Citations

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Abstract Distal radius fracture (DRF) open reduction and internal fixation (ORIF) is a common procedure performed across inpatient and outpatient settings. This study compared postoperative complications and healthcare utilization between these settings using a large national claims database. Patients aged 18 years and older who underwent DRF ORIF were identified in the PearlDiver Mariner database using International Classification of Diseases and Current Procedural Terminology codes. Service location determined surgical setting. Patients with pathological fractures, malignancy, or polytrauma were excluded. Cohorts were propensity matched 1:1 based on age, sex, Charlson and Elixhauser comorbidity indices, and relevant comorbidities. The matched cohort included 9,697 inpatient and 9,697 outpatient DRF ORIF cases. Serious postoperative complications occurred in 16.8% of inpatient procedures versus 5.0% of outpatient procedures. Inpatient surgery was associated with higher odds of surgical site infection (OR 2.23, 95% CI: 1.78–2.79), wound dehiscence (OR 2.57, 95% CI: 1.07–6.17), and deep vein thrombosis (OR 7.75, 95% CI: 3.53–17.04). Inpatients also had greater odds of emergency department visits (OR 1.17, 95% CI: 1.05–1.31), readmissions (OR 3.64, 95% CI: 2.91–4.54), reoperations (OR 2.15, 95% CI: 1.70–2.73), and higher 90-day reimbursements. Inpatient DRF ORIF was associated with significantly higher complication rates and increased postoperative healthcare utilization compared with outpatient procedures, with the largest absolute differences seen in readmissions, reoperations, and 90-day reimbursements. These associations are unlikely to be causal, as inpatient admission typically reflects greater medical necessity and clinical complexity not fully captured by administrative data. Nonetheless, because admission status is readily available at the point of care, it may serve as a practical flag to identify patients who warrant closer post-discharge surveillance and individualized follow-up planning. III.

Background New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms. Methods The American Heart Association convened 75 multidisciplinary experts for the Amyloid‐Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β‐Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus‐based guidance for clinicians. Results This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co‐occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision‐making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions. Conclusions Building on lessons learned from the establishment of stroke systems of care, the consensus‐based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground‐breaking therapies.

Background Cardiac involvement by extranodal natural killer/T-cell lymphoma (ENKTL) and aggressive NK-cell leukaemia (ANKL) is exceedingly rare and presents with heterogeneous manifestations, often leading to diagnostic uncertainty and delay. We contribute three additional biopsy- or autopsy-proven cases and place them in the context of a literature review of previously reported cases classified according to the 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors. Case series Three men (ages 58–72) presented with diverse cardiac manifestations. A 72-year-old with progressive dyspnoea and cardiogenic shock had cMRI findings interpreted as myocarditis on an infiltrative substrate; endomyocardial biopsy confirmed cardiac infiltration by ENKTL. Despite brentuximab vedotin (BV)-based therapy he died shortly thereafter. A 60-year-old with encephalopathy, biventricular dysfunction, and widespread nodal/multiorgan disease had nodal pathology consistent with EBV-negative ANKL according to the criteria of the 5th edition of the WHO Classification of Hematolymphoid Tumors; he declined chemotherapy and died within six days, with autopsy confirming multiorgan (including myocardial and bone marrow) infiltration. A 58-year-old with prior sinonasal ENKTL treated with four cycles of SMILE developed a new right atrial mass one month later; the mass was diagnosed by cMRI/PET-CT concordance and an extracardiac (EBUS-lung) tissue confirmation of the same recurrence. BV followed by gemcitabine/oxaliplatin failed to control progression and he died approximately one month after cardiac spread. Across cases, CD56 was positive in all, EBER in two, and CD30 was expressed variably. Conclusions Cardiac ENKTL/ANKL is a rapidly fatal entity with protean features. Multimodal imaging aids early recognition and tissue targeting, but definitive diagnosis rests on tissue confirmation. L-asparaginase-based chemotherapy remains the treatment backbone; CD30- and PD-L1-guided agents such as BV, PD-1 blockade, and daratumumab may offer transient control after biomarker-guided selection but lack randomized data in cardiac disease. Across the reported experience, survival after cardiac involvement was uniformly short, typically days to a few months. Our three cases add to this literature by illustrating the diversity of cardiac presentations, the variable CD30 expression relevant to brentuximab vedotin use, and the contribution of multimodal imaging to diagnosis. Findings from our series and the pooled literature are descriptive rather than constituting a formal survival analysis, and underscore the need for earlier diagnosis and prospective investigation.

