Citations

Abstract Description Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy derived from transformed B cells of germinal center (GC) or post-GC origin. DLBCL incidence is elevated in immunodeficient persons with reduced T cells, such as among HIV+ patients. Yet a causal link between T cell deficiency and DLBCL is incompletely understood. Using a mouse model of spontaneous DLBCL, we show that suboptimal T cell function, but neither zero nor full T cell function, can be a driver of B cell lymphomagenesis. In CD3δ-/- mice, which exhibit reduced number, signaling, and function of T cells, we observed progressive disruption of splenic architecture and eventual DLBCL development with ∼100% incidence. In contrast, lymphoma did not develop in wild-type mice, or CD3e-/-z-/- mice with complete T cell absence. This showed that poor-but-positive suboptimal T cells were required for GC B cell transformation and outgrowth. Mechanistically, CD3δ-/- mice exhibited altered GC dynamics at steady state and in response to immunization. Compared with wild-type mice, CD3δ-/- mice had a diminished T follicular regulatory (TFR) compartment and exhibited defective T follicular helper (TFH) cell differentiation when antigen challenged, indicating compromised regulation of the GC reaction. Indeed, defective GC B cell entry and differentiation was also observed. Our data thus suggest that suboptimal function of T helper subsets can lead to dysegulated GC reactions and B cell lymphomagenesis. Funding Sources Supported by AAI Intersect Fellowship Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Abstract BACKGROUND Many cancers demonstrate upregulated amino acid transport. In glioblastoma (GBM), evidence for upregulated amino acid flux includes high signal on amino acid PET imaging, increased expression of LAT1 (L-type amino acid transporter 1), and elevated extracellular amino acid levels via microdialysis. LAT1-targeted therapies have shown antitumor effects in certain cancer models by restricting essential amino acid supply and inhibiting the mTOR pathway, but their utility for GBM remains unknown. In this study, we evaluated impacts of a competitive LAT1 inhibitor, nanvuranlat, and a non-competitive inhibitor, JPH034 against glioblastoma. METHODS Murine (CT-2A, GL261) and human (GBM6, GBM39) GBM cell lines were tested under varying concentrations of nanvuranlat or JPH034. The competitive impacts of added essential amino acids, serum, and albumin were evaluated in vitro. Survival impacts were evaluated in an intracranial CT-2A glioma model. RESULTS Supplementing essential amino acids in vitro significantly decreased tumor cell sensitivity to nanvuranlat but did not change the IC50 of JPH034. Conversely, supplementing serum or albumin significantly reduced tumor cell sensitivity to JPH034 but did not change the IC50 of nanvuranlat. These findings were reproducible in all human and murine cell lines tested. In the intracranial mouse model, JPH034 treatment prolonged median overall survival from 16 days in the control group to 18.5 days, representing a 2.5-day extension (p = 0.060). CONCLUSION The antitumor effects of nanvuranlat and JPH034 on glioma cells in vitro, are influenced by concentrations of essential amino acids and albumin. Specifically, amino acids decreased impact of the competitive inhibitor (nanvuranlat) while albumin decreased impact of the non-competitive inhibitor (JPH034). These results suggest that the composition of the tumor microenvironment, which is impacted by BBB-disruption within GBM may differentially attenuate the therapeutic efficacy of certain drugs including LAT1 inhibitors.

Aim Cefazolin, a first generation cephalosporin, is the standard of care for perioperative antibiotic prophylaxis in hip and knee arthroplasty patients. Research has shown that prosthetic joint infection (PJI) rates are significantly higher when non-cefazolin antibiotics are used for perioperative TKA and THA prophylaxis. Cefazolin contains an R1 side chain that has not shown cross reactivity with other cephalosporins. Despite these data, the declaration of a cephalosporin allergy causes uncertainty regarding the optimal antibiotic choice in these patients. The purpose of this study was to determine the safety of administering perioperative cefazolin in patients with a cephalosporin allergy undergoing joint arthroplasty. Methods We identified all patients (n=1267) with a documented cephalosporin allergy who underwent total hip or knee arthroplasty at a high volume academic medical center from 2016-2024. We compared patients who received perioperative cefazolin despite the presence of a cephalosporin allergy (n=481) to patients who received alternative antibiotic prophylaxis (n=786). The primary outcome measure was the incidence of IgE mediated allergic reactions within the first 72 hours postoperatively. Secondary outcomes included 90-day complication rates including PJI, C. difficile infection, adverse events and readmission. Results The incidence of allergic reaction in cephalosporin allergic patients who received cefazolin was 0.0% (0/481) compared to 0.51% (4/786) in patients who received alternative antibiotics prophylaxis (p=0.12). There were no significant differences in the incidences of PJI (0.23% vs. 0.30%; p=0.83), C. difficile infection (0.0% vs. 0.0%) or readmission (3.95% vs. 4.34%; p=0.75) within 90 days. There was one adverse event related to cefazolin administration which was urethral irritation and was self-limited. There were three adverse events related to alternative antibiotic prophylaxis including cutaneous manifestations, GI distress and headache in a patient with idiopathic intracranial hypertension. All four allergic reactions in the alternative antibiotic prophylaxis cohort required supportive treatment with IV corticosteroids, fluids and antihistamines. Conclusion In this cohort of hip and knee arthroplasty patients, cefazolin administration in the setting of a cephalosporin allergy resulted in a 0.0% incidence of IgE mediated allergic reactions. These data and the fact that cefazolin's unique R1 side chain is not shared by any other cephalosporins suggests that cefazolin can safely be administered to most patients with a documented cephalosporin allergy.

