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Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

Abstract Introduction Ovarian cancer (OvCa) remains the most lethal gynecologic malignancy, with older women experiencing the poorest outcomes. Aging profoundly remodels the ovarian tumor immune microenvironment (TME), promoting regulatory T cell (Treg) mediated immune evasion; however, the underlying metabolic mechanisms remain unclear. Methods Using young (3-month) and aged (22-month) female mice injected intraperitoneally with ID8p53⁻/⁻ OvCa cells, we investigated how age associated metabolic reprogramming influences tumor immunity Results Aged OvCa bearing mice exhibited accelerated tumor progression, reduced survival (median 54 vs. 72 days), decreased CD4+ and CD8+ T cells, and an expanded Treg population. Metabolomic profiling revealed increased succinate accumulation in ascites, tumor tissue, and serum of aged mice and elderly OvCa patients. Exogenous succinate enhanced CCR4+FOXP3+ Treg frequency and upregulated IL-10 and TGF-β secretion. Elevated levels of CCL22, a CCR4 ligand, were also detected in ascites from aged mice and patients, suggesting a chemokine-driven reinforcement of Treg recruitment. PBMCs from aged patients displayed an OXPHOS-reprogrammed CCR4+FOXP3+ Treg subset with heightened suppressive capacity, markedly inhibiting CD4+ and CD8+ effector cytotoxicity. Treatment with AA6, an α-ketoglutarate dehydrogenase inhibitor that blocks succinate synthesis, reduced CCR4+FOXP3+ Treg accumulation, restored effector T-cell function, and significantly prolonged survival in aged OvCa-bearing mice. Conclusion Together, these findings reveal a novel succinate—CCR4 metabolic—chemokine axis that drives Treg mediated immunosuppression in aged OvCa. Targeting this pathway offers a promising strategy to restore anti-tumor immunity and overcome age-related immunotherapy resistance in ovarian cancer. Funding Source N/A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

ABSTRACT Reliable assessment of infarct severity is essential in experimental stroke research, yet commonly used approaches such as 2,3,5‐triphenyltetrazolium chloride (TTC) staining and magnetic resonance imaging require additional tissue processing, specialized equipment, or substantial time and cost. In this study, we developed and validated a rapid visual Infarct Score to determine infarct volume and evaluate neuroprotective efficacy in rat middle cerebral artery occlusion (MCAO) models. A retrospective analysis was performed using data from 315 male Sprague–Dawley rats, including TTC‐derived infarct volume, visual Infarct Score, neurological deficit scores, and body weight changes. The Infarct Score demonstrated the strongest correlation with infarct volume among individual indicators in both nontreatment (Rho = 0.71) and treatment cohorts (Rho = 0.68). We further developed a Comprehensive Score by integrating the Infarct Score with the Longa 5‐point score at 48 h, which showed the highest overall correlation with infarct volume (Rho = 0.75 in both cohorts) and strong discrimination of infarct severity (AUC = 0.90). Interrater reliability analysis demonstrated excellent agreement among independent raters (intraclass correlation coefficient = 0.89; Kendall's W = 0.83, both p < 0.001). Neuroprotective interventions, including therapeutic hypothermia, nitroglycerin, and remote ischemic conditioning combined with physical exercise, significantly reduced infarct volume, Infarct Score, Comprehensive Score, neurological deficits, and weight loss. These findings indicate that the Infarct Score offers a rapid, practical, and cost‐effective method for infarct assessment, whereas the Comprehensive Score further improves the predictive accuracy and may serve as a useful tool for evaluating stroke severity and treatment outcomes in preclinical studies.

Background: Platelet-rich plasma (PRP) is an emerging therapy that demonstrates potential benefits for knee osteoarthritis (OA); however, the accessibility of PRP remains limited, in part, because its use is not covered by insurance. Purpose: To identify factors contributing to health disparities in PRP treatment for knee OA using machine learning models. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The authors collected data from electronic medical records at 2 upper Midwest medical centers (Mayo Clinic and Detroit Medical Center) from 2022 to 2023 encompassing demographic, socioeconomic, and clinical factors. Data collection encompassed age, sex, race, ethnicity, area deprivation index, marital status, income, rurality, insurance, employment, language, religion, treatment site, and region. Logistic regression and random forest models were applied to 3667 samples (80% training, 20% testing), comparing PRP recipients against a standard care group. Models were evaluated using 10-fold cross-validation to ensure robust performance assessment. Results: Logistic regression revealed that increased age, widowed status, lower income, rural residence, unemployment/disability, and Medicaid/Medicare insurance were associated with lower odds of receiving PRP. Upper-middle income, contracted insurance, and treatment at the Mayo-Arizona and Mayo-Florida sites were associated with higher odds. The model achieved areas under the curve of 0.83 (training set) and 0.82 (testing set). Random forest analysis identified distance to care, age, area deprivation index, income, and treatment site as top predictors, with areas under the curve of 0.92 (training) and 0.87 (testing). Conclusion: The current study demonstrated that both models discerned key barriers (income, distance to care, retirement status) and facilitators (regional differences) affecting PRP accessibility. These findings provide potential policy initiatives aimed at improving PRP access for underserved demographics, offering a quantitative blueprint to foster equitable access to regenerative therapies for knee OA.