ABSTRACT HLA‐DRB1*10:52 is characterised by a single nucleotide substitution in codon 133 in exon 3.

Background Glioblastoma (GBM) remains the most aggressive primary adult brain cancer attributed to its immunosuppressive nature. Radiation therapy (RT) and concurrent temozolomide chemotherapy are the standard treatments for GBM. Emerging evidence indicates that metformin has potential as an anti-tumor agent that can reshape the immune landscape across various malignancies. We thus postulate that metformin may enhance the anti-tumor effect of RT by modulating the immunosuppressive milieu in GBM. Methods We first explore multiple in vitro conditions, with or without pre-induction, and mimicked a tumor microenvironment to demonstrate a highly context-dependent effect of metformin on the polarization of bone marrow-derived macrophages (BMDMs). We then investigated the antitumor activity and immune-modulatory effects of metformin in combination with RT in GBM-bearing mice. Results The in vitro experiment showed that metformin inhibited the immunosuppressive effects of IL-4/IL-13 but also the immunostimulatory effects of Lipopolysaccharide (LPS) on BMDMs, demonstrating bidirectional immunomodulatory properties that depend on the baseline inflammatory stimulus. In tumor cell co-culture environment, metformin exhibited context-dependent immunoregulatory effects, predominantly promoting M1-associated activation. Notably, concurrent metformin treatment counteracted M2 polarization typically induced by the tumor microenvironment. In a high m-MCSF inducted M2-dominated condition, metformin preferentially shifted the highly polarized M2 phenotype toward an M1-like state in a time and dose-dependent manner but with limited promotion of M1 subtype maturation. RNAseq results on BMDM treated with metformin showed increased homeostasis. Metformin showed dose-dependent immunomodulatory effects when combined with RT in vitro . In syngeneic GBM mouse models, concurrent metformin + RT significantly prolonged survival and reduced tumor burden by reprogramming tumor-associated macrophages (TAMs), elevating intratumoral CD8+ T-cell infiltration and the CD8+/Treg ratio, increasing circulating CD8+ T cells, reversing RT-induced expansion of monocytic myeloid-derived suppressor cells (mMDSCs), and expanding CD4+ and CD8+ effector memory populations in peripheral blood. Conclusion Metformin demonstrates inhibitory effects on M2 phenotype of macrophages. However, it is not a simple M2 inhibitor; instead, it functions primarily as a neutralizer of highly polarized macrophage states by promoting transcriptomic homeostasis. This context-dependent activity enables metformin to relieve the profoundly immunosuppressive TME of GBM to potentiate the anti-tumor effects of RT and by enhancing systemic immune memory.

ABSTRACT Background While vaccination is a key strategy to mitigate the severity of coronavirus disease 2019 (COVID‐19) in children, the risk factors for symptomatic, medically attended (hereon referred to as “symptomatic”) COVID‐19 and the impact of vaccination are not well defined among pediatric solid organ transplant recipients (PSOTR). Methods PSOTR aged six months through 21 years at 11 centers in the Pediatric Infectious Diseases Transplant Network (PIDTRAN) were analyzed retrospectively for symptomatic COVID‐19 between July 2021 and May 2023. Using a Cox proportional hazards model, risk factors associated with COVID‐19‐associated hospitalization, in‐hospital oxygen use, mechanical ventilation, and the impact of COVID‐19 vaccination were analyzed. Results Of 1370 PSOTR, 410 (29%) had symptomatic COVID‐19 infection. Among those with symptomatic infection, 115 (28%) were hospitalized, 35 required in‐hospital oxygen, and three required mechanical ventilation. In the study, 45% were unvaccinated against COVID‐19. Compared to unvaccinated PSOTR, incompletely vaccinated PSOTR had 56% lower hazard (95% CI 0.26, 0.72, p = 0.001) of COVID‐19‐associated hospitalization whereas completely vaccinated did not have a statistically significant difference in hazard of hospitalization. Receipt of at least one dose of the bivalent vaccine was also associated with 92.5% lower hazard (95% CI 0.010, 0.55, p = 0.011) of hospitalization. Risk factors for hospitalization included chronic kidney disease, underlying heart disease, neurodevelopmental delay, and lymphocytopenia. Conclusions Most PSOTR with symptomatic COVID‐19 did not require hospitalization or respiratory support. Several comorbidities and lymphocytopenia are associated with severe COVID‐19 in PSOTR. COVID‐19 vaccination, mostly, protected PSOTR against COVID‐19‐associated hospitalization, but vaccine uptake among PSOTR was low. image