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (<5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (>70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P < .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.

Introduction: Carotid artery intraplaque hemorrhage (IPH) is increasingly recognized as a predictive marker of cerebrovascular events. Despite widespread utilization of contrast-enhanced CT angiography (CTA) for the evaluation of carotid atherosclerosis, diagnosis of IPH on CTA is challenging, limiting risk stratification capabilities. We evaluated convolutional neural networks (CNN) for detection of histology-proven IPH in carotid CTA. Methods: The study included carotid endarterectomy patients from our center who had preoperative CTA and available plaque specimens from the Mayo Clinic Carotid Artery Atherosclerosis Trial (MCAT) Biobank. A validated segmentation model localized common and internal carotid arteries (CCA/ICA). CCA bifurcation served as landmark after a large language model, Llama3.0-70B, verified culprit plaque proximity to the bifurcation from CTA reports. A 3×3×4cm box around ipsilateral CCA bifurcation was sampled from CTA volumes and images were labeled IPH by histology study of carotid specimen (Fig 1). Given limited cases with concurrent imaging and histology, we employed a robust cross-validation strategy: 22 cases (20%) held-out for testing, with remaining data 86 cases used for 5-fold cross-validation (stratified by IPH presence). The five resulting models independently generated IPH probability scores, and ensembled predictions calculated by three methods to enhance generalizability: Majority and weighted voting based on binary IPH class and soft voting based on IPH probability scores. Results: Of 418 patients with histological analysis, 130 had CTA studies available. After excluding 22 cases lacking histological consensus, 108 cases were analyzed. In the 22 test cases the mean age was 68.1±8.5 years and 59% were male; In the cross-validation folds age ranged from 67.1±6.9 to 75.3±7.6 years 56-82% were male. Individual models' performance on the test set showed mean ROC-AUC of 0.79 (95% CI: ±0.05) and average precision of 0.85 (±0.05) (Fig 2). The ensemble approach achieved superior performance with soft voting demonstrated 82% ROC-AUC, 77% accuracy, 79% precision, 85% sensitivity, and 82% F1-score for IPH detection, outperforming majority voting and weighted voting (Fig 3). Conclusion: Automated IPH detection in widely available CTA imaging can turn it to a powerful stroke risk assessment tool, supporting personalized prevention strategies and surgical decision-making, ultimately reducing cerebrovascular morbidity and mortality.

Background: Whether oral anticoagulation (OAC) can be discontinued after the resolution of left ventricular thrombus (LVT) remains controversial, particularly in patients without risk factors such as left ventricular aneurysms. This study aimed to identify patients who may safely discontinue OAC. Methods: We conducted a retrospective cohort study of patients with LVT resolution who completed their anticoagulation course and excluded patients with left ventricular (LV) aneurysm. Clinical and echocardiographic factors were compared between patients who experienced LVT recurrence (n = 22) and those without recurrence during follow-up (n = 94). Results: The cohort had a mean age of 64.5 ± 15.0 years, and half (50%) were male. Most had an ischemic cardiomyopathy (64.6%). LVT recurred in 19% (22/116) of patients following initial resolution. Patients with recurrence were older (mean age 71.3 ± 11.9 vs. 63.4 ± 15.7 years, p = 0.03) and were more likely to have prior ischemic stroke and arterial thromboembolism (18.2% vs. 4.3%, p = 0.02 for both). At the time of thrombus resolution, LVEF was significantly lower among patients who had recurrence (33.4 ± 13.6% vs. 42.5 ± 15.5%, p = 0.012). Stroke, systemic embolism, and mortality rates were similar regardless of recurrence status. Recurrence risk by presence or absence of stroke and LEVF >50% on the LVT resolution echocardiogram is shown in Figure 1. Notably, no recurrences were observed among patients with both LVEF > 50% and no history of stroke (0/32), which was statistically significant compared to each other category. Conclusion: Among patients without left ventricular aneurysm who discontinued oral anticoagulation after LVT resolution, those with preserved LVEF (>50%) and no prior history of stroke had a very low risk of recurrence, with no events observed in this subgroup. These findings suggest that some patients may safely discontinue anticoagulation after LVT resolution.

