Death In Patients Research Articles

Disproportionality analysis of the safety profile of rufinamide in the real world: an evaluation of the FDA adverse event reporting system database.

The antiepileptic drug rufinamide (RUF), was recently introduced to alleviate seizures in patients with Lennox-Gastaut syndrome (LGS). However, little is known about its adverse reactions. The objective of this study is to probe, assess, and share evidence on RUF safety profiles via data from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis of RUF-associated adverse drug events (ADEs) was assessed through the calculation of the reporting odds (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-Poisson shrinker (MGPS). A total of 338 ADE reports related to RUF were collected. Nervous system disorders were the most frequently reported positive signals. Notably, new unexpectedly significant ADEs were detected. Among them, atonic seizures, sudden unexplained death with epilepsy, seizure clusters, multiple-drug resistance, Stevens‒Johnson syndrome, and other possible novel signals deserve awareness. An examination of age-specific differences in the detected signals indicated that nearly half of the ADEs observed in children receiving RUF were categorized as psychological or neurological system diseases. Our disproportionality analysis of ADEs within 4 weeks of treatment revealed high RORs for electrocardiogram Qt shortened, sudden unexplained death in patients with epilepsy, and atonic seizures. Our study revealed prospective signals of new ADEs linked to RUF as well as revealed that both prescribers and patients were more conscious of the risks involved in its clinical use.

Extracellular Fluid Volume and Mortality after Kidney Transplantation.

High extracellular fluid volume (ECV) is associated with an increased risk of death in non-transplanted patients with chronic kidney disease (CKD). By contrast, both the determinants and the prognosis value of ECV in kidney transplant recipients (KTR) remain unclear. We studied a bicentric prospective cohort of 2057 KTR, who underwent glomerular filtration rate measurement (mGFR) three months after transplantation. We calculated ECV from iohexol plasma disappearance curve and analyzed its association with patient's characteristics and outcomes. Mean ECV and mGFR were 14.6±2.6L/1.73m2 and 52±16mL/min/1.73m2, respectively. Multiple linear regression identified male gender, older donor and recipient ages, deceased donor, non-preemptive transplantation, diabetes, cardiac arrhythmia, heart failure, proteinuria and higher mGFR as independent factors associated with increased ECV. In multivariable cause specific cox analyzes, higher tertiles of ECV were associated with increased mortality [tertile 1 as reference; hazard ratio (95% confidence interval) for tertile 2: 1.65 (1.11-2.47); tertile 3: 1.80 (1.18-2.74)] but not graft loss. Increased ECV, 3 months after transplantation, was a predictor of reduced mGFR at 12 months after adjusting for three months mGFR and other confounding factors (β coefficient: -0.06; 95%CI [-0.09 to -0.02]). an elevated ECV 3 months after KT is independently associated with increased mortality and decreased mGFR at 12 months, but not with graft loss.

The value of electroencephalography features in the prognostic evaluation of large hemispheric infarction patients at different time intervals.

Large Hemispheric Infarction (LHI) is a devastating disease with high mortality. This study aimed to use electroencephalography (EEG) to evaluate the death risk of LHI patients and identify suitable evaluation time. This study retrospectively collected clinical and EEG data from 73 LHI patients, dividing them into death and survival group at discharge. EEG data was classified as 1-5 days and 6-14 days after onset according to the time intervals of cerebral edema. Regression and receiver operator characteristic curve (ROC) analysis were applied to explore the impact of temporal changes in various EEG and clinical features on death. The areas under ROC curve (AUC) of death prediction for non-α frequency on non-infarct side at 6-14 days after onset was significantly higher than that at 1-5 days (p = 0.004). And there was no significant difference between the AUC of seizure activity for death prediction at 1-5 days and 6-14 days (p = 0.418). Multivariate regression analysis revealed that non-α frequency on non-infarct side and seizure activity at 6-14 days after onset were the independent risk factors for the death of LHI patients. Additionally, above two EEG features significantly improved the death predictive efficacy of clinical features in LHI patients with the integrated discrimination improvement index (IDI) of 0.174 (p = 0.015) and the net reclassification improvement (NRI) of 1.314 (p<0.001). Non-α frequency on non-infarct side and seizure activity were reliable indicators for death prediction. 6-14 days after onset was the better time window for death evaluation of LHI patients through EEG.

Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.

Morphological Changes Of The Heart In Sudden Death Psychiatric Patients

Although sudden cardiac death is often reported in epileptic or psychiatric patients, the etiologyis not fully understood. The aim of this study was to examine whether morphological changes of the heart contribute to sudden cardiac death in epileptic or psychiatric patients, compared with control decedents.Cases of sudden cardiac deathsdue to fatal arrhythmia in patients with epilepsy or psychiatric disease were selected from forensic autopsies performed at the Shiga Prefecture from 2014 to 2021.As the control group, autopsied healthy decedents were selected. The heart weight to normal heart weight ratio, ventricular wall thickness, cardiomyocyte width, nuclear diameter and nuclear density of the left and right ventricle and interventricular septum were examined. The left and right ventricular wall thickness and cardiomyocyte to be smaller in epileptic patients, however, no significant differences were found. The nuclear diameter/body surface area of the left ventricle was significantly smaller in epileptic and psychiatric patients than in control patients.The smaller nuclei of cardiomyocytes in epileptic and psychiatric patients may relate to the etiology of sudden cardiac death.

GSDME-mediated Pyroptosis Contributes to Chemotherapy-induced Platelet Hyperactivity and Thrombotic Potential.

Thrombotic complications due to platelet hyperreactivity are a major cause of death in patients undergoing chemotherapy. However, the underlying mechanisms are not fully understood. Herein, using human and GSDME-/- mouse platelets, we showed that GSDME is functionally expressed in anucleate platelets and GSDME-mediated pyroptosis, a newly identified form of cell death in mammalian nucleated cells, contributes to platelet hyperactivity in cisplatin-based chemotherapy. Cisplatin or etoposide activates caspase-3 to cleave GSDME, thereby releasing the N-terminal fragment of GSDME (GSDME-N) toward the platelet plasma membrane, subsequently forming membrane pores and facilitating platelet granule release. This eventually promotes platelet hyperactivity and thrombotic potential. We identified flotillin-2, a scaffold protein, as a GSDME-N interactor that recruits GSDME-N to the platelet membrane. loss of GSDME protects mice from cisplatin-induced platelet hyperactivity. Our results provide evidence that targeting GSDME-mediated pyroptosis could reduce thrombotic potential in chemotherapy.

Case–control study on risk factors for in-hospital mortality in patients with severe COVID-19

ObjectiveThe purpose of this study was to identify independent risk factors affecting patient survival and explore predictors of severe cases of coronavirus disease 2019 (COVID-19).MethodsWe conducted a retrospective, observational, case–control study on adult patients with severe COVID-19 who were admitted to affiliated hospitals in Tianjin between December 18, 2022, and January 31, 2023. We used univariate and multifactorial logistic regression analyses to analyze demographic indicators, comorbidity profiles, and laboratory parameters in two groups of patients (deceased and surviving) to identify independent risk factors for death in patients with severe COVID-19.ResultsPatients in the deceased group were older than those in the survival group (p = 0.018), and there were more cases of coexisting respiratory insufficiency in the deceased group (p = 0.002). Additionally, laboratory test results for white blood cell count (WBC) and creatine kinase (CK) showed significantly higher values in the deceased group (p = 0.047 and p = 0.029, respectively), while arterial oxygen partial pressure (PAO2) showed significantly lower values compared to the survival group (p = 0.021). Age, respiratory insufficiency, WBCH (highest WBC value), CKH (highest CK value), and PAO2F (first PAO2 value) had area under curve (AUC) values of 0.698, 0.838, 0.721, 0.744, and 0.633, respectively.ConclusionThe main risk factors for mortality in patients with severe COVID-19 that we identified in this study were the advanced age of patients, coexisting respiratory insufficiency, elevated levels of WBC and CK, and decreased levels of PAO2. Elevated WBC and CK laboratory parameters, in particular, demonstrated good predictive value for in-hospital mortality risk.

