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BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

Importance Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood. Objective To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated. Design, Settings, and Participants This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor−positive ERBB2 -negative (formerly HER2 -negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025. Intervention Random assignment to CET or ET. Main Outcomes and Measures Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes. Results Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was −3.02 (95% CI, −5.33 to −0.72; P = .01) for premenopausal and −2.37 (95% CI, −3.92 to −0.82; P = .003) for postmenopausal participants. Conclusions and Relevance This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT01272037

Objectives: In the United States, training for physicians who manage critically ill adult patients (intensivists) evolved through parallel subspecialty critical care medicine (CCM) pathways with significant commonality. The Society of Critical Care Medicine Adult Critical Care Physician Core Knowledge and Skills Task Force aimed to delineate the common core knowledge and skills required of all intensivists. Design: A master list of content areas and procedural skills was compiled from all CCM subspecialty program requirements and blueprints of the certification examinations. Using a modified Delphi approach, participants were asked to categorize the knowledge items as “advanced knowledge is essential,” “general, but not advanced, knowledge is essential,” or “knowledge is not essential.” Procedures were categorized as “intensivist performs routinely,” “intensivist only performs in an emergency,” or “intensivist knows” about the procedure. Setting: Representatives from CCM stakeholder organizations, including accreditation and certification organizations, critical care societies, and program directors’ societies, were invited to participate. SUBJECTS: Members of the Adult Critical Care Physician Core Knowledge and Skills Task Force of the Society of Critical Care Medicine. Interventions: For the first two rounds of the modified Delphi process, Research Electronic Data Capture was used. For the third and fourth rounds, the process was completed through online meetings with Zoom (Zoom Video Corporations, San Jose, CA) utilizing Zoom’s polling feature. Measurements and Main Results: A total of 541 items were determined to be essential, with 145 requiring advanced knowledge and 323 requiring general knowledge. For 73 items, consensus regarding advanced vs. general could not be achieved, but they remained essential. Only eight items were felt to be nonessential. Of the 16 procedures, most were categorized as “intensivist performs.” Conclusions: The large number of items included in the list of essential knowledge and skills demonstrates the complexity of modern CCM. Utilization of a common framework across the subspecialties of CCM could lead to greater harmonization among the fellowship program requirements and certification examinations.

BACKGROUND: End colostomy reversal with colorectal anastomosis (Hartmann’s reversal) is a technically challenging procedure associated with significant morbidity due to adhesions and distorted anatomy after the index surgery. OBJECTIVE: To compare perioperative outcomes of open, laparoscopic, and robotic approaches for Hartmann’s reversal. DESIGN: Retrospective analysis of prospectively maintained data. SETTINGS: High-volume tertiary referral center with specialized colorectal surgery expertise. PATIENTS: A total of 218 patients who underwent Hartmann’s reversal between May 2018 and April 2023. MAIN OUTCOME MEASURES: Primary outcomes included hospital length of stay and rate of conversion. Secondary outcomes included overall complication rates and time to return of bowel function. RESULTS: Of 218 patients, 139 (63.8%) underwent open surgery, 48 (22.0%) underwent laparoscopic surgery, and 31 (14.2%) underwent robotic surgery. Robotic surgery had the lowest estimated blood loss (median 