existing staging systems. Results Among 43 patients with ATTR-CM, 16 experienced MACE over a median 518 days. AUCs ranged from 0.74 to 0.88 at 3 months and 0.56–0.62 at 12 months. All variables trended toward association with MACE: SUV mean ( P = 0.02), SUV max ( P = 0.03), %ID ( P = 0.06), and CAA ( P = 0.06). After age adjustment, cut-points for SUV max (5.8) and SUV mean (3.5) remained associated with MACE. Adding imaging variables to the National Amyloidosis Centre and Columbia staging systems did not significantly improve prognostic accuracy (Δ χ 2 : 0.40–2.48, P = 0.11–0.53). Interobserver reproducibility was high (intraclass correlation coefficients = 0.89–0.99). Conclusion Quantitative Tc-99m–PYP SPECT/CT metrics were associated with short-term outcomes in ATTR-CM, but did not improve established staging systems. Findings are hypothesis-generating and require validation in larger cohorts.

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

Community engagement and trust are vital to medical education and improving health. The experience of national level, extramural seed grant programs to support faculty in both education and health care delivery with the focus of building trust has not been previously reported. The authors reviewed a total of four cohorts of the “Building Trust: Advancing Health Equity” grant recipients supported by the ABIM Foundation and other funding partners. Over $1.5 million was awarded from 2021 to 2024, which represented 92 grants ranging from $2,500–$40,000 each. The geographic regions receiving the most grants and funding were the middle and south Atlantic, and the Pacific regions in the United States. University programs received more grants and funding than affiliated or community programs. The majority of project types primarily focused on developing educational curricula for internal medicine residents (68%) and engaging with local communities (19%). The approach to implementation often included service-learning and community experts (29%), quality improvement and patient care delivery methods (22%), and traditional curriculum development (21%). The most common education topic themes were health equity and social determinants of health (43%) and addressing bias in care delivery and learning environment (20%). The Building Trust grant program reflects the unique needs of local communities and supported innovative practices and educational techniques. Implementation support was provided to grantees through shared experiences and mentorship. Evaluating outcomes upon completion of grants will be an imperative next step. This serves as a model that can inform institutions and other professional organizations approaching implementation of seed grant funding.

Abstract Improved understanding of how chimeric antigen receptor (CAR) and endogenous T‐cell phenotypes associate with progression‐free survival (PFS) is needed to individualize and improve immunotherapy outcomes in multiple myeloma (MM). We characterized and investigated the prognostic value of immune dynamics defined with multidimensional and computational flow cytometry in 258 bone marrow aspirates from 107 MM patients treated with idecabtagene vicleucel in the KarMMa trial. At screening, there was an association between longer PFS and increased percentages of PD1 + cytotoxic T cells and ICOS − TIGIT + Tregs. At Month 1 after infusion, the presence of >1% CAR‐T cells, a CD4/CD8 CAR‐T‐cell ratio >0.09, and greater abundance of non‐activated non‐cytolytic CAR‐T cells identified patients with longer PFS. Notably, 47 of the 115 endogenous T‐cell clusters were prognostic at the latest assessment performed after CAR‐T infusion. Lower percentages of ICOS + TIGIT − Tregs showed the strongest association with longer PFS. Altogether, this large dataset of dynamic immune profiling throughout treatment with anti‐B‐cell maturation antigen (anti‐BCMA) CAR‐T cells uncovered that the T‐cell composition prior to apheresis as well as CAR‐T and endogenous T‐cell phenotypes after infusion associates with PFS. These findings have potential for translation into routine laboratory practice for improved understanding of response and resistance to CAR‐T cells in relapsed/refractory MM.