Impact of the fibrosis-4 index in patients with ST-elevated myocardial infarction.

The fibrosis-4 (FIB4) index, a simple, noninvasive marker used for hepatic diseases, represents adverse outcomes. The aim of the present study was to evaluate whether the FIB4 index can predict adverse outcomes in patients with ST-elevation myocardial infarction (STEMI). We investigated patients with STEMI who underwent primary percutaneous coronary intervention (PCI) and were alive at discharge. The cut-off FIB4 index at discharge was investigated using the survival classification and regression tree (CART) model to predict adverse outcomes. The primary outcome was all-cause mortality. Between January 2006 and December 2018, 1354 patients with STEMI (median age, 68 years; men, 76.1%) were investigated. The median value of the FIB4 index was 1.21 (0.84-1.78). The CART model divided the study population into low (FIB4 index <0.945; n = 435), intermediate (0.945 ≤ FIB4 index < 2.185; n = 692), and high (FIB4 index ≥2.185; n = 227) groups based on the significant predictive values for all-cause death. During a median follow-up period of 4.3 years, all-cause death occurred in 208 patients (15.4%). The Kaplan-Meier analysis showed a significant increase in mortality with higher FIB4 index values (log-rank, P < 0.001). The multivariate Cox regression model revealed that the FIB4 index was an independent risk predictor for all-cause death in patients with STEMI [low group as reference vs. intermediate group, hazard ratio: 1.975; 95% confidence interval (CI): 1.166-3.346; P = 0.011 and vs. high group, hazard ratio: 4.633; 95% CI: 2.549-8.418; P < 0.001]. The FIB4 index was associated with the risk of all-cause mortality in patients with STEMI who underwent primary PCI.

Bioinformatics-based analysis of EMT-related genes in cervical cancer patients

Background: In most cases, patients who are not screened canonically have advanced disease by the time they are first diagnosed. Therefore, invasive metastasis is the main feature and cause of death in patients with advanced cervical cancer. Methods: The GEO database was searched for analytical data on cervical cancer. The GSE9750 dataset was employed to identify differentially expressed genes (DEGs) in tumor samples compared to normal samples, carry out enrichment analysis, build protein-protein interaction (PPI) networks to identify key genes (Hub gene), and perform between diagnostic genes and immune infiltrated cells. Results: A total of 1440 DEGs and 46 differential genes linked to EMT were screened. GO enrichment produced 455 results, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment （KEGG ）yielded a total of 18 pathways. A PPI network was built using 46 differential genes related to EMT, and 9 Hub genes were also validated. Nine hub genes had exactly the same up- and down-regulation trend as before in the external verification set, but only six hub genes were ultimately determined to be diagnostic genes after further validation by the external verification set. The results of the KM (Kaplan-Meier) survival study also revealed five prognostic genes related to survival, namely MMP1, CXCL8, SSP1, MMP3, and VCAM1. Conclusion: The genes MMP1, CXCL8, SSP1, MMP3, and VCAM1are crucial in the development of EMT in patients with cervical cancer and can be employed as both diagnostic and therapeutic targets during the progression of EMT in cervical cancer patients.

Ultra-Small Copper-Based Multienzyme-Like Nanoparticles Protect Against Hepatic Ischemia-Reperfusion Injury Through Scavenging Reactive Oxygen Species in Mice.

Hepatic ischemia-reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end-stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra-small copper-based multienzyme-like nanoparticles with catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) catalytic activities significantly scavenge the surge-generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra-small copper SOD-like activity and manganese dioxides CAT-like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N-acetylcysteamine acid (NAC), an FDA-approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next-generation nanomedicines for scavenging ROS.