77.5 vs 100 mL laparoscopic and 150 mL open, p < 0.0001). Conversion to open surgery occurred in 16.1% of robotic cases compared with 35.4% of laparoscopic cases ( p = 0.0618). Minimally invasive approaches were associated with shorter hospital length of stay (median 3.0 vs 4.0 days, p < 0.0001) and faster return of bowel function (median 2.0 vs 3.0 days, p = 0.0095) compared to open surgery. Overall 30-day morbidity was 23.4%, with no significant difference among approaches ( p = 0.30). The temporal trend showed increasing adoption of robotic techniques, from 0% in 2018 to 53.8% in 2023, and a decrease in the proportion of cases approached by open surgery, from 76.9% in 2018 to 23.1% in 2023. LIMITATIONS: Retrospective design and single-institution experience with limited follow-up duration. CONCLUSIONS: Minimally invasive approaches to Hartmann’s reversal are associated with improved short-term outcomes compared to open surgery. The robotic approach shows promise in reducing conversion rates, potentially extending the benefits of minimally invasive surgery to more patients undergoing this challenging procedure. See Video Abstract . COMPARACIÓN DE LOS ENFOQUES ABIERTO, LAPAROSCÓPICO Y ROBÓTICO PARA LA REVERSIÓN DE HARTMANN: LA EXPERIENCIA DE LA CLÍNICA MAYO ANTECEDENTES: La reversión de la colostomía terminal con anastomosis colorrectal (reversión de Hartmann) es un procedimiento técnicamente complejo asociado a una morbilidad significativa debido a las adherencias y la distorsión anatómica tras la cirugía inicial. OBJETIVO: Comparar los resultados perioperatorios de los abordajes abiertos, laparoscópicos y robóticos para la reversión de Hartmann. DISEÑO: Análisis retrospectivo de datos mantenidos prospectivamente. ENTORNO: Centro terciario de referencia de gran volumen con experiencia especializada en cirugía colorrectal. PACIENTES: Un total de 218 se sometieron a la reversión de Hartmann entre mayo de 2018 y abril de 2023. PRINCIPALES MEDIDAS DE RESULTADOS: Los resultados primarios incluyeron la duración de la estancia hospitalaria y la tasa de conversión. Los resultados secundarios incluyeron las tasas generales de complicaciones y el tiempo de recuperación de la función intestinal. RESULTADOS: De los 218 pacientes, 139 (63,8 %) se sometieron a cirugía abierta, 48 (22,0 %) a cirugía laparoscópica y 31 (14,2 %) a cirugía robótica. La cirugía robótica tuvo la menor pérdida de sangre estimada (mediana, 77,5 ml frente a 100 ml en laparoscopia y 150 ml en cirugía abierta, p < 0,0001). La conversión a cirugía abierta se produjo en el 16,1 % de los casos robóticos frente al 35,4 % de los casos laparoscópicos ( p = 0,0618). Los abordajes mínimamente invasivos se asociaron con una estancia hospitalaria más corta (mediana de 3,0 días frente a 4,0 días, p < 0,0001) y un retorno más rápido de la función intestinal (mediana de 2,0 días frente a 3,0 días, p = 0,0095) en comparación con la cirugía abierta. La morbilidad global a los 30 días fue del 23,4 %, sin diferencias significativas entre los distintos enfoques ( p = 0,30). La tendencia temporal mostró un aumento en la adopción de técnicas robóticas, del 0 % en 2018 al 53,8 % en 2023, y una disminución en la proporción de casos abordados mediante cirugía abierta, del 76,9 % en 2018 al 23,1 % en 2023. LIMITACIONES: Diseño retrospectivo y experiencia de una sola institución con una duración de seguimiento limitada. CONCLUSIONES: Los enfoques mínimamente invasivos para la reversión de Hartmann se asocian con mejores resultados a corto plazo en comparación con la cirugía abierta. El enfoque robótico es prometedor para reducir las tasas de conversión, lo que podría ampliar los beneficios de la cirugía mínimamente invasiva a más pacientes que se someten a este procedimiento tan complejo. ( AI-generated translation ).

