Citations

Abstract BACKGROUND Glioblastoma (GBM) is a universally lethal brain cancer with limited durable responses to immunotherapy, largely due to its immunosuppressive tumor microenvironment (TME). Ephrin receptor A3 (EphA3), a receptor tyrosine kinase minimally expressed in normal tissue, is enriched on GBM cells, glioma stem cells (GSCs), and M2-like tumor-associated macrophages (TAMs). We hypothesize that dual targeting of TAMs and tumor cells by EphA3-CAR-T is a viable treatment strategy. METHODS We developed EphA3-directed second-generation CAR-T cells (EphA3-CAR-T) incorporating the single-chain variable fragment of ifabotuzumab, an anti-EphA3 monoclonal antibody, achieving >90% transduction efficiency. We evaluated antitumor efficacy in vitro; the functional activities of EphA3-CAR-T on GSCs were assessed via selective cytotoxicity, T cell proliferation, degranulation assays, and depletion of M2-like macrophages. In vivo, 1 × 10⁶ EphA3⁺ U251 MG cells and/or 1 × 10⁶ ex vivo–polarized M2-like macrophages were implanted in the flanks of NOD-SCID-γ⁻/⁻ mice. Comparative studies with EGFRvIII-directed CAR-T cells were also performed. RESULTS Immunohistochemistry confirmed EphA3 expression across both tumor and immune compartments in patient-derived specimens. EphA3-CAR-T cells demonstrated potent, selective cytotoxicity (p<0.001), T cell proliferation (p<0.001), and CD107α degranulation (p<0.001) against EphA3⁺ GBM and GSCs, while also reversing TAM-mediated immunosuppression via depletion of ex vivo–polarized M2-like macrophages (p<0.05), compared to other validated CAR-Ts. In vivo, EphA3-CAR-T significantly reduced tumor volume (p<0.001) and improved survival (p<0.01), in the presence of TAMs. In contrast, EGFRvIII CAR-T cells were inactivated under the same TME conditions. EphA3-CAR-T cells remained active in models co-engrafted with macrophages, suggesting preserved function within the immunosuppressive TME. CONCLUSIONS EphA3-CAR-T therapy addresses a major barrier to CAR-T success in GBM: TME-mediated immunosuppression. This tumor- and TME-targeting approach demonstrated robust preclinical activity. These findings support the clinical translation of EphA3-CAR-T cells as a next-generation immunotherapy for GBM.

Background Robotic-assisted TKA may allow for more reproducible balancing and implant positioning. However, few RCTs have directly compared modern robotic-assisted TKA to conventional TKA. Questions/purposes (1) Do patients undergoing robotic-assisted TKA perform better on the Timed Up and Go (TUG) test and Stair Climb test (SCT) than patients undergoing conventional TKA at 1 and 6 months after surgery? (2) Do patients undergoing robotic-assisted TKA demonstrate better patient-reported outcomes, including Knee Injury and Osteoarthritis Outcome Score (KOOS), EQ-5D, and VAS scores, than patients undergoing conventional TKA at 1 and 6 months after surgery? (3) Do patients undergoing robotic-assisted TKA demonstrate better radiographic alignment and position than patients undergoing conventional TKA? Methods In this double-blind RCT, 60 patients were randomized to robotic-assisted TKA (n = 30) or conventional TKA (n = 30) without the use of a tensioning device. All care was otherwise standardized, using mechanical alignment guides. The primary outcome measures were the TUG and SCT tests; results were collected by a blinded observer at 6 months postoperatively. These time points were chosen based on the maximal early improvement in patient-reported outcomes and bimodal distribution of the TUG and SCT tests, worsening in the immediate postoperative period, and improving within the first 6 months. Secondary outcome measures were KOOS, EQ-5D, and VAS scores; radiographic measurements; and operative time. Standard bivariate statistical analysis was conducted. The mean ± SD age of the cohort was 66 ± 7 years, with no differences between groups (p = 0.21). Ninety-three percent (28 of 30) of patients in the robotic-assisted group were White versus 97% (29 of 30) in the conventional TKA group (p > 0.99). Women made up 57% (17) of the robotic-assisted cohort and 60% (18) of the conventional TKA cohort. No differences were noted between the robotic-assisted and conventional TKA groups in BMI, Charlson comorbidity index, or American Society of Anesthesiologists (ASA) classification. Results Patients undergoing robotic-assisted TKA did not perform better than those who underwent conventional TKA on the TUG (11 versus 11 seconds; p = 0.88) or SCT (15 versus 15 seconds; p = 0.93) tests. Patients undergoing robotic-assisted TKA did not demonstrate better mean ± SD scores on the KOOS pain subscale than patients undergoing conventional TKA (86 ± 14 versus 80 ± 17; p = 0.15). Patients undergoing robotic-assisted TKA did not demonstrate better radiographic alignment and position than patients undergoing conventional TKA based on hip-knee-ankle angle (178° versus 178°; p = 0.89). No differences between the two groups were noted at the 1-month follow-up in TUG and SCT test results. Conclusion In this study, patients who underwent robotically assisted TKA did no better in terms of function, patient-reported outcomes, or radiographic measures than did patients who underwent conventional TKA. Until or unless future studies demonstrate benefits of robotically assisted TKA that are large enough for patients to perceive, we recommend against its use. Level of Evidence Level I, therapeutic study.

