Kaplan-Meier Analysis Research Articles

Abstract 4141437: Identification of Mitochondrial-related Diagnostic Biomarkers of Acute Type A Aortic Dissection and Pan-Cancer Analysis

Background: Acute Type A Aortic Dissection (ATAAD) is a lethal disease with limited predictability globally. Cancer, a severe public health issue worldwide, has now become the second leading cause of death in America. In this study, we aimed to explore potential common mechanisms and therapeutic targets between ATAAD and cancer. Aims: Identify mitochondrial-related diagnostic biomarkers of ATAAD and their roles in various cancers. Methods: ATAAD-related datasets GSE52093, GSE98770, GSE190635 were downloaded from GEO and merged after removing batch effects. We verified 119 mitochondrial-related differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Using five machine learning methods (LASSO, SVM, Decision Tree, Random Forest, and Boruta algorithm), we identified two mitochondrial-related diagnostic biomarkers of ATAAD: PPIF and CASQ1. The diagnostic accuracy was performed using receiver operating characteristic (ROC) curves. RT-qPCR was used to detect PPIF and CASQ1 expression. Immune infiltration analysis suggested that PPIF may play a key role in tumor immune microenvironment. We utilized TCGA and GTEx databases, Kaplan-Meier analyses and Cox regression analyses to assess PPIF expression and survival analysis in 33 cancer types. qPCR and Western Blot (WB) assays verified PPIF overexpression in lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC). CCK-8, wound-healing and transwell assays further verified PPIF’s proliferative, migratory and invasive abilities in LUAD and UCEC. Results: Our study identified PPIF and CASQ1 as hub mitochondrial-related diagnostic biomarkers of ATAAD. Besides its close association with tumor immune infiltration, PPIF also overexpressed in multiple cancer types. Survival analysis suggested the prognostic value of PPIF in most cancers. Experimental results further verified that PPIF promotes the proliferation, migration, and invasion of LUAD and UCEC. Conclusions: PPIF and CASQ1 are potential mitochondrial-related diagnostic biomarkers of ATAAD, not previously reported. Pan-cancer analysis implies that PPIF may serve as a key prognostic and therapeutic target in multiple cancers. PPIF may act as a hub gene linking ATAAD and cancer, offering new insights to reduce ATAAD incidence in cancer patients.

Abstract 4118178: Echocardiographic Measure of Right Ventricular-Pulmonary Arterial Coupling Predicts Survival in Lung Cancer

Background: Echocardiographic indicators of pulmonary hypertension have been reported to predict decreased survival in lung cancer. We sought to test the hypothesis that this may be associated with impaired right ventricular (RV)-systolic pulmonary arterial pressure (sPAP) coupling, further enhancing the prognostic strength of echocardiography in lung cancer. Methods: This prospective observational study included 220 patients with non-small cell lung cancer (NSCLC) examined by Doppler, strain and 3D echocardiography before starting therapy. Prediction of overall survival was assessed by univariable analysis followed by multivariate Cox regression, receiver operating characteristic (ROC) curves and Kaplan-Meier analyses. Results: Echocardiographic examination was on average within normal limits, even though 30% of the patients had sPAP ≥35 mm Hg. In univariable analysis, overall survival was associated with measures of RV systolic function and probability of pulmonary hypertension. In multivariate Cox regression, only RV global longitudinal strain (GLS)/sPAP (HR: 5.766 [95% CI: 1.025–32.443]) and Eastern Cooperative Oncology Group performance status <2 (HR: 0.332 [95% CI: 0.171–0.644]) independently predicted survival. The optimal ROC curve-derived RV GLS/sPAP cut-off to predict survival was −0.54%/mm Hg. Among patients in Union for International Cancer Control (UICC) stage 4, those with impaired RV-arterial coupling (RV GLS/sPAP >−0.54%/mm Hg) had worse survival than those with maintained RV-arterial coupling (HR: 2.8 [95% CI: 1.5–5.3]); the latter subgroup had similar survival compared with patients in UICC stage 3 (HR: 0.57 [95% CI: 0.28–1.14]). Conclusion: RV GLS/sPAP as an echocardiographic measure of RV-arterial coupling adds to prognostication by the UICC status in NSCLC.