Abstract Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable response rates in relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma. However, durable remissions occur in only 40% of treated patients, highlighting mechanisms of therapeutic resistance and immune escape. While cytotoxicity is principally executed by CAR T-cells, monocytes shape CAR-T cell efficacy and orchestrate cytokine-driven immunity. In this study, we defined distinct metabolic profiles of T-cell and monocyte subsets based on clinical response. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing (scTCR-seq) were performed on peripheral blood mononuclear cells at three timepoints: before lymphodepletion (BL), at peak CAR-T expansion (PK), and one-month post-infusion (M1). Data were processed with CellRanger v7.0.1 and analyzed with the immunopipe pipeline (Wang et al., 2025). Seurat v4.3.0 was utilized for unsupervised hierarchical clustering analysis; subsets identified included classical monocytes (CM), intermediate monocytes (IM), non-classical monocytes (NM), and monocytic myeloid derived suppressor cells (mMDSC). Metabolic profiles were compared across patients achieving ≥6-month complete remission (CR, n=16), primary refractory disease (PD1, n=4), or relapsed after a prior response (PD2, n=12). A total of 107035 T cells and 129981 monocytes from 77 serial samples in 32 patients were analyzed. CR patients had a higher T-cell:monocyte ratio than PD1/PD2 at all time points, especially at BL and PK (BL 1.2 vs 0.4, p=0.011; PK 1.3 vs 0.3, p=0.027). Clinical responses were compared with metabolic pathway analysis and identified oxidative phosphorylation (OXPHOS) as the dominant pathway. OXPHOS was consistently enriched in PD cohorts across T-cell subsets, particularly in PD1 vs CR at BL (mucosal-associated invariant T-cell (MAIT) and T peripheral memory (Tpm)), and at PK (CD4/CD8 memory precursor effector cells (MPEC) and activated MPECs (MPECa), CD4 T-helper 1 proliferating (Th1p), CD4 Th2 activated (Th2a), regulatory T-cell (Treg), CD8 naive senescent (CD8NS), CD8 T effector memory (Tem) tumor recirculating (TR), CD8 Tpm, CD8 T resident memory (Trm) TR and MAIT Tpm). By M1, OXPHOS enrichment in CD4/CD8MPECa, CD4Th2a, CD8NS, CD8TemTR reversed, now predominant in CR although CD8Tpm and CD8TrmTR remained enriched in PD1. In the monocyte subsets at BL, PD2 showed OXPHOS enrichment in CD163+ monocytes (mono), IM IL1, mMDSC SIRPA, mMDSC TGFβ, and CM IL6 subsets compared to PD1 and CR, while PD1 showed OXPHOS enrichment in IM CD38, CM TGFβ, and mMDSC HIF1A vs CR and PD2. This persisted at PK. By M1, the pattern reversed and mirrored that of T-cells, with CR patients showing OXPHOS enrichment in CD163+mono, CM IL6, CM TGFβ, IM CD38, mMDSC HIF1A, mMDSC SIRPA and mMDSC TGFβ, and additionally in CM EMT, CM p53, NM, NM CD36 vs PD1/PD2. Glycolysis/gluconeogenesis (GLY) was also enriched across subsets. In T-cells, PD1 vs CR showed GLY enrichment in CD4Th2a, CD8Tpm, CD8Tpm proliferating and MAIT Tpm at PK. In monocytes, GLY was enriched in PD1/2 vs CR at BL (CD163+mono, CM IL6) and PK (CD163+mono, IM CD18, mMDSC SIRPA). By M1, GLY metabolism was enriched in CR vs PD1/PD2 in CD163+mono, CM IL6, mMDSC SIRPA. Additional GLY enriched subsets at CR vs PD1 included CM, CM p53, EMT, IM CD38, IM IL1, mMDSC HIF1A, NM, NM CD36. Inositol phosphate metabolism (IP) was predominantly enriched in PD2 vs CR at BL (CD8NS, CD8Tcm, CD8Tpm activated), PK (CD4Th2, CD8NS, CD8Tem TR, CD8Tpm proliferating, γδT Tem) and M1 (CD4/CD8 MPECa, CD4 Th1/Th2, CD8NS, CD8Tpm, CD8 Tpm proliferating, Treg and MAIT Tpm). Notably, Treg was the only T-cell subset enriched for IP at PK in CR vs PD1/PD2. Additionally, the TCA cycle was enriched in PD1 Tregs and Th2 cells at BL and PK vs CR/PD2. A higher T-cell:monocyte ratio in CR vs PD1/PD2 supports prior evidence that elevated pre-lymphodepletion lymphocyte:monocyte ratios predict better outcomes. We identified distinct metabolic signatures in T-cells and monocytes between CR and PD1/PD2. OXPHOS enrichment in T-cells and monocytes at M1 in CR patients may reflect oxidative programming as a hallmark of sustained anti-tumor immunity. Conversely, GLY enrichment in PD1 T-cells at PK may reflect short-lived effector states lacking persistence. Overall, these findings highlight metabolic profiling as a promising predictive biomarker and therapeutic programming target to enhance CAR T-cell outcomes.