Background: Ventricular tachycardia (VT) is a major contributor to death among ischemic heart disease (IHD) patients. In this systematic review and meta-analysis, we evaluate the efficacy of catheter ablation in patients with ischemic cardiomyopathy. Methods: We conducted a meta-analysis by searching the electronic database up to April 2025. Seven studies, including 1192 patients, were identified. A random-effect model was used to estimate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Trial sequential analysis was conducted to assess sample size adequacy. Results: Among Ischemic heart disease patients with ICDs, VT ablation was associated with a significant reduction in ICD shocks (RR = 0.50, 95% CI [0.34–0.74]), a trend toward reduced VT storm (RR = 0.64, 95% CI [0.40–1.04], p = 0.07), and lower rates of cardiovascular hospitalization (RR = 0.73, 95% CI [0.53–1.01], p = 0.06) compared to ICD alone. However, no significant differences were observed when compared to patients receiving ICD plus antiarrhythmic drugs (AADs). Additionally, VT ablation showed no significant impact on mortality or VT/VF recurrence compared to either ICD alone or ICD with AADs. Trial Sequential Analysis provided conclusive evidence for VT/VF recurrence outcomes, while further data are required for other outcomes. Conclusion: Among ischemic heart disease patients with ICD, VT ablation reduces ICD shocks, VT storm, and cardiovascular hospitalizations compared to ICD-only, but offers no significant advantage over ICD combined with antiarrhythmic drugs. VT ablation does not impact mortality or the recurrence of VT/VF. Trial Sequential Analysis confirmed conclusive evidence for VT/VF recurrence, while additional data is needed for other outcomes.

Introduction: Knee injuries constitute a significant proportion of sports-related injuries. Osseous oedema can present in specific patterns with certain injuries Objective: This study aims to analyse the patterns of bone marrow contusion in the lateral tibial condyle (LTC) post knee trauma, categorising the condyle into anterior, middle, and posterior thirds, and to evaluate the prevalence of associated ligamentous and meniscal injuries. Materials and Methods: A cross-sectional study was conducted on 150 patients (92 males, 58 females) with an average age of 16.9 years, who underwent MRI within one week following knee trauma. The LTC was divided into anterior, middle, and posterior thirds for analysis. The bone marrow contusion patterns, along with associated ACL, MCL, PCL, LCL, medial meniscus, and lateral meniscus injuries, were documented. Results and Analysis: Bone marrow oedema in the LTC was observed as follows: anterior one third in 6, middle third in 13, and posterior third in 31 cases. The analysis revealed the following injury associations: Anterior one-third osseous oedema was associated with ACL injuries in two cases, MCL injuries in 3, PCL in 1, and medial meniscus injuries in 1. Middle one-third osseous oedema was associated with ACL injuries in 11 cases, MCL injuries in 3, medial meniscus injuries in two cases, and lateral meniscus injuries in 2. Posterior third osseous oedema was associated with ACL injuries in 28 cases, MCL injuries in 9, and medial meniscus injuries in four cases. Conclusion: The study highlights a clear association between the location of LTC bone marrow oedema and specific patterns of ligamentous and meniscal injuries. The posterior third, with the highest incidence of oedema, showed a strong correlation with ACL and MCL injuries, while anterior and middle oedema also demonstrated significant associations with ACL and MCL, and varied involvement of meniscal injuries. These insights contribute to a more comprehensive understanding of knee injury mechanisms, advocating for precise diagnostic strategies and potentially guiding more effective treatment protocols in radiological and orthopaedic practice.