ABSTRACT Introduction Chronic gastroduodenal disorders remain challenging to manage, and new diagnostic approaches are needed to better delineate underlying causes and guide therapeutic decisions. Body Surface Gastric Mapping (BSGM) technologies combine high‐resolution gastric myoelectrical activity measurements with symptom and psychological profiling to provide mechanistic insights into gastric motor and sensory dysfunction. An International Working Group convened to derive the first consensus classification of BSGM phenotypes (the “Auckland Classification”). Methods A Technical Group conducted a systematic literature and clinical database review to identify objective test biomarkers and candidate disease mechanisms. Evidence was synthesized across 50 studies (primarily in gastroparesis, chronic nausea and vomiting, and functional dyspepsia), and BSGM phenotypes were mapped to existing treatment guidelines. Subsequently, iterative review and development of consensus was performed by a Consensus Group composed of international clinical experts familiar with BSGM. Eleven statements underlying the classification were then derived and circulated as a final survey to establish agreement. Results Six BSGM phenotypes were endorsed: three defined by myoelectrical abnormalities (Dysrhythmic, High Frequency, and Low Meal Response) and three by characteristic symptom associations (Sensorimotor, Continuous, and Delayed Onset Symptoms). Published studies plausibly linked these phenotypes to mechanisms including interstitial cell of Cajal depletion, vagal impairment, hypomotility, visceral hypersensitivity, gut‐brain dysregulation, and small bowel dysfunction. Phenotypes were also mapped to existing mechanism‐based treatment guidelines. Ten out of the eleven statements had > 80% agreement. Conclusions The Auckland Classification, derived by international consensus, presents a structured framework for BSGM‐defined patient phenotypes. Evidence and mechanism‐based treatment options are suggested for each phenotype to provide a foundation for research, further validation, and a pathway for integrating BSGM into clinical care.

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

ABSTRACT Objective Little is known about shifting from pediatric to adult‐focused multiple sclerosis (MS) care. This study aims to explore transition of care and follow‐up in the US pediatric‐onset MS (POMS) population. Methods Surveys were distributed to 10 sites in the US Network of Pediatric MS Centers (US NPMSC) about transition‐of‐care practices. A cohort of POMS/clinically isolated syndrome (CIS) at 12 US NPMSC sites was analyzed. The primary comparison was between < 18 and ≥ 18‐years of age. The primary outcome was 1‐ and 2‐year lapse in last follow‐up visit, measured from last recorded database visit to data lock date or, if ≥ 18 years of age, up to 1 year after a patient reached their site's typical transition age, if earlier. Secondary outcomes were baseline factors associated with follow‐up lapse. The model was adjusted for preidentified confounders. Results Compared with < 18 years, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse. In POMS/CIS, the estimated hazard was 1.61 for 1‐year lapse (95% confidence interval [CI] 1.32–1.97, p < 0.001) and 1.40 for 2‐year lapse (95% CI 1.11–1.76, p = 0.004). In POMS‐only, the estimated hazard was 1.70 for 1‐year lapse (95% CI 1.33–2.18, p < 0.001) and 1.49 for 2‐year lapse (95% CI 1.11–1.99, p = 0.007). Platform injectable disease‐modifying therapy was associated with greater and intravenous with lesser hazard of lapse in follow‐up, while MS was associated with lower hazard than CIS. Conclusion Variable transition‐of‐care practices and barriers were reported by major US POMS centers. Before typical transition age, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse than < 18. Developing standardized, targeted transition‐of‐care practices in POMS may be important.