Purpose Large aneurysms have a higher rupture risk, yet no available in vivo animal model consistently produces large aneurysms for testing endovascular therapies. Recent research suggests that adding calcium chloride (CaCl 2 ) to elastase yields larger aneurysms in a surgical rabbit model. We evaluated whether this effect translates to an endovascular approach by comparing aneurysm sizes created using elastase alone versus a CaCl 2 –elastase combination. Methods Aneurysms were created in the right common carotid artery of New Zealand rabbits. One group received 1 mL porcine elastase; the other received elastase plus 0.055 g CaCl 2 (0.5 M). After four weeks, patency was confirmed via digital subtraction angiography. Two blinded co-authors measured the neck, width, and height of the aneurysms. Aneurysm volumes were estimated using AngioCalc.com. Statistical analyses were performed using either the Mann–Whitney U -test or t -test based on data distribution. Results Twenty-nine (29) New Zealand rabbits were included in the study: six in the CaCl 2 and elastase groups, 23 in the elastase-alone group. All induced aneurysms remained patent at follow-up. Mean neck size was significantly larger in the CaCl 2 + elastase group than in the elastase-alone group (4.4 ± 1.1 mm vs 3.5 ± 0.95 mm; respectively, p = 0.02). Differences in width (4.1 ± 0.92 mm vs 3.4 ± 0.36 mm; p = 0.06), height (9.0 ± 1.1 mm vs 9.1 ± 2.1 mm; p = 0.46), and volume (83.5 ± 38.35 mm ³ vs 53.0 ± 16.94 mm³; p = 0.11) were not significant between CaCl 2 + elastase and elastase-alone, respectively. Conclusions CaCl 2 modestly increased neck size but did not significantly enlarge overall aneurysm dimensions. Further studies are needed to assess its utility in endovascular aneurysm models.

BACKGROUND: The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has significantly increased in recent years. GLP-1 RAs delay gastric emptying, resulting in early satiety and weight loss. This may increase the risk of pulmonary aspiration of residual gastric contents (RGC) during anesthesia delivery. Evidence is urgently needed to guide perioperative anesthesia management for patients taking GLP-1 RAs. This study evaluated preoperative factors that may be associated with high RGC. METHODS: Adult patients who were taking GLP-1 RAs and scheduled to receive anesthesia at 3 hospitals between June 30, 2023, and August 15, 2024, were evaluated via preoperative point-of-care gastric ultrasonography (GUS). The primary outcome was high RGC, defined by the presence of solids food or >1.5 mL/kg of clear liquids on GUS, and its association with preoperative factors (eg, existing medical conditions, indication and route of taking GLP-1 RAs, length of taking GLP-1 RAs, days of withholding GLP-1 RAs before surgery, and preoperative fasting periods). Data are presented as median (interquartile range [IQR]). RESULTS: Among the 316 patients (60.9 years [52.1–68.9] of age; 167 [52.8%] females) included in the study, 113 (35.8%) had high RGC. A higher percentage (5.3%; 6/113) of patients in the high RGC group had an opioid prescription for pain management within 3 months of the GUS assessment compared to the low RGC group (1.0%; 2/203; P = .027). No statistical difference was found between the groups in other existing medical conditions, indication and route of taking GLP-1 RAs, and length of taking GLP-1 RAs. Of the 294 patients taking weekly injections, there were 187 (63.6%) with low RGC and 107 (36.4%) with high RGC. Patients with low RGC withheld their GLP-1 RAs for 8 days [5–10], while patients with high RGC withheld for 6 days [3–9] ( P = .003). Receiver operating characteristic (ROC) analysis found ≤7.5 days of withholding the medication as cutoff for increased prevalence of high RGC in patients taking GLP-1 RA injections. Patients with low RGC fasted from solid food for 20.0 hours [14.8–40.8], and patients with high RGC fasted from solid food for 15.0 hours [12.8–19.0] ( P < .001). ROC found ≤21.3 hours of fasting from solid food as the cutoff for increased prevalence of high RGC. CONCLUSIONS: GLP-1 RA usage may delay gastric emptying. In preoperatively fasting adults, ≤7.5 days of withholding injections and ≤21.3 hours of fasting from solid food are associated with high RGC.