Citations

Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)–phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.

Since its US Food and Drug Administration approval in 2016, magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy has grown into one of the procedures of choice among patients with essential tremor (ET). Approved applications for the procedure have expanded over time from unilateral thalamotomy to treat ET and Parkinson disease tremor to bilateral staged thalamotomy for ET. As the procedure expands to healthcare environments beyond large academic centers, guidance is required to ensure that the responsible clinicians are appropriately trained to undertake this operative procedure. Although multidisciplinary movement disorder teams are important for the optimal management of patients, MRgFUS lesions are inherently surgical interventions. Neurosurgeons are trained to evaluate these patients, consider surgical alternatives and conduct these operations, particularly after completing a fellowship in the subspecialty of stereotactic and functional neurosurgery. At present, all high-level evidence regarding the safety and efficacy of MRgFUS lesions to treat movement disorders derives from procedures performed by neurosurgeons, so those results may not be generalizable to other physicians. Based on these considerations and potential liability issues, the American Society for Stereotactic and Functional Neurosurgery, which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, puts forth this position statement that only neurosurgeons appropriately trained to conduct functional neurosurgery procedures should conduct MRgFUS surgical lesions.

Abstract Background Radiation-induced heart disease (RIHD) may develop months to years following radiation therapy for cancers near the heart such as lung or breast cancer. Several mouse models of RIHD exist to study the pathogenesis of disease, but to our knowledge no studies have examined whether sex differences exist in RIHD in mice. Methods Female and male BALB/cJ mice received one whole heart dose of 22 Gray (Gy) radiation via a C5 collimator vs. sham controls that received 0 Gy, anesthesia and were placed in the X-ray machine for the same length of time. Mechanisms of cardiotoxicity were examined at 24 h (innate cardiotoxicity), day 10 (acute cardiotoxicity) and day 35 (chronic cardiotoxicity) post irradiation. Results Females and males developed dsDNA breaks from radiation at day 10 but females had more damage than males ( p < 0.001). Vessel area and cardiac hypertrophy were increased by radiation at day 10 and 35 but were higher in males than females at day 35 ( p < 0.001, p = 0.001, respectively). Bulk RNA sequencing of the heart at day 10 revealed that females and males developed similar gene pathway responses to radiation by upregulating cellular repair pathways and downregulated mitochondrial function. However, females upregulated the master regulator of mitochondrial function, Pgc1α ( p = 0.0001), suggesting improved mitochondrial repair in females. By day 35, males developed heart failure with reduced ejection fraction (HFrEF), inflammatory dilated cardiomyopathy (iDCM) and fibrosis while females developed heart failure with preserved ejection fraction (HFpEF) without inflammation or fibrosis. Conclusions We observed sex differences in nearly every cardiac parameter that we examined following radiation exposure. BALB/c males exposed to 22 Gy radiation developed HFrEF and iDCM by day 35 while females developed HFpEF. Further research is needed to better understand mechanisms driving sex differences in RIHD using translational animal models.