ABSTRACT As artificial intelligence (AI) continues to rapidly reshape health care, there is a critical need for clear frameworks for clinicians to ensure ethical, equitable, and effective integration and use of AI in patient care. Key integrations of AI include enhancing health communications, patient engagement, clinicians' training, pharmaceutical advertising, clinical decision‐making, and automation of clinical operations and workflow. However, there are growing concerns related to regulatory gaps, the spread of misinformation, security threats, patient and data privacy leaks, and widening health disparities gaps. These concerns are exacerbated by limited institutional infrastructure and limited AI literacy of clinicians and patients. Recent policy developments reflect efforts to guide responsible AI development and use. While progress has been made, the lack of standardized human oversight remains a critical gap, particularly as policies may not fully consider the challenges and complexities at institutional, societal, technical, and individual levels. Thus, herein, the Drug Information Practice and Research Network (DI PRN) of the American College of Clinical Pharmacy (ACCP) : (1) explores current and emerging multifaceted challenges, a call to action, and opportunities of AI integration in health care including examination of the regulatory, ethical, operational, and health equity implications; and (2) provides practical recommendations for responsible use of AI through DI PRN‐developed example case‐based approaches and best practices infographics to enhance AI literacy for diverse learners including clinicians, trainees, and patients. This DI PRN opinion paper highlights the importance of proactive governance frameworks and equips and empowers diverse learners with practical AI literacy tools to confidently engage with AI technologies in patient care.

Abstract Context Thyroid nodules are common in clinical practice, and inappropriate selection of patients for thyroid biopsy can contribute to thyroid cancer overdiagnosis or delayed diagnosis. Objective This work aimed to evaluate the frequency of inappropriate thyroid biopsies in practice, following a framework that integrates thyroid nodule ultrasound (US) features and patient-specific clinical factors. Methods This cross-sectional study was conducted at a single academic center in the United States. Participants included adult patients who underwent their first thyroid fine-needle aspiration (FNA) biopsy between January 1, 2016, and December 31, 2023, at the University of Florida. Data collection included thyroid US characteristics, clinical factors (eg, comorbidities, patient preferences), and context for biopsy decision-making. Main outcome measures included the appropriateness of thyroid biopsy assessed using a tiered framework incorporating US features and additional clinical factors. Results A total of 899 patients were evaluated, with 441 meeting the inclusion criteria and undergoing 481 thyroid biopsies. Of these, 388 of 481 (80.7%) were classified as likely appropriate (L-APP) based on the American College of Radiology Thyroid Imaging Reporting and Data System criteria. In 34 of 481 (7%) of cases, clinical factors such as thyroid cancer risk features, comorbidities, symptoms, or patient preferences led to reclassification from likely inappropriate (L-INAP) to L-APP. In 50 of 481 (10%) of cases, limited life expectancy (eg, chemotherapy, end-stage disease) led to reclassification from L-APP to possibly or extremely inappropriate (EXT-INAP). EXT-INAP biopsies occurred in only 0.8% (4/481) of cases. Conclusion This study underscores the value of integrating US findings with clinical context to guide thyroid biopsy decisions and enhance patient-centered care.