Abstract 4132351: Soluble Urokinase Plasminogen Activator Receptor Levels Predict Incident Cardio-Kidney-Metabolic Disease Risk

Introduction: Given the rising global incidence of cardio-kidney-metabolic (CKM) syndrome, there is an urgent need for novel risk prediction strategies for CKM disease. Hypothesis: As soluble urokinase plasminogen activator receptor (suPAR) levels have been associated with the development of cardio-kidney disease, we hypothesized that elevated suPAR levels would predict incident CKM disease risk. Methods: A total of 25,596 UK Biobank participants without CKM disease at enrollment were analyzed for the association of suPAR levels and incident CKM disease. CKM disease was defined as the first occurrence of CVD (heart failure, atrial fibrillation/flutter, coronary heart disease, stroke, and peripheral artery disease), chronic kidney disease (CKD), or metabolic disease (type 2 diabetes mellitus and obesity). Incident CVD, CKD, and metabolic disease were also analyzed separately as secondary outcomes. Kaplan-Meier analysis was performed to visualize the association between suPAR levels and the primary composite CKM outcome. Competing-risk regression, while accounting for competing non-CKM disease death, was performed to examine the association between suPAR levels and the primary composite CKM outcome. Models were adjusted for demographics, traditional risk factors, and CRP levels. Results: The mean age was 56.0 (SD 8.3) years, 44% were male, and 94% were White. suPAR levels were associated with a significantly higher rate of composite CKM events (P<0.001) (Figure 1). During a median follow-up of 13.5 [IQR 1.7] years, 5,012 (20.0%) composite CKM events, 3,599 (8.3%) incident CVD events, 863 (3.4%) incident CKD events, and 1,397 (4.7%) incident metabolic disease events occurred. suPAR levels (per SD) significantly predicted the primary composite CKM outcome (sHR 1.23, 95% CI 1.19-1.27) after adjustment. suPAR levels (per SD) also significantly predicted incident CVD (sHR 1.24, 95% CI 1.19-1.29), incident CKD (sHR 1.41, 95% CI 1.30-1.53), and incident metabolic disease (sHR 1.17, 95% CI 1.10-1.24) after adjustment. Conclusion(s): In this large, longitudinal cohort study of UKB participants, plasma suPAR levels were a significant predictor of CKM disease risk, independent of demographics, traditional risk factors, and CRP levels.

Abstract 4137424: Circulating Levels of the Pro-Fibrotic Collagen Hormone Endotrophin are Associated with the Risk of Experiencing Major Adverse Cardiovascular Events in Individuals with Type 2 Diabetes – The Thousand&2 Study

Introduction: Cardiovascular disease (CVD) complications are the leading cause of mortality in individuals with type 2 diabetes (T2D). Abnormal extracellular matrix (ECM) remodelling leads to the release of ECM protein fragments into circulation, reflecting these complications. Endotrophin, a pro-fibrotic and -inflammatory hormone, released during collagen type 6 formation, has been linked to adverse outcomes in T2D, but not previously in a long-term perspective. Aim: To assess the 12-year prognostic value of circulating endotrophin levels, measured by PRO-C6, to predict the risk of major adverse cardiovascular events (MACE) in a large cohort of individuals with T2D. Methods: Endotrophin levels were measured with the NordicPRO-C6™ ELISA in 909 serum samples from the Thousand&2 study, which was initiated in 2011 and examined individuals with T2D, with and without known CVD. Clinical data were collected at baseline. Follow-up was 100% complete and performed on the 1 st of May 2024 with the registration of data on MACE from the Danish national registers. The primary outcome was MACE, defined as incident events of hospital admission for ischemic heart disease, heart failure, stroke, or all-cause mortality. PRO-C6 was split into tertiles and examined for survival probability by Kaplan-Meier analysis. Univariate Cox proportional hazard regression analysis was conducted to examine the association between PRO-C6 and the risk of MACE. A multivariable Cox model was additionally conducted, adjusted for age at baseline, sex, systolic blood pressure, duration of diabetes, HbA1c, estimated glomerular filtration rate, use of statins, albuminuria status, and current or prior smoking. Results: The baseline mean (±SD) age of the cohort was 64 (±10) years, 66% were males, mean (±SD) PRO-C6 was 11.9 (±7.01) ng/ml, the median follow-up time was 10.6 years, and number of MACE recorded was 472. The risk of experiencing MACE was significantly higher in the third tertile compared to the first and second tertile (Log-Rank p < 0.001). In the univariate Cox model, the estimated hazard ratio (HR), corresponding to a 2-fold increase of PRO-C6, was HR [95% Confidence Interval(CI)] = 2.1 [1.8-2.4], P <0.001. In the fully adjusted Cox model, PRO-C6 remained significantly associated with the risk of MACE (HR [95% CI] = 1.5 [1.2-1.8], P <0.001). Conclusion: Elevated circulating endotrophin is associated with MACE in T2D, independent of common risk factors.