Changes in the Treatment and Prevention of Heart Failure Based on the 2023 Focused Update of the 2021 European Society of Cardiology Guidelines

Introduction and Objective:The 2023 update to the 2021 ESC Guidelines for diagnosing and treating acute and chronic heart failure introduces significant changes in pharmacotherapy and prevention. Staying informed about these updates is crucial given the evolving landscape of heart failure management. This review provides an overview of the latest recommendations and supporting evidence. Review Methods:A comprehensive review of scientific publications and guidelines from PubMed, Google Scholar, Clinical Key, Via Medica Journals, and relevant clinical guidelines was conducted to ensure the most recent evidence is considered. Brief Description of the State of Knowledge:Heart failure is a growing global concern. The 2023 update highlights key management changes. Recent trials, including EMPEROR-Preserved and DELIVER, show empagliflozin and dapagliflozin reduce heart failure hospitalization and cardiovascular death in patients with mildly reduced and preserved ejection fraction. The guidelines now recommend intravenous iron for patients with reduced or mildly reduced ejection fraction and iron deficiency. For those with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone, a non-steroidal mineralocorticoid antagonist, are recommended to reduce heart failure hospitalization and prevent renal function decline. Summary:The 2023 ESC Guidelines update offers revised recommendations for heart failure management and prevention, integrating the latest clinical trial data and meta-analyses. Key areas include the use of SGLT2 inhibitors, iron deficiency management, and preventive strategies for high-risk populations. Implementing these guidelines can significantly improve preventive and therapeutic outcomes for heart failure patients.

Single-cell RNA sequencing identifies a subtype of FN1 + tumor-associated macrophages associated with glioma recurrence and as a biomarker for immunotherapy

BackgroundGlioma is the most common primary malignant tumor in the brain, and even with standard treatments including surgical resection, radiotherapy, and chemotherapy, the long-term survival rate of patients remains unsatisfactory. Recurrence is one of the leading causes of death in glioma patients. The molecular mechanisms underlying glioma recurrence remain unclear.MethodsOur study utilized single-cell sequencing, spatial transcriptomics, and RNA-seq data to identify a subtype of FN1 + tumor-associated macrophages (FN1 + TAMs) associated with glioma recurrence.ResultsThis study revealed an increased abundance of FN1 + TAMs in recurrent gliomas, indicating their potential involvement as a critical factor in glioma recurrence. A negative correlation was observed between the abundance of FN1 + TAMs in primary gliomas and the interval time to recurrence, suggesting poor prognosis for glioma patients with high levels of FN1 + TAMs. Further investigation showed that FN1 + TAMs were enriched in hypoxic tumor regions, implying that metabolic changes in tumors drive the production and recruitment of FN1 + TAMs. Additionally, FN1 + TAMs were found to contribute to the regulation of an immunosuppressive microenvironment in gliomas, and their abundance might serve as an indicator of patients’ sensitivity to immunotherapy. Finally, we developed a user-friendly website, PRIMEG (http://www.szflab.site/PRIMEG/), for exploring the immune microenvironment of primary and recurrent gliomas.ConclusionOur findings highlight a subtype of FN1 + TAMs associated with glioma recurrence, providing new insights into potential therapeutic targets. Moreover, the abundance of FN1 + TAMs hold promise for predicting immune therapy response and aiding in more precise risk stratification of recurrent glioma patients.

The relationship of short-term exposure to meteorological factors on diabetes mellitus mortality risk in Hefei, China: a time series analysis.