Abstract Disclosure: S. Saad-Omer: None. M. Stan: None. M.R. Castro: None. J. Brito: None. J.E. Hallanger-Johnson: None. M.M. Ryder: None. Background: Thyroid fine needle aspiration (FNA) is a widely utilized diagnostic tool for evaluating thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) provides a standardized framework for classifying cytologic findings and guiding management. This study retrospectively reviews thyroid FNA cases at a large academic institution to analyze the distribution of Bethesda classifications.Methods: A retrospective review was conducted of all thyroid FNA cases done in the department of Endocrinology at a large academic institution performed from January 1st 2019 to October 3rd 2023. Thyroid FNA results were divided into categories according to the Bethesda classification system, such as benign, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm (FN), suspicious for malignancy, malignancy and non-diagnostic. FNA results that were not able to be classified were labelled as other.Results: A total of 3,291 thyroid FNA cases were included in the analysis. The distribution of cases across the Bethesda categories revealed a significant proportion of benign findings, with 73.6% classified as benign. This was followed by 8.1% follicular neoplasm, 6.56% Papillary Thyroid Cancer, 6.62% Non-diagnostic, 2.4% Atypical, and 2.3% Suspicious. 0.5% of FNA results were classified as other.Conclusion: Overall our cohort was found to have similar findings in terms of benign and confirmed PTC nodules compared to recent literature; however, the rate of atypical and non-diagnostic nodules was found to be lower. Presentation: Monday, July 14, 2025

Abstract Disclosure: Y. Ahmed: None. S.M. Saad-Omer: None. R.M. Castro: None. M. Rivera: None. M.N. Stan: None. Background: Fine-needle aspiration (FNA) is a cornerstone in the evaluation of thyroid nodules. Its accuracy during long term follow up is not well established though. Our project aims to address that. Objective: To assess long-term accuracy of FNA results at Mayo Clinic Rochester including diagnostic classifications, procedural and cytologic variables, and concordance with surgical pathology. Methods: We conducted a retrospective cohort study of patients who underwent thyroid FNA at Mayo Clinic Rochester in 2014, to allow for the long-term follow-up. Descriptive statistics summarized patient demographics, nodule characteristics, and procedural factors. Cross-tabulation was used to evaluate concordance between FNA cytology and surgical pathology. This is an interim analysis. Results: Among 199 patients (from 741 FNAs that year), the mean age was 58.6 ± 14.1 years, and 73.7% were female. The average BMI was 29.6 ± 6.4 kg/m². Most had non-toxic multinodular goiter (69.3%) or non-toxic solitary nodules (27.6%). Nodules were 45% solid, 8% cystic, and 47% mixed, with a mean size of 2.3 cm. FNA results were predominantly benign (Bethesda II, 80%), followed by malignant (Bethesda VI, 8%), suspicious for follicular neoplasm (Bethesda IV, 7.5% ), non-diagnostic (Bethesda I, 3%), and suspicious for malignancy (Bethesda V,1%). There were no cases read as Bethesda III (AUS) in 2014. Of the 16 Bethesda VI cases, 15 had surgery; 14 were confirmed malignant, and 1 was benign (Hurthle cell adenoma). Both Bethesda V cases that underwent surgery were benign. Of the 15 Bethesda IV cases, 12 had surgery; 11 were benign and 1 was malignant and 3 had long term follow up (2 benign, and one malignant based on the available data). Overall the malignancy rate for Bethesda IV was 13.3%. Surgery was performed in 12 Bethesda II cases, with final pathology available for 11; 9 were confirmed benign, while 2 were malignant. In the other 147 cases of benign FNAs that didn’t undergo surgery we have not identified any indication of necessity for surgery during the mean of 9 years of follow-up, presumably indicating their benign character. Overall malignancy rate for this group was 1.3%. We had only 6 non diagnostic FNAs (Bethesda I), with all of them during follow up proven benign (2 by surgery, 2 by repeat FNA and 2 by long term follow up). Conclusion: Long term follow up data (over 9 years) support the continued reliability of Bethesda II and VI , while conversely raising questions about the significance of the Bethesda V classification. The malignancy rate in Bethesda IV (likely including the Bethesda III category at the time) is consistent with our institutional data, although it remains lower than that reported by other institutions. We’re currently enriching our cohort to verify and strengthen our conclusions. Presentation: Monday, July 14, 2025