Background Graft-versus-host disease (GVHD) remains a major determinant of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Existing GVHD prediction models demonstrate modest discrimination and limited generalizability, and calibration drift across external populations is rarely characterized despite its essential role in the clinical interpretability of predicted probabilities. Objectives To develop and externally validate an explainable machine learning framework for predicting acute and chronic GVHD and associated overall survival in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS) undergoing allo-HSCT, and to systematically characterize calibration across heterogeneous external validation cohorts to inform deployment requirements. Study Design The model was developed on three publicly available registry-derived datasets (N = 2,509) and externally validated across six independent cohorts (N = 14,788) comprising adult and pediatric allo-HSCT recipients, including a regional Middle Eastern cohort (UAE and Jordan). A standardized preprocessing pipeline harmonized heterogeneous datasets. Gradient boosting models (CatBoost) were used for binary GVHD prediction; exploratory overall survival analysis used a Cox proportional hazards model with predicted acute GVHD risk as a covariate. Discrimination (AUROC with bootstrap 95% CI), calibration (logistic recalibration intercept and slope with analytical 95% CI), and feature importance (SHapley Additive exPlanations, SHAP) were assessed in training out-of-fold and all external cohorts. Results In internal validation, AUROC was 0.63 (95% CI 0.61–0.65) for acute GVHD and 0.72 (95% CI 0.70–0.74) for chronic GVHD. External validation demonstrated AUROC ranges of 0.51–0.57 (acute) and 0.54–0.64 (chronic), with consistent performance across disease subgroups despite substantial heterogeneity in transplant practices and feature availability. In exploratory survival analysis, the acute-GVHD-informed Cox model achieved a training-cohort C-index of 0.679 (95% CI 0.658–0.697); external C-indices ranged from 0.47–0.53. Calibration analysis identified systematic external risk overestimation (negative calibration intercept in 10 of 11 evaluable external cohort-target combinations) with heterogeneous slope drift requiring cohort-specific recalibration. Key predictors included recipient age, graft source, conditioning intensity, GVHD prophylaxis, and HLA match ratio. Conclusions An explainable, externally validated GVHD prediction framework was developed using heterogeneous registry-derived datasets, with systematic characterization of calibration drift across multiple external cohorts, an analysis rarely reported in prior GVHD prediction literature. Predictive performance was modest for acute GVHD and moderate for chronic GVHD, constrained by missing immunobiological variables and incomplete HLA characterization. Per-cohort recalibration is required before clinical deployment, with prospective validation and benchmarking against established GVHD risk scores identified as priority next steps.

Summary: Microsurgery is a specialized field within plastic surgery constrained by the high cost and limited availability of surgical microscopes, particularly in resource-limited settings. This lack of access hinders trainees from developing essential microsurgical skills. Previous efforts have explored smartphone-based alternatives, but there remains a need for high-fidelity, accessible training microscopes. This study presents a novel, low-cost, travel-friendly surgical microscope designed for microsurgery training. Modified binocular objective lenses enable near-field stereoscopic viewing using a dual-mirror array. A 3D-printed chassis provides the correct top-down orientation, and an integrated light source operates on standard or battery power, ensuring usability in low-resource environments. Initial testing demonstrated a fixed 6.5× magnification, allowing trainees to perform end-to-end anastomoses on 2-mm vessels. Prototypes were deployed for microsurgery training in the United States, Rwanda, Ethiopia, and Vietnam through the SHARE (Surgeons in Humanitarian Alliance for Reconstruction, Research and Education) plastic surgery organization, Nuoy Reconstructive International, and the senior author’s home institution. The authors’ investigation continues to assess the effectiveness of the microscope compared with state-of-the-art surgical microscopes. By offering a low-cost, portable solution without compromising image quality, this innovation has begun to transform microsurgical education and operating room–based microscopy worldwide, increasing accessibility for trainees and patients in diverse settings.