The study aims to explore whether short-term exposure to meteorological factors has a potential association with the risk of diabetes mellitus (DM) mortality. During the period 2015-2018, we collected daily data on meteorological factors and deaths of diabetic patients in Hefei. A total of 1101 diabetic deaths were recorded. We used structural equation modeling to initially explore the relationships among air pollutants, meteorological variables, and mortality, and generalized additive modeling (GAM) and distributional lag nonlinear modeling (DLNM) to explore the relationship between meteorological factors and the mortality risk of DM patients. We also stratified by age and gender. The mortality risk in diabetic patients was expressed by relative risks (RR) and 95% confidence intervals (CI) for both single and cumulative days. Single-day lagged results showed a high relative humidity (RH) (75th percentile, 83.71%), a fairly high average temperature (T mean) (95th percentile, 30.32°C), and an extremely low diurnal temperature range (DTR) (5th percentile, 3.13°C) were positively related to the mortality risk of DM. Stratified results showed that high and very high levels of T mean were significantly positively linked to the mortality risk of DM among females and the elderly, while very high levels of DTR were linked to the mortality risk in men and younger populations. In conclusion, this study found that short-duration exposure to quite high T mean, high RH, and very low DTR were significantly positively related to the mortality risk of DM patients. For women and older individuals, exposure to high and very high T mean environments should be minimized. Men and young adults should be aware of daily temperature changes.

Identification of factors predicting low-risk febrile neutropenia admissions in adults with acute myeloid leukemia (AML).

Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML and is a major driver of healthcare resource utilization. While FN risk models exist, these have largely been developed and validated in solid tumors. We therefore examined whether baseline characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. We identified adults with high-grade myeloid neoplasm (³10% blasts in blood/marrow) who received intensive chemotherapy and were admitted for FN from 2016-2023. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A "lower-risk [LR]" outcome was defined as LOS <72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. We identified 397 FN admissions in 248 patients (median age 61 [range: 29-77] years). The median hospital LOS was 6 (range: 1-56) days; 10% required ICU admission and 3.5% died inpatient. Only 15% of admissions were LR. Infection was identified in 59% of admissions. Physiologic parameters including heart rate, blood pressure and fever height were the best predictors of LR admission and infection. We developed MV models to predict LR admission and infection with AUCs of 0.82 and AUC 0.72, respectively. Established FN and critical illness models were not predictive of outcomes in AML, where we could not identify a lower risk group; thus an AML-specific FN risk model requires further development and validation.

12351 Real World Performance of the Afirma Xpression Atlas in Bethesda V and Vi Thyroid Nodules: A Private Practice Experience

Abstract Disclosure: M.S. Tkach: None. E. Coughlin: None. A. Pinero-Pilona: None. Fine Needle Aspiration (FNA) is a cornerstone of the diagnosis of thyroid cancer. The Bethesda System for Reporting Thyroid Cytopathology (BS-TCP), developed in 2010, and genomic sequencing classifiers (GSC) now allow clinicians to objectively identify the risk of malignancy of thyroid nodules (“TN”) prior to surgical interventions. For further characterization, the Afirma Xpression Atlas (XA) was created and launched in May 2018, utilizing RNA sequencing to evaluate fusions and variants. As of 2023, the Afirma XA panel includes 905 genomic variants and 235 fusions from 593 genes. Post-validation studies for the Afirma XA have focused on large academic centers, but applicability or extrapolation to smaller endocrinology practices is less clear, potentially due to different patient population and thyroid cancer prevalence. This study was designed to analyze and measure the performance of the Afirma XA in BS-TCP V and VI TN classified as GSC suspicious for malignancy in a small endocrinology practice. We conducted a retrospective cohort analysis comparing all BS-TCP V and VI TN with their respective final surgical pathology results between June 2018 and December 2023. 76 TN meeting the criteria for BS-TCP V or VI classification were identified. We excluded any TN (12 total) for which pathology data was unavailable; reasons ranged from lack of patient follow-up to patient's death with no autopsy available. Forty-seven thyroid TN were therefore included, and the BS-TCP VI category was the predominant cytopathology discovered, representing 78.7% of the TN in this group. Afirma XA was able to identify genomic alterations in 78.7% of all included TN (thus 78.7% is its sensitivity). Sensitivity of XA was found to be 70% in BS-TCP V (n=10) and 81.1% in BS-TCP VI (n=37). 83% of the analyzed TN were from female patients and 17% were from male patients; there was no statistically significant difference between XA frequency in TN from male vs. female patients. 100% of all BS-TCP V and VI TN (n=47) as determined by the cytopathologist were associated with cancer on pathology; thus, the sensitivity of the cytopathology itself is 100%, and positive predictive value of XA in both groups was 100%. Age and nodule size were not significantly associated with XA presence or absence overall. XA was overwhelmingly comprised of BRAF :p:V600E c.1799T&amp;gt;A mutations: 70.2% of of XA findings showed this mutation (50% in V and 75.6% in VI). Our percentage of XA on BS-TCP V and VI nodules reflects similarity to prior large studies in academic centers. Based on this data, we conclude that XA is a valuable tool for high-risk TN classification and treatment guidance; it can both aid in surgical planning and determine options for potential pharmacotherapy. We conclude that in our study, the relation between XA and cytopathology in BS-TCP V and VI nodules correlates well with data from large academic center studies, even in a small private practice. Presentation: 6/3/2024