Background: Polyetheretherketone (PEEK) is a commonly used material for cranioplasties due to its advantages over other materials and autologous bone grafts. PEEK has an increased malleability, which increases postoperative aesthetics and adapts well to the cranial contours; it is also associated with a lower rate of infection when compared with autologous cranioplasties. Despite these benefits, there is limited information on the practical aspects of modifying PEEK cranioplasties after their initial placement. Case Series: We present 2 cases of patients who had previously undergone PEEK cranioplasty being treated with deep-brain stimulation (DBS), which was placed through their PEEK implant. The first was an 18-year-old male who had previously undergone cranial vault closure with bone grafts following a craniotomy. Later, when a deep-brain stimulator was planned, it was discovered that the bone grafts had significant resorption and a lack of structural integrity. Therefore, bone grafts were replaced with a custom PEEK implant cranioplasty before the DBS electrodes were placed via drilling through the PEEK implant to access the brain at a later surgery. The second patient was a 39-year-old male who developed epilepsy after a stroke, requiring craniotomy. DBS was unable to be performed initially due to significant resorption of the patient’s native bone. Therefore, a PEEK cranioplasty was performed in preparation for a staged, subsequent placement of DBS electrodes through the implant. Both patients recovered uneventfully following surgery, with noticeable improvement in functional (reduction in seizure frequency) and aesthetic outcomes. Systematic Review: A literature review was conducted using PubMed with keywords related to PEEK cranioplasties. After screening titles, abstracts, and full-text papers, it was found that 3 previously documented cases have involved drilling through PEEK implants: one by Mallela et al, involving SEEG electrode placement; one by Marrone et al, concerning a burr hole for evacuating a chronic subdural hematoma; and one by Ledesma et al, regarding the placement of subdural grid electrodes. Conclusions: This case series highlights how PEEK cranioplasties can be drilled through for therapeutic procedures, such as DBS electrode implantation, without compromising their structure. These cases illustrate the versatility, safety, and adaptability of PEEK implants for additional necessary interventions.

Background: Accurate identification of patients with metabolic dysfunction–associated steatohepatitis (MASH) at risk of disease progression (at-risk MASH) is critical for guiding resmetirom and semaglutide therapy. Inconsistent definitions of at-risk MASH complicate clinical risk classification and comparisons across studies. This study aimed to standardize the definition of at-risk MASH and propose optimized MRE-based liver stiffness (LS-MRE) cutoffs to improve noninvasive risk stratification and better guide pharmacotherapy. Methods: In this prospective study, 413 patients with suspected or diagnosed MASLD from two medical centers underwent liver biopsy and MRE. Results: A simplified definition of at-risk MASH (MASH with fibrosis stage≥2) identified a broader group of patients requiring clinical attention than a stricter definition requiring NAFLD Activity Score≥4 with ≥1 point in steatosis, inflammation, and ballooning (n=122 vs. 77). LS-MRE alone showed the highest diagnostic accuracy for identifying at-risk MASH using the simplified definition (AUC 0.91 [0.87, 0.95]) and cirrhosis (AUC 0.93 [0.88, 0.99]), compared with FIB-4 and individual laboratory parameters (AST, ALT, and platelet count) ( p <0.01 for all, paired DeLong tests). Optimized LS-MRE cutoffs (2.8–6.4 kPa) captured 25 additional biopsy-proven pharmacotherapy candidates (28% of all eligible patients) compared to AASLD guidelines–recommended cutoffs (3.1–4.4 kPa), improving sensitivity (80% vs. 50%) with acceptable specificity (73% vs. 88%). Conclusions: A simplified definition of at-risk MASH enables broader identification of treatment candidates. LS-MRE demonstrates excellent diagnostic performance and improves noninvasive risk stratification when paired with optimized cutoffs. These findings support the use of MRE to guide resmetirom and semaglutide eligibility and improve access to emerging therapies.