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Introduction: Life-support limits (i.e., code status), the first step in the continuum of palliation and end-of-life (EoL) care, stem from decisions made by patients and their providers to align care near the EoL with patients’ wishes. The pandemic created health care strain that may have influenced life-support limitation practices among patients with serious COVID-19. In this study, we examine variations in life-support limitations (do-not-resuscitate, DNR; do-not-intubate, DNI) depending on the hospital and period of hospitalization. Methods: We included all adults admitted to a hospital in the United States with COVID-19 from January 2020 to December 2021 using the VIRUS registry. Our outcome was any life-support limitation on admission (DNR, DNI, or both) using regression modeling. Main exposures were hospital and period of hospitalization (early vs. late pandemic). Covariates included age, sex, race/ethnicity, comorbidities, and hospitalization diagnoses. Results: There were 42,383 patients from 75 hospitals in the US. The median age was 63 (interquartile range: 50–75), 46.5% were female, and 37.5% were non-Hispanic White. The life-support limitation rate was 7.9%, and the palliative care consultation rate was 2.3%. The odds of life-support limitation were 1.86 (95% CI: 1.6–2.1) depending on the hospital, but the period of hospitalization was not associated with odds of life-support limitation. Older age was associated with the greatest increased odds (4.1 per standard deviation ∼ 17.9 years, 95% CI: 3.9–4.4), followed by comorbidities including paralysis (2.4, 95% CI: 1.8–3.0) and dementia (2.3, 95% CI: 2.0–2.6). Conclusions: After adjusting for patient-level factors, we report significant inter-hospital but no temporal variation in life-support limitation upon admission with COVID-19. Future studies should investigate specific practices that led to health care resilience to temporal practice variations in life-support limitation during the pandemic.

ImportancePatients with kidney failure (KF) receiving long-term dialysis have increased incidence of atrial fibrillation (AF). Patients with KF and AF have increased risk of stroke, death, and bleeding compared with age-matched cohorts. In KF, the use of oral anticoagulants (OACs) increases hemorrhage risk, offsetting potential benefits and making left atrial appendage occlusion (LAAO) a potentially promising solution for risk reduction in AF.ObjectivesTo compare the outcomes and safety of OACs and LAAO for risk reduction of AF in patients with KF.Design, Setting, and ParticipantsThis retrospective cohort study assessed patients with KF enrolled in the US Renal Data System registry between January 1, 2015, and December 31, 2018, who were diagnosed with AF after initiation of long-term dialysis. On average, patients met inclusion criteria for 22 months. Data analysis was completed in May 2024.ExposureMedicare claims were used to identify patients who received OACs and LAAO after AF diagnosis. A propensity-matched cohort was created based on the CHA2DS2-VASc score and year of treatment.Main Outcomes and MeasuresDeath, nonfatal bleeds, and nonfatal strokes.ResultsThe final cohort included 2344 patients with KF and a new AF diagnosis (median [IQR] age, 66.0 [57.0-73.0] years; 1341 [57.2%] male). Of these patients, 293 received LAAO and 2051 received OACs. A total of 2194 patients (93.6%) were receiving hemodialysis, with the remaining 150 (6.4%) receiving peritoneal dialysis. In the LAAO group, 79 deaths (27.0%) and 21 nonfatal strokes (7.2%) occurred, and 117 patients (39.9%) experienced 234 bleeding events. In the OAC group, 729 deaths (35.5%) and 163 strokes (8.0%) occurred, and 687 patients (33.5%) experienced 1114 bleeding events. After accounting for correlation between bleeds and death, the joint frailty model showed evidence of a treatment association of LAAO compared with OACs on recurrent bleeding events (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98) and death (HR, 0.47; 95% CI, 0.30-0.72). There was a reduced risk of nonfatal stroke in the LAAO group (HR, 0.55; 95% CI, 0.32-0.94), but this finding was not significant after adjustment (HR, 1.18; 95% CI, 0.76-1.81).Conclusions and RelevanceIn this cohort study, LAAO compared with OACs was associated with improved survival and reduced bleeding risk in patients with KF and AF. These findings suggest that these data should be considered in shared decision-making in consideration of LAAO for patients with KF and AF.