Robotic kidney transplant has superior outcomes compared to open kidney transplant: results of a propensity match analysis.

Several studies have demonstrated the feasibility of robotic kidney transplant (RKT) as a safe alternative to open kidney transplant (OKT). However, significant selection bias in RKT patient selection limits meaningful comparison between the two techniques. This is a single-center retrospective review of a prospectively maintained kidney transplant database (2021-2024). Outcomes after the first 50 "non-selected" RKTs are compared with a contemporary cohort of 100 OKTs after propensity score matching for age, gender, BMI and type of donation (living vs deceased). Data pertinent to recipient demographics, intraoperative parameters, and short-term post-operative outcomes were collected and compared. Both groups were well-matched for recipient age, gender, BMI, and donation type. RKT group had significantly longer total operative time (RKT 258min vs. OKT 183min; p < 0.0001) and warm ischemia time (RKT 37min vs. OKT 31min; p < 0.0001) but significantly less blood loss (OKT 155ml vs. RKT 93ml). Average length of hospital stay for both groups was 5days, with OKT group demonstrating significantly higher rates of post-operative complications (OKT 31% vs. RKT 14%; p = 0.028), return to OR (OKT 15% vs. RKT 2%; p = 0.021), hematoma (OKT 13% vs. RKT 2%; p = 0.0355), and lymphocele (OKT 25% vs. RKT 6%; p = 0.0039). OKT group also had higher 30-day readmission rate (OKT 31% vs. RKT 14%) and post-operative opioid requirement (OKT 93 MME vs. RKT 65; p = 0.0254). There were no differences in rates of wound infection, urine leaks, delayed graft function, acute rejection, graft loss, and patient death between the two groups. RKT is a safe and viable alternative to OKT as a first-choice procedure for all patients with ESRD. RKT offers many advantages over OKT which can lead to its wider adoption in the coming years as the new standard of care for ESRD patients.

7076 Inhibiting Oxidosqualene Cyclase, An Enzyme In The Cholesterol Biosynthetic Pathway, Suppresses Lung Metastasis Of Triple-Negative Breast Cancer Cells