Abstract Introduction: Lymphomas are among the most common malignancies in dogs, and their morphologic and biological similarities to human counterparts have established them as widely accepted models of human disease. However, emerging molecular data suggest that conservation varies by subtype, and that many common lymphoma subtypes are principally convergent rather than homologous conditions, requiring a critical reassessment of when and how canine lymphomas provide relevant models of human disease. Methods: We employed conventional pathology, immunohistochemistry, and next generation sequencing platforms, including single-cell sequencing and spatial genomics, to characterize the transcriptional landscape and cellular organization of canine lymphomas, complemented by population metadata. Results: Our analysis revealed that canine DLBCL lacks the traditional GCB/ABC bifurcation seen in humans. While activation of NFκB pathways is seen commonly in these tumors, a germinal center-like DLBCL subtype is not apparent in dogs, and the transcriptional signatures are distinct from those of activated B-cell like DLBCL. Instead, we identified a novel canine-specific DLBCL subset driven by an AP-1-associated transcriptional signature, mirroring advanced human follicular lymphoma rather than human DLBCL. In contrast, emerging data suggest that downregulation of quiescence programs might be a shared feature of both human and canine MZLs, making this subtype a candidate for conserved disease mechanisms. While canine T-cell lymphomas exhibited extensive transcriptional heterogeneity, the samples in our dataset did not align with established human T-cell subgroups, suggesting that high incidence in dogs might not equate to molecular similarity. Conclusions: Our results suggest canine and human lymphomas are principally convergent rather than homologous diseases whose evolution and topological organization are constrained by developmental programs. The distinct transcriptional programs of canine and human DLBCLs reveal informative biological divergence, while potential shared features of MZL suggest contexts where comparative oncology may illuminate conserved disease mechanisms. Canine T-cell lymphomas exhibit extensive transcriptional heterogeneity that, at present, defies simple classification, mirroring challenges in their human counterparts and underscoring the need for larger studies to establish molecular patterns that inform causation, prognosis, and treatment. These findings highlight contexts where distinct and conserved molecular features between canine and human lymphoma can reveal shared and divergent disease mechanisms, ultimately underscoring the need for subtype-specific validation as canine lymphomas are adopted as models of human disease. Use of AI: Generative AI was used to improve clarity and readability of the abstract. AI was not used to conduct the study or to produce new text or material. Citation Format: Jaime F. Modiano, Amy E . Treeful, Grace E. Walker, Davis M. Seelig, Caitlyn M. Callaghan, Timothy D. O'Brien, Shruthi Naik, Aaron L. Sarver. Different paths to the same destination: Molecular divergence and functional convergence in human and canine lymphomas [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A023.

Abstract Background Oligodendrogliomas were previously defined by histology, but since 2016, the WHO has integrated molecular signatures to create the entity of IDH-mutant 1p/19q-codeleted oligodendroglioma. These tumors harbor recurrent genetic alterations—including IDH mutations, CIC and FUBP1 loss-of-function mutations, and PI3K-activating mutations—that collectively define a genetic profile distinct from IDH-mutant astrocytoma and IDH wild-type glioblastoma. The paucity of faithful model systems has impeded progress in advancing mechanistic insights and therapeutic development for oligodendroglioma. Results To test whether recurrent mutations found in oligodendroglioma patients would drive tumor formation in mice, we utilized in utero electroporation to introduce combinations of gain- and loss-of-function mutations into the developing cortex. Initial tests that included expression of IDH-and PIK3CA-mutants with Cic and Fubp1 loss (termed Oligo) were non-tumorigenic but biased cells towards glial lineages. Introducing Cdkn2a-loss, which is normally suppressed by IDH-associated epigenetic changes in human tumors, to the Oligo combination (termed Oligo-Cdkn2a) resulted in fully penetrant tumor formation. Histopathological review showed the Oligo Cdkn2a-loss mouse model resembled grade II/III oligodendroglioma with rounded nuclei and open chromatin. If Trp53-loss is used (termed Oligo-Trp53) in place of Cdkn2a-loss, tumor histology shifts to a more astrocytic phenotype with angulated nuclei with denser chromatin, demonstrating a direct impact of Trp53-loss on histological features. Bulk RNA-sequencing verifies metabolic alterations driven by the presence of IDH-mutations in Oligo-Cdkn2a mouse models compared to an IDH wild-type GBM model. Single-cell transcriptional profiling shows that Oligo-Cdkn2a tumors contain an increased population of tumor cells that resemble more differentiated oligodendrocytes. Examination of the tumor immune microenvironment within Oligo-Cdkn2a and IDHWT GBM mouse models is being performed to determine changes in immune cell infiltration and transcriptional programs. Conclusion We have created, to our knowledge, the first murine model of IDH-mutant 1p/19q-codeleted oligodendroglioma that incorporates Cic loss. This immune-competent mouse model of IDH-mutant 1p/19q-codeleted oligodendroglioma offers a powerful new tool for interrogating tumor biology and evaluating preclinical therapeutic strategies.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.