Abstract Early-phase clinical trials of BTK degraders in relapsed/refractory CLL have shown response rates of over 80%, including in patients with BTK mutations that confer resistance to conventional BTK inhibitors (BTKi). The molecular basis of resistance to BTK degraders is unknown and, given the promise of this class of drugs, would hold implications for therapy sequencing and the design of next-generation BTK degraders. To this end we identified five patients at Memorial Sloan Kettering who developed progressive disease while being treated on the phase 1 trials of zelebrudomide (NCT04830137, 4 patients) or bexobrutideg (NCT05131022, 1 patient). In two patients, one treated with zelebrudomide and the other with bexobrutideg, a pre-existing BTK A428D mutation had expanded at progression, rising from &lt;1.5% at the start of treatment to &gt;25%. In both cases, the increase in frequency of BTK A428D coincided with the loss of BTK degradation in peripheral blood B cells. No mutation in cereblon, the ligase utilized by these BTK degraders, was detected. To validate these clinical findings we generated wild-type and BTK A428D knock-in single-cell clones in TMD8 and HBL1 cells. BTK A428D conferred resistance to BTKi, including ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, as well as the clinical-stage BTK degraders zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1, WO 2023183811). BTK A428D’s pan-resistance is unique compared to previously studied BTKi resistance mutations which remain susceptible to at least one BTKi and all clinical-stage BTK degraders tested. To understand how BTK A428D confers pan-resistance to BTKi and BTK degraders we conducted surface plasmon resonance studies which demonstrated that BTKi and all four clinical-stage BTK degraders tested are unable to bind BTK A428D. We next solved the crystal structure of apo BTK A428D to 1.8Å, which revealed that the mutant aspartate, which is larger and negatively charged compared to the wild-type alanine, sterically blocks BTKi and degraders from accessing residues in the hinge region of the kinase that are required for drug binding. We next asked why BTK A428D, despite conferring pan-resistance, has only been detected in 1.1% of patients treated with BTK inhibitors. Intriguingly, we noted that in one of our index patients, the frequency of BTK A428D declined and became undetectable after the withdrawal of zelebrudomide, suggesting a fitness defect. To assess this hypothesis, we compared the proliferation rates of five TMD8 wild-type and five BTK A428D single-cell clones; the BTK A428D clones grew more slowly and were consistently outcompeted in mixing studies. In summary, low-frequency BTK A428D mutations can expand under the selection pressure of BTK degraders and confer clinical resistance by preventing drug binding. The mutation, however, is outcompeted in the absence of BTK-targeted therapies. These findings provide rationale for the investigation of combination therapies and the development of next-generation BTK degraders capable of circumventing BTK A428D. Citation Format: Quinlan Sievers, Hao Lu, Allison Cool, Stefan Grajewski, Tim Kong, Mark Noviski, Xiaoli Mi, Emel Ficici, Ratul Mukerji, James Iuliano, Jordan Ye, Mateo Sanchez Garcia de los Rios, Hugo Bousquet, Sarah Whelan, May Tan, Christopher Phelps, Jahan Raman, Ryan Notti, Lizbeth Mendoza Navarrete, Samantha Sekeres, Eria Lamkin, Eduardo Bravo, Mark Ewalt, Prioty Islam, Anthony Mato, Lindsey Roeker, Justin Taylor, Meghan Thompson, Gwenn Hansen, Omar Abdel-Wahab. BTK A428D is a recurrent pan-resistance mutation to BTK degraders in clinical trials [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 PR004.

Abstract Background: Canine nodal marginal zone lymphoma (MZL) is the second most common histologic diagnosis of diffuse B-cell lymphomas in dogs, but a molecular profile that can distinguish this condition from the more common canine diffuse large B-cell lymphoma (DLBCL) has been elusive. Here, we use single-cell sequencing to define the transcriptomic signatures of canine MZL before and after oncolytic virotherapy followed by traditional chemotherapy. Objective: The aims of this study were to define the canine MZL transcriptome at single cell resolution and to evaluate its changes in the face of selective pressures introduced by therapy. Methods: Longitudinal biopsies and fine needle aspirates were collected from a dog with MZL enrolled in an immunotherapy trial. Peripheral blood B-cells from healthy dogs served as reference controls. Single-cell sequencing was done using the 10x Genomics Chromium GEM X platform (v3.1), and data was aligned to the canFam4_Y genome. Quality control, clustering, and cell annotation were performed using Seurat in R (v4.4.0). Differential gene expression analysis (DGEA) was performed on 500 randomized MZL B-cells and 500 healthy canine B-cells. InferCNV was deployed on the longitudinal MZL samples for prediction of tumor B-cell CNV profiles. Results: When compared to normal peripheral blood B-cells, the tumor cells were characterized by downregulation of quiescence-associated genes, including KLF2. Copy number analysis uncovered loss on canine chromosome 20 (CFA20) encoding KLF2, gain on CFA13, and gains on CFA32 and CFA36. While an anti-viral T-cell response was identified after VSV treatment, the B-cell subpopulations retained stable transcriptomes, with a disappearance of proliferating B-cells after chemotherapy. Conclusion: This is the first report describing the molecular properties of canine MZL at single cell resolution. Clonal diversity was apparent in the tumor, with copy number loss on CFA20, presumably leading to loss of KLF2. The transcriptional features of the tumor cells remained stable even in the face of a T-cell response to an oncolytic virus. Taken together, the results document silencing of KLF2 as a key phenotypic homology between canine and human MZL, supporting the potential for comparative approaches to enhance our understanding of the significance of KLF2 silencing in this disease. Citation Format: Elise Weir, Grace Walker, Jaime F. Modiano, Aaron L. Sarver, Shruthi Naik, Amy Treeful. Reduced KLF2 expression in canine marginal zone lymphoma mirrors human disease [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 A043.