Abstract Disclosure: Y. Liang: None. S.M. Hyder: None. Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu proteins that are commonly targeted in breast cancer therapies. As a consequence, women who suffer from TNBC have poor prognosis and limited treatment options, and are usually administered toxic, non-specific chemotherapeutic agents. Drug-resistance almost always occurs, leading to tumor metastasis, the main cause of patient death. New non-toxic therapeutic strategies to control metastasis of TNBC are urgently needed. Cholesterol is an essential structural and functional component of cell membranes that is necessary for the growth of both primary tumors and metastatic colonies that reside in distant organs. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy. Treatment with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently, we targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor metastasis. Potent small molecule inhibitors of OSC have been identified. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors. We developed a mouse model for studying lung metastasis using a MDA-MB-231 variant (LM2) TNBC cell line obtained from Dr. Massagué (Memorial Sloan-Kettering Cancer Center). These are aggressive cells, and injection of only 2 X 105 cells produces detectable lung metastatic colonies in approximately 4-6 weeks. We inoculated female nu/nu mice, 5-6 weeks old, with 2 X 105 MDA-MB-231/LM2 cells in 0.1 ml DMEM/F12 medium without serum via tail vein. Five days after tumor cell inoculation animals received 20 mg/kg (n=6), 40 mg/kg (n=7) RO (ip) or vehicle alone (n=7) every other day for two weeks. Animals were then sacrificed, and both lungs harvested and immediately fixed in Bouin’s fixative. Metastatic colonies on the lung surface were identified and counted under a dissecting microscope. Our study showed that RO effectively reduced lung metastasis without affecting animal weight. Compared with 56 + 7 colonies (Mean ± SEM) in controls given vehicle alone, RO significantly reduced lung metastatic colonies to 28 ± 5 in animals exposed to 20 mg/kg and 6 ± 1 in 40 mg/kg treated animals (p&amp;lt;0.05, ANOVA). Reduction in number of colonies in 40 mg/kg group was also significantly different from colonies counted in 20 mg/kg treated animals. Our study is the first to demonstrate that disruption of cholesterol biosynthesis in a model of human TNBC leads to reduced metastasis in lungs. Further studies will determine mechanisms through which RO suppresses TNBC metastasis to the lungs. Supported by Zalk Missouri Professor Endowment Funds. Presentation: 6/3/2024

8091 Clinical Features Associated with ICU Admission and Mortality in Thyroid Storm and Impending Thyroid Storm

Abstract Disclosure: E.D. Zhang: None. I. Hussain: None. Introduction: Thyroid storm is a rare, life-threatening manifestation of thyrotoxicosis characterized by a clinical syndrome of acute multi-organ failure, which can result in significant morbidity and mortality. Impending thyroid storm is a stage of thyrotoxicosis that may progress to thyroid storm if untreated. The aim of this study was to evaluate the demographics and outcomes of patients with thyroid storm at our institution and determine the clinical features associated with severe complications and mortality. We also evaluated the differences in clinical features and outcomes in patients diagnosed with impending thyroid storm versus thyroid storm. Methods: This was a retrospective single-center cohort study evaluating patients aged 18 years or older who were clinically diagnosed with thyroid storm or impending storm at two affiliated tertiary academic centers from 2008-2021. A search of the electronic medical record system using ICD-10 codes for thyroid storm identified patient charts which were reviewed for eligibility. Results: This study included 121 admissions, with 75 (62.0%) patients with thyroid storm and 46 (38.0%) patients with impending thyroid storm. Our study cohort was notably more racially and ethnically diverse than prior U.S. studies with 5.0% non-Hispanic White, 52.9% Black, 33.9% Hispanic, and 8.3% Asian patients. The mortality rate was 4.7%, with all patient deaths occurring in the thyroid storm group. Multivariable logistic regression analysis showed atrial fibrillation (OR 4.09, 95% CI 1.21, 13.85, p=0.02) and acute respiratory failure (OR 22.18, 95% CI 2.29, 215.19, p=0.008) to be significantly associated with a composite outcome of intensive care unit (ICU) admission or death. Comparison of impending storm and thyroid storm groups showed fever (p=0.02), acute respiratory failure (p=0.03), and ICU admission (p=0.02) to be significantly different between groups. Conclusions: This study describes the largest published single-center cohort of patients treated for thyroid storm in the United States. Furthermore, our study contributes importantly to the data for racial/ethnic minorities who are under-represented in prior studies. The mortality rate in this study is lower than most recent studies. The presence of atrial fibrillation and acute respiratory failure were noted to be significantly associated with a composite outcome of ICU admission or death, and the five fatal cases had high rates of cardiac arrest and shock. These findings suggest that complications involving cardiopulmonary compromise are clinically important in predicting severe disease and poor outcomes. Acute respiratory failure was also noted to be significantly different between impending storm and thyroid storm groups indicating that while not currently included in existing diagnostic systems, it is an important complication of thyroid storm that may have prognostic value. Presentation: 6/2/2024