Abstract Background The isocitrate dehydrogenase (IDH) mutation status is a key molecular marker in diagnosing and treating brain tumors. Currently, it is determined via invasive tissue biopsy. Recent advances in deep learning (DL) have offered promising non-invasive alternatives for determining IDH status. However, their clinical translation is hindered by a significant gap between DL predictions and their clinical applicability. The limited transparency of many DL-networks and inadequate evaluation metrics hinders trust and adoption, as clinicians require clear and validated insights for determining IDH status. These challenges highlight the need for robust validation and measures of predictive reliability to make DL-predictions clinically actionable. Methods We developed a unique approach for non-invasive prediction of IDH status using MRI. We combine a voxel-wise-segmentation network(MC-net) with Bayesian logistic regression (BLR) to provide an IDH status and estimate confidence scores. We utilized a comprehensive dataset of 2,481 glioma cases from eight institutions. Results Our framework(MC-net + BLR) demonstrated robust performance achieving 96.4% and 95.1% classification accuracies on diverse databases, with an AUC of 0.98. The BLR was implemented exclusively on held-out test data, ensuring that the derived confidence scores are independent of the training or validation phases. The derived confidence scores showed a low Brier score of 0.0125, highlighting its superior calibration and uncertainty quantification. Conclusion The developed framework provides an IDH status and a confidence score, offering clinicians an additional layer of assurance in prediction reliability. It bridges the gap between high-performing DL models and their clinical applicability by addressing the challenges in prediction reliability. Our framework is a significant advancement in non-invasive determination of IDH-status and confidence-informed therapeutic decision-making in neuro-oncology.

Abstract The combination of enfortumab vedotin and pembrolizumab (EVP) has recently revolutionized care for patients with previously untreated locally advanced and metastatic urothelial carcinoma. However, predictive biomarkers of response, the optimal duration of EVP for patients who respond well to therapy, and the role of circulating tumor DNA to monitor treatment response have not yet been fully elucidated. In this molecular tumor board, we summarize 6 patients from 4 different academic institutions with unresectable or oligometastatic urothelial carcinoma who achieved long-term remission on surveillance after a short duration of EVP treatment that resulted in complete response on follow-up imaging followed by consolidative radical cystectomy. We discuss potential predictive biomarkers for patients with exceptional response to EVP. These findings highlight the need to determine an optimal duration of EVP to maximize efficacy while minimizing adverse events. We aim to further define and explore the value of local therapy with consolidative cystectomy in the setting of unresectable, locally advanced, oligometastatic disease, or those with metastatic disease who achieve complete response of disease outside of the bladder. Identifying this subset of patients who may be candidates for this type of multidisciplinary management may result in durable treatment-free remission.

Abstract The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P< .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T–related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

ABSTRACT Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19‐directed chimeric antigen receptor T‐cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30–86) and median prior lines of therapy was 4 (range: 1–18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow‐up of 25 months (range: 1–72) from CAR T infusion, the 2‐year overall survival (OS) was 57% (95% CI: 53–60) and progression‐free survival (PFS) was 43% (95% CI: 40–47). The 2‐year cumulative incidences of relapse or progression (rel/prog) and non‐relapse mortality (NRM) were 47% (95% CI: 44–51) and 9% (95% CI: 7–11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell–associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.

ABSTRACTIntroductionIntramyocardial needle ablation is a novel technique for treating refractory ventricular tachycardia (VT) and premature ventricular complexes (PVC). However, studies defining the effectiveness and safety of this procedure are limited. This meta‐analysis aims to evaluate the safety and effectiveness of needle ablation for VT and PVC refractory to standard ablation.MethodsEmbase, Ovid (includes Medline), and ClinicalTrials.gov were searched from inception to December 31, 2024. Human studies on needle ablation for recurrent VT and PVC were included. Primary outcome was immediate effectiveness (no immediate post‐procedural inducible VT or PVC). Secondary outcomes were long‐term effectiveness (no clinical VT or PVC at 6 months) and safety (composite measure of peri‐ and post‐procedural complications).ResultsA total of five studies including 180 patients (140 VT; 40 PVC) were analyzed. Mean ages ranged from 54 to 66 years. Among 129 patients with VT, immediate effectiveness was 75% (95% CI, 54–92; I2 80%), and cumulative freedom from clinical VT dropped to 43% at 6 months (95% CI, 35–52; I2 0%). Among 40 patients with PVC, immediate effectiveness was 82% (95% CI, 67–94; I2 0%), and long‐term effectiveness was 76% (95% CI, 61–90; I2 0%). Safety outcomes were reported in 19% of patients (95% CI, 13–27; I2 0%) and 10% of patients (95% CI 1, 23; I2 0%) in the VT and PVC arm, respectively. Death related to ablation was report in 7 patients (5.0%) only in the VT studies.ConclusionIntramyocardial needle ablation is an emerging alternative approach for refractory VT and PVC ablation, showing cautious but promising results and safety profiles. Prospective studies and an international registry could provide valuable insights needed for optimal patient selection and protocol refinement.

Abstract Purpose: Navtemadlin is a potent small-molecule inhibitor of MDM2, which has completed a phase 0 window-of-opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient-derived xenografts (PDX). Experimental Design: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53–wild-type GBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX compared with 100 mg/kg in a non-amplified PDX. Central nervous system distribution was limited by blood–brain barrier efflux (Kp_brain = 0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood–brain barrier efflux (Rag−/−Abcb1a−/−Abcg2−/−), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in three (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusions: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of patients with GBM.