ABSTRACT Purpose Magnetic resonance elastography (MRE) of the heart has predominantly utilized breath‐held acquisitions with limited anatomic coverage. This work investigates the feasibility of 3D, free‐breathing cardiac MRE. Methods A 3D hybrid radial and EPI acquisition is utilized and combined with retrospective binning of k ‐space via physiologic monitoring, iterative reconstruction, MRE processing and inversions, and post‐processing specialized for cardiac imaging. Results Feasibility of free‐breathing stiffness mapping of the left ventricular myocardium was demonstrated in 11 participants. Myocardial stiffness estimates were obtained throughout the left ventricle for seven temporal states of the cardiac cycle. Stiffness estimates were presented in participant‐specific images, 17‐segment bullseye plots, and stiffness plots throughout the cardiac cycle. Results indicate increased stiffness in systolic states, with localized stiffness heterogeneity observed between participants, illustrating a key benefit of 3D cardiac MRE acquisition. Mean stiffness estimates obtained through 11 subjects were 4.44 ± 0.68 kPa (begin‐systole), 5.74 ± 0.94, 5.42 ± 0.87 (end‐systole), 3.84 ± 0.71 (begin‐diastole), 3.51 ± 0.74, 3.54 ± 0.52, and 3.55 ± 0.59 kPa (end‐diastole). Statistical testing indicated significant differences in stiffness across cardiac states with one‐way, repeated‐measures ANOVA ( p < 0.001) and Friedman's test ( p < 0.001). Experiments in scanning three participants with and without applied motion indicated that stiffness changes were more robustly detected in systole than in diastole, although patterns were subject‐specific. Comparison of free‐breathing stiffness measurements against reference breath‐held measurements yielded similar systolic stiffness estimates. Conclusions This study establishes the feasibility of free‐breathing, 3D cardiac MRE in healthy volunteers. With the current framework, stiffness estimation appears more robust in systole, and the reliability of diastolic estimates is limited and subject‐specific.

Abstract Introduction: Patients with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM) have historically experienced poor clinical outcomes, prompting the development of novel therapeutic options. Idecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor (CAR) T cell therapy approved for this population, while teclistamab became the first approved bispecific antibody. Both target B-cell maturation antigen (BCMA) and are increasingly used in real-world (RW) settings. Most comparative evidence to date is derived from single-arm clinical trials with cross-trial adjustments. RW studies offer an opportunity to directly compare these therapies and assess their relative effectiveness in routine clinical practice. Methods: We conducted a comparative effectiveness analysis of ide-cel and teclistamab in patients with TCE RRMM using RW data from the United States Flatiron Health electronic health record-derived, deidentified database (January 2011 to April 2025 data cut). Adults who received either index therapy at any line of treatment after becoming TCE (ie, previously exposed to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) were included. Exclusion criteria were prior exposure to CAR T cell therapy, bispecific antibodies, or belantamab mafodotin; absence of index treatment; or lack of post-index follow-up. Index dates (T0) represent the date of infusion for ide-cel and the start of treatment for teclistamab. Seventeen prognostic covariates were selected a priori based on published rankings and used to balance treatment groups via inverse probability of treatment weighting (IPTW) with average treatment effect weights. Cox proportional hazards models were used to estimate unadjusted and IPTW-adjusted HRs with 95% CIs for progression-free survival (PFS) and overall survival (OS). As the ide-cel cohort only included infused patients, additional analyses were performed to emulate a real-world intention-to-treat population given the potential immortal time bias (patients in the ide-cel cohort were required to survive between apheresis and infusion). Specifically, patients in the teclistamab cohort who died within the first 24 days (median turnaround time for ide-cel manufacturing in United States in 2024) were excluded and 2 scenarios were performed to re-align T0 based on this 24-day period (either shifting teclistamab T0 forward or ide-cel T0 backward). Lastly, sensitivity analyses assessed differences in restricted mean survival time (dRMST) at 12 and 24 months. Results: A total of 281 patients met the inclusion criteria (ide-cel, N=106; teclistamab, N=175), with median follow-up of 22.4 and 13.7 months, respectively. IPTW adjustment balanced all covariates between groups (effective sample size: ide-cel, n=68; teclistamab, n=135). Adjusted analyses showed improved PFS with ide-cel versus teclistamab (HR, 0.67; 95% CI, 0.47–0.97), with median PFS of 11.3 versus 6.5 months. OS was also improved with ide-cel (HR, 0.59; 95% CI, 0.35–0.98); median OS was not reached in either group due to insufficient follow-up. There was a consistent trend of HRs favoring ide-cel versus teclistamab for both PFS and OS in both scenario analyses addressing the potential immortal time bias. Further, sensitivity analyses using dRMST confirmed statistically significant improvements in both PFS and OS with ide-cel across all scenarios at all time points evaluated. Conclusions: In this RW analysis, ide-cel was associated with superior PFS and OS compared with teclistamab in patients with TCE RRMM. These findings support emerging RW evidence favoring BCMA-directed CAR T cell therapies over bispecific antibodies and may inform treatment sequencing decisions in this high-risk population.