Abstract: Extracorporeal membrane oxygenation (ECMO) is increasingly used to support patients with severe cardiac or respiratory failure. Neurological complications occur across ECMO configurations and represent a major contributor to mortality and long-term disability. Major neurological complications include ischemic and hemorrhagic stroke, hypoxic ischemic brain injury, seizures, delirium, spinal cord and peripheral nervous system injury, and brain death. The mechanisms underlying neurological injury during ECMO are multifactorial and are influenced by ECMO configuration, reflecting differences in cerebral perfusion, gas exchange, anticoagulation exposure, and precannulation physiologic insults. This review synthesizes neurological complications associated with ECMO, neurological monitoring, and outcomes.

Tackling hospital emergency department (ED) overcrowding is a paramount challenge for healthcare systems. To combat this issue, an innovative approach is to identify patients who can be served vertically (i.e., in a seated position) and route them to a dedicated area termed the vertical processing pathway (VPP). Successfully implementing this design requires understanding which patients should be routed to the VPP and when. Currently, the decision to leverage the VPP is made in an ad hoc fashion. To assist our partner hospital and other EDs in capturing the value of the VPP, we develop a machine learning model that provides personalized risk scores predicting whether each arriving patient needs an ED bed. We use these scores as input to a stochastic patient flow model and analytically characterize the optimal VPP policy that minimizes length of stay. We then combine our results to derive an interpretable VPP patient streaming protocol suitable for implementation in practice and conduct a before-and-after experiment in which we leverage empirical analyses to evaluate the impact of integrating it into practice. The implemented protocol led to an 11-minute (4.2%) reduction in ED length of stay in our partner hospital without any adverse effect on quality-of-care outcomes. This effect was statistically significant and remained robust after controlling for various confounding factors and potential sources of endogeneity. Our VPP protocol can also be utilized in other EDs, offering operational improvements without requiring additional resources. This paper was accepted by Stefan Scholtes, healthcare management. Funding: S. Saghafian received financial support from the NSF [Grant CMMI-15 62645], “Data-Driven Management of Post-Transplant Medications,” which partially enabled this work, as well as funding and support from the Harvard Data Science Initiative and the Harvard Mossavar-Rahmani Center for Business and Government. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2024.07517 .

Diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, arises from various pathogenic mechanisms including gene translocations and fusions. Detection of gene rearrangements using fluorescence in situ hybridization (FISH) is a standard practice for DLBCL diagnosis and guides treatment decisions. High-throughput chromosome conformation capture (Hi-C) DNA sequencing is a next-generation sequencing-based technology to identify genome-wide rearrangements using a single assay. In this study, Hi-C sequencing was performed using FFPE tissues from 159 patients with DLBCL, and identified 746 cancer genes at or proximal to the rearrangement breakpoints with a total of 1903 occurrences. Focusing on clinically important rearrangements, Hi-C detected 102 rearrangements of MYC, BCL2, and/or BCL6 in 92 patients and revealed the fusion partners, including 25 rearrangements missed by FISH. Causes of FISH negative results included FISH-cryptic breakpoints, complex or faint FISH signals, low percentage of FISH positivity, and issues related to tissue fixation. Moreover, in 20 patients (12.6%), Hi-C sequencing detected 22 rearrangements characteristic of other lymphoma types, including CCND1 rearrangements that could lead to reclassification as mantle cell lymphoma. Survival analysis for genome-wide rearrangements using machine learning models identified MYC, PD-L1, CCND1, BCL2, NTRK1/PRCC, RRAS, and FANCE rearrangements with significant prognostic effects in the DLBCL cohort. In conclusion, Hi-C sequencing detects gene rearrangements crucial for diagnosis in an unbiased and molecular manner and showed high sensitivity and specificity in our study. These advantages of Hi-C sequencing offer help to improve the workflow of clinical pathology laboratories, diagnostic precision, and treatment of large B-cell lymphoma.

Myeloid sarcoma (MS) is a tumor mass involving any extramedullary site composed of myeloid-lineage blasts with myeloid, myelomonocytic, or monocytic differentiation. Distinguishing MS from malignant histiocytic neoplasms (MHNs) is diagnostically challenging due to morphologic and immunophenotypic overlap, particularly for MS with monocytic differentiation, which can mimic MHNs, especially the subtypes of histiocytic sarcoma and interdigitating dendritic cell sarcoma, leading to potential misdiagnosis and inappropriate management. Cyclin D1 overexpression is implicated in MHNs, but its utility in differentiating these entities has not been systematically characterized. We evaluated cyclin D1 immunostaining in 43 MS cases and 30 MHNs. The median age at MS diagnosis was 59 years (range: 0.1 to 90), while the median age at MHN diagnosis was 62 years (range: 9 to 90), with heterogeneous sites of involvement. Cyclin D1 evaluation showed 100% MHNs with strong cyclin D1 positivity in ≥50% tumor cells, compared with 7% MS with weak-to-intermediate positivity in a minor subset of tumor cells. Additional immunohistochemical evaluation showed no difference in PU.1 expression in MHNs (93%) versus MS (84%) but demonstrated a higher proportion of OCT2-positivity in MHNs over MS (52% vs. 23%, P <0.05). Our study demonstrates a high sensitivity (100%) and specificity (93%) in utilizing cyclin D1 to distinguish MHNs (mature phenotype) from MS (immature phenotype) in diagnostic practice. It is particularly valuable in challenging scenarios of MS with the absence of immature/myeloid lineage-defining markers (MPO, CD34, or CD117) and provides a cost-effective tool to resolve this diagnostic pitfall, ensuring an accurate subclassification.