Abstract Recent single-cell transcriptomic studies of follicular lymphoma (FL) have revealed heterogeneity among malignant B (MB) cells and selected components of the tumor microenvironment (TME), but have been constrained by relatively small sample sizes and a lack of spatial context. We performed comprehensive cellular profiling and spatial dissection of over five million cells by integrating single-nucleus RNA sequencing (snRNA-seq) from 182 samples (FL, n = 167; control, n = 15) with single-cell spatial transcriptomics (ST) from 386 samples (FL, n = 365; control, n = 21). After stringent quality control, 1,289,073 and 3,968,427 cells from snRNA-seq and ST data, respectively, were analyzed. Unsupervised clustering of snRNA-seq data identified 58 TME cell subtypes. To extend this classification to the ST dataset, we integrated snRNA-seq and ST data by co-embedding them into a shared principal component space, enabling robust batch correction and cell-type label transfer across modalities. Using this supervised annotation framework, ST data recapitulated 54 TME cell subtypes. MB, proliferating MB (MBprolif), and healthy B (HB) cells were classified using sample-level unsupervised clustering in ST. Macrophages exhibited previously uncharacterized heterogeneity in transcriptomic profiles and spatial distribution. We identified CXCL13-expressing macrophage subtypes with high intra- and peri-follicular abundance, termed follicular macrophages (FMs). Non-negative matrix factorization of intrafollicular cell fractions identified five TME archetypes: FM, follicular stroma, two follicular T, and HB archetypes. The FM archetype was enriched for intrafollicular macrophages, including FMs, and showed a significantly higher proportion of grade 3A/3B cases (53.4%) compared to other archetypes (≤16.5%). It was also associated with a higher frequency of high tumor burden requiring treatment initiation rather than a watch-and-wait (WW) approach. Among patients managed by WW, those with the FM archetype showed significantly shorter event-free survival (EFS) compared to those with non-FM archetypes, whereas this association was not observed among treated patients. The percentage of intrafollicular macrophages (IFMP) showed excellent predictive performance for the FM archetype (area under the curve: 0.90). IFMP calculated in a published multiplex spatial protein imaging dataset from an independent cohort of 242 FL patients validated the associations between high IFMP and both pathology grade 3A/3B and shorter EFS in WW patients. Consistently, spatial neighborhood and cell–cell communication analyses revealed co-localization of FMs and MBprolif cells, forming a distinct niche with activated signaling mediated by FM-derived CXCL13, APRIL, and BAFF. Our integrative multi-modal analysis defines previously unrecognized cellular heterogeneity and spatial architecture in FL and highlights macrophage-enriched follicular ecosystems associated with aggressive clinicopathological features, providing a framework for improved biological understanding and patient management. Citation Format: Yoshiaki Abe, Bijal Thakkar, Atish Kizhakeyil, Ashley Wilson, Andrew L. Feldman, Jared Henderson, Amy Ayers, Sara Borgschatz, R. Andrew Harkins, Priya Lakra, Daisuke Kaji, Jonathon B. Cohen, David Russler-Germain, Eric Mou, Francisco Vega, Jennifer Chapman, Giorgio Inghirami, Carla Casulo, Izidore S. Lossos, Jean L. Koff, Chijioke Nze, Peter Martin, Sergei Syrbu, Kiran Vij, David L. Jaye, James R. Cerhan, Christopher R. Flowers, Anne J. Novak, Richard Burack, Dai Chihara, Mamiko Sakata-Yanagimoto, Joshua Tobin, Xubin Li, Michael R. Green. Spatially resolved microenvironment profiling reveals distinct follicular lymphoma archetypes [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 A049.

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.