Abstract BACKGROUND Children exposed to poverty during frontline therapy for B-lymphoblastic leukemia (B-ALL) experience inferior overall survival (OS), higher relapse rates, and earlier relapse than their peers. Real-world data describing treatment patterns and survival after relapse of B-ALL are lacking and, as a result, the impact of poverty following relapse remains poorly understood. This study evaluated the association of poverty exposure, proxied by insurance status, with post-relapse survival and explored potential explanatory mechanisms, including disease biology and therapy utilization. METHODS Data from Retrospective Study of Contemporary Approaches to First Relapse in B-ALL (ReCALL-1), a multicenter retrospective cohort study of patients &lt; 30 years old with first relapse of B-ALL from 2018-2022, were used. The primary exposure was poverty, proxied by insurance status at relapse, categorized as any private insurance (poverty unexposed), public-only insurance (poverty exposed), no insurance, or unknown; the latter two were not included in comparative analyses due to low numbers. The primary outcome was OS. Secondary outcomes included measurable residual disease (MRD)-negative second complete remission (CR2), relapse after CR2, non-relapse mortality (NRM), with relapse treated as a competing risk, and receipt of cellular and immunotherapies. RESULTS Among 462 patients from 31 U.S. institutions, 41% had private insurance, 47% public-only insurance, 2% no insurance, and 10% unknown. Compared to privately insured patients, those with public insurance were more likely to be Hispanic (56% vs 19%, p&lt;0.001) and have non-English preferred language (30% vs 6%, p&lt;0.001). Non-Hispanic Black patients comprised 9% of those with public insurance and 5% of those with private insurance. Disease characteristics that differed by insurance status at relapse included: Ph-like cytogenetics, more common in publicly insured (23% vs 11%, p=0.002), and infant ALL, more common in privately insured patients (10% vs 5%, p=0.06). Publicly insured patients were more likely to have experienced major organ toxicity during frontline therapy (32% vs 18%, p=0.002) and very early relapse (&lt;18m from diagnosis: 43% vs 32%, p=0.07). Other demographic and disease characteristics, including relapse site and cytomolecular features, were similar by insurance status. With a median follow-up of 51 months from relapse, 4-year OS differed by insurance (log-rank p=0.02): 72% for private vs 56% for public insurance. After adjusting for race/ethnicity and language, public insurance increased the hazard of death by 65% (aHR 1.65 95% CI 1.13-2.42, p=0.004). The association remained, but was attenuated, when unbalanced disease characteristics (time to relapse, infant ALL, Ph-like cytogenetics, prior organ dysfunction) were included (aHR 1.47, 95% CI 1.00-2.16, p=0.05). Rates of MRD-negative CR2 were similar (85% public vs 87% private). However, point estimates suggested publicly insured patients had more relapse after CR2 (44% vs 37%, p=0.42) and higher 4-year NRM (16% vs 10%, Gray's test p=0.12), though neither were significant. Treatment choices for first relapse did not differ by insurance status. Utilization of intensive reinduction (91% vs 95% for public vs private, p=0.18) and clinical trial enrollment (22% for both) were similar. Receipt of cellular therapies did not significantly differ by public vs private insurance: Chimeric Antigen Receptor-T cells (CAR-T: 38% vs 34%, p=0.41), hematopoietic cell transplant (HCT: 42% vs 47%, p=0.32). Use of blinatumomab trended higher in those with private insurance (36% vs 45%, p=0.07), and inotuzumab was similar (11% for both, p=0.87). Median time from relapse to CAR-T or HCT was comparable (to CAR-T 102 vs 100 days, to HCT 117 vs 114 days). CONCLUSION This is the first study to demonstrate differential survival by insurance type, a proxy for poverty exposure, after first relapse of B-ALL. In this large multicenter, real-world cohort, patients with public insurance had worse OS after relapse than those with private insurance. The survival disparity existed independent of other SDOH factors. Adjustment for known high-risk disease features only partially accounted for the observed differences in OS. In contrast, rates of MRD-negative CR2 and receipt of CAR-T and HCT were comparable across insurance types. These findings highlight the urgent need to identify effective interventions that will ensure equitable outcomes after relapse.