7993 Thienopyrimidine-Based Estrogen Receptor Modulators Adopt Unique Ligand Binding Poses to Elicit Anti-Proliferative Activities in ER+ Breast Cancer Cells

Abstract Disclosure: E.C. Fink: None. S.L. Mateus: None. N. Meganathan: None. V.K. Sammeta: None. J.D. Norris: None. D.P. McDonnell: None. T. Willson: None. S.W. Fanning: None. One in eight women will be diagnosed with breast cancer in their lifetimes. Estrogen receptor alpha (ER) drives breast cancer pathology and is expressed in approximately seventy percent of tumors. Hormone therapies are used to treat and prevent the metastasis of ER+ breast cancers and these patients have favorable 5-year survivals. However, most breast cancer patient deaths are ER+. While the next generation of antiestrogens have shown promise in the advanced setting, more work needs to be done to fully address these mortalities. ER is a ligand-dependent master transcriptional regulator, whereby ligand-specific ER conformational ensembles redirect multiple programs to produce oncogenic or therapeutic endpoints. To better understand ER structure-activity relationships, we have developed new antiestrogenic small molecules based on a thienopyrimidine scaffold. Comprehensive structural, ER activity, and cancer endpoint profiling shows that these new molecules adopt a unique ligand binding pose, which perturbs new structural elements within the orthosteric hormone binding pocket. These molecules downregulate ER target genes and halt the proliferation of ER+ breast cancer cells. Presentation: 6/3/2024

7076 Inhibiting Oxidosqualene Cyclase, an Enzyme in the Cholesterol Biosynthetic Pathway, Suppresses Lung Metastasis of Triple-negative Breast Cancer Cells

Abstract Disclosure: Y. Liang: None. S.M. Hyder: None. Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu proteins that are commonly targeted in breast cancer therapies. As a consequence, women who suffer from TNBC have poor prognosis and limited treatment options, and are usually administered toxic, non-specific chemotherapeutic agents. Drug-resistance almost always occurs, leading to tumor metastasis, the main cause of patient death. New non-toxic therapeutic strategies to control metastasis of TNBC are urgently needed. Cholesterol is an essential structural and functional component of cell membranes that is necessary for the growth of both primary tumors and metastatic colonies that reside in distant organs. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy. Treatment with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently, we targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor metastasis. Potent small molecule inhibitors of OSC have been identified. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors. We developed a mouse model for studying lung metastasis using a MDA-MB-231 variant (LM2) TNBC cell line obtained from Dr. Massagué (Memorial Sloan-Kettering Cancer Center). These are aggressive cells, and injection of only 2 X 10[5] cells produces detectable lung metastatic colonies in approximately 4-6 weeks. We inoculated female nu/nu mice, 5-6 weeks old, with 2 X 10[5] MDA-MB-231/LM2 cells in 0.1 ml DMEM/F12 medium without serum via tail vein. Five days after tumor cell inoculation animals received 20 mg/kg (n=6), 40 mg/kg (n=7) RO (ip) or vehicle alone (n=7) every other day for two weeks. Animals were then sacrificed, and both lungs harvested and immediately fixed in Bouin’s fixative. Metastatic colonies on the lung surface were identified and counted under a dissecting microscope. Our study showed that RO effectively reduced lung metastasis without affecting animal weight. Compared with 56 + 7 colonies (Mean ± SEM) in controls given vehicle alone, RO significantly reduced lung metastatic colonies to 28 ± 5 in animals exposed to 20 mg/kg and 6 ± 1 in 40 mg/kg treated animals (p&amp;lt;0.05, ANOVA). Reduction in number of colonies in 40 mg/kg group was also significantly different from colonies counted in 20 mg/kg treated animals. Our study is the first to demonstrate that disruption of cholesterol biosynthesis in a model of human TNBC leads to reduced metastasis in lungs. Further studies will determine mechanisms through which RO suppresses TNBC metastasis to the lungs. Supported by Zalk Missouri Professor Endowment Funds. Presentation: 6/3/2024