Abstract Background: TP53-mutated myeloid neoplasms (MNs) represent one of the most lethal subgroups of blood cancers. The World Health Organization (WHO-5) recognize TP53-mutated (TP53mut) myelodysplastic syndrome (MDS) and International Consensus Classification (ICC) recognize TP53mut MDS and acute myeloid leukaemia (AML) as distinct disease entities, acknowledging their dismal prognosis and the urgent need for novel therapeutic strategies. However, key discrepancies exist between the classifications, creating uncertainty in diagnosis, influencing therapeutic decisions, and complicating clinical trial enrolment for patients with uniformly poor survival. Importantly, neither classifications included TP53-mutated myelofibrosis (MF), other myeloproliferative neoplasms (MPN), and MDS/MPN overlap syndromes, despite growing evidence that these cases carry similar adverse outcomes. To address these critical gaps, we conducted a comprehensive analysis across the full spectrum of TP53-mutated MN. Methods: We included TP53mut cases with variant allele frequency (VAF ≥2%) of AML, MDS, MDS/MPN overlap, myelofibrosis and other MPN managed at the Mayo clinic (Rochester, USA) and Local Health Network in South Australia (Australia). Cases were classified according to the revised 4th edition WHO classification (WHO-4R). Biallelic TP53 loss was defined as: (i) ≥2 mutations with VAF ≥2%; (ii) single TP53mut with VAF ≥2% plus 17p loss on karyotype, FISH, or SNP array; or (iii) single TP53mut with VAF ≥50% with or without 17p loss. Monoallelic loss was defined as a single TP53mut with VAF &lt;50% without 17p loss or copy neutral loss of heterozygosity. The primary endpoint was overall survival (OS) from diagnosis, censored at allogeneic transplantation. Conditional inference tree analysis was performed to define the effect of individual predictors on OS. Results: We identified 853 TP53mutMN cases including WHO-4R-defined AML (BM/PB blasts ≥20%, n=314; 36.8%), MDS with excess blasts-2 (EB-2; BM 10–19% or PB 5–19%, n=129; 15.1%), MDS-EB-1 (BM 5–9% or PB 2–4%, n=100; 11.7%), and MDS with low blasts (LB; BM &lt;5% and PB &lt;1%, n=228; 26.7%). MF included chronic phase (MF-CP, n=48; 5.6%), accelerated phase (MF-AP, n=7; 0.8%), and blast phase (MF-BP, n=17; 2.0%). Additional cases comprised other MPN-chronic phase (n=3, 0.4%) and MDS/MPN overlap syndromes (n=7, 0.8%). Of 848 evaluable TP53mut MN, 616 (72.6%) harbored biallelic TP53 loss and 232 (27.4%) had monoallelic loss, with 42.4% (n=98) of monoallelic cases harboring a complex karyotype (CK). Biallelic loss was highly prevalent in AML (83.1%), MDS (70.4%), and MDS/MPN overlap (71.4%), but was less frequent in cases with MPN (33.3%) and MF-chronic phase (25.0%). Across the spectrum, the frequency of biallelic loss increased stepwise with disease progression, rising from MDS-LB (62.8%) to MDS-EB1 (76.0%), MDS-EB2 (79.5%), AML (83.1%), and MF-AP/BP (79.2%) (P&lt;0.0001). In multivariable analysis, WHO-4R category, TP53mut VAF, biallelic loss and CK were independent predictors of poor survival in TP53mut MN. Conditional inference tree analysis stratified the cohort into seven prognostic groups with distinct median OS: (1) AML, MF-BP/AP, and MDS/MPN overlap regardless of mono/biallelic and CK status (n=335, 39.7%; median OS 4.0 months); (2) MDS-EB1/EB2 with biallelic loss or monoallelic plus CK (n=212, 25.1%; 7.2 months); (3) MDS-LB, MF-CP and MPN with CK (n=156, 18.5%, OS 10.2 months); (4) biallelic MDS-LB (n=28, 3.3%; OS 15.6 months), (5) monoallelic MDS-EB1/EB2 without CK (n=20, 2.4%; OS 26.2 months), (6) monoallelic MDS-LB without CK (n=57, 6.7%; OS 33.4 months), and (7) MF-CP and other MPN without CK (n=36, 4.3%; OS 37.0 months). This analysis defines a clear stepwise risk gradient, identifying subsets with extremely poor prognosis versus a relatively indolent disease. Conclusions: This is the first study to evaluate the prognostic impact of TP53mut MN across the entire MN spectrum, providing a framework for future refinement of TP53-driven disease classification. Key findings include: (i) MF-AP/BP and MDS/MPN overlap exhibit survival outcomes as dismal as AML, irrespective of the TP53 allele status; and (ii) complex karyotype is a surrogate for “biallelic equivalent”, refining risk interpretation in monoallelic cases. Overall, our study defines seven prognostic subgroups spanning all TP53mut MN, offering a foundation for risk-adapted clinical trial design and future classification updates.