Abstract 4144595: Real-World Outcomes of Impella 5.5 in Advanced Heart Failure Patients Undergoing Evaluation for Heart Transplant

Background: Impella 5.5 provides robust support as temporary mechanical circulatory support (t-MCS) device in advanced heart failure patients in cardiogenic shock. Understanding short- and long-term outcomes is crucial. Hypothesis: Impella 5.5 supports advanced heart failure patients in cardiogenic shock and successfully bridges them to cardiac replacement without affecting long-term survival. Methods: From February 2020 to April 2024, all patients who received an Impella 5.5 and underwent evaluation for advanced therapies at Houston Methodist Hospital were identified. Implantation of Heartmate 3 (HM3) Left Ventricular Assist Device (LVAD), orthotopic heart transplantation (OHT), mortality, and device removal after Impella implantation were assessed. For HM3 LVAD patients, outcomes were categorized as death, transplantation, or survival. Survival after OHT was analyzed using Kaplan-Meier analysis and compared to patients who received OHT without Impella 5.5. Cumulative incidence rates was calculated using Competing risk regression. Results: 140 patients were identified, median age 59.4 years (50.4-66.5), majority Caucasian (54%) and Black (36%). 89 (63.6%) were either bridged to advanced therapies or recovered. 52 (37.1%) underwent OHT, 21 (15%) received an HM3 LVAD, and 51 (36.4%) died post-implantation. 3 (2.1%) died post-transplant. Post-LVAD, 6 (4.3%) died, 3 (2.1%) underwent OHT, and 12 (8.6%) were alive with LVAD. 10 (7.1%) survived after Impella 5.5 removal, 2 (1.4%) went to hospice, and 1 (0.7%) was transferred to another hospital. 3 (2.1%) are currently hospitalized. Fig1a shows outcomes. Fig1b indicates death within 90 days of Impella implantation. 3-year survival of patients bridged with Impella to OHT (N=55) was 94%, comparable (p=0.27) to patients receiving OHT without Impella (N=215)(Fig 1c). Conclusion: Mortality for cardiogenic shock patients remains high. Using Impella 5.5 with a cardiac replacement strategy can salvage some patients. Long-term outcomes for patients bridged to heart transplant with Impella 5.5 are similar to those without the device. Further studies on predictors of early adverse outcomes post-implant can help mitigate risks for advanced heart failure patients in cardiogenic shock.

Abstract 4121812: Longitudinal Trajectory-Based Classification of Heart Failure with preserved Ejection Fraction: A Machine Learning Approach

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heterogeneous pathophysiology and dynamic changes in cardiac structure and function. Current research predominantly focuses on left ventricular ejection fraction (LVEF) or left ventricular structures with predefined categories. This study hypothesized that applying unsupervised methodologies to longitudinal echocardiography will reveal distinct trajectory patterns in cardiac structure and function related to clinical outcomes in HFpEF patients. Methods: This retrospective cohort study, conducted at UC Davis Medical Center (2014 to 2022), consisted of adult patients with HFpEF. The inclusion criteria included ICD HF codes, a left ventricular ejection fraction (LVEF) ≥50%, and a Brain natriuretic peptide (BNP) ≥100 pg/ml or N-terminal-pro BNP (NT-proBNP) ≥225 pg/ml. Longitudinal data were analyzed using unsupervised machine learning, including UMAP for dimensionality reduction and Gaussian Mixture Models for clustering. Primary and secondary outcomes included all-cause mortality and changes in BNP levels, respectively. Results: The study included 1,626 patients. The cohort had a median age of 69 years, was 57.5% female, and 51.8% white. Three distinct echocardiographic trajectory patterns emerged (p<.05) among the HFpEF cohort. Trajectory #1 (n=568) exhibited a high-stable pattern with the highest mortality rates, Trajectory #2 (n=512) showed a high-decreasing pattern with high mortality rates, and Trajectory #3 (n=546) had a low-increasing pattern with the lowest mortality rates. Trajectories varied significantly in baseline characteristics and longitudinal echocardiographic changes, with Trajectory #3 having a lower baseline left ventricular mass index (p<.001) and a higher mean arterial pressure ( p =.001) compared to the other trajectories. Kaplan-Meier survival analysis indicated significant differences in survival among the trajectories ( p =.004). Conclusion: The study utilized unsupervised analysis of longitudinal echocardiographic data to identify three distinct HFpEF trajectories, each associated with unique clinical features and outcomes. These findings underscore the heterogeneity of HFpEF and highlight the potential trajectory-based patient stratification to improve targeted intervention strategies. Future validation in larger, multicenter cohorts is warranted to enhance HFpEF management and patient prognosis.

Abstract 4144521: Racial disparities in heart transplantation: long term graft survival and non-mortality outcomes

Background: There is conflicting evidence on whether racial disparities still exist in heart transplant (HT) outcomes, with prior studies focusing primarily on differences in short-term mortality. We examined disparities in HT survival over a longer follow-up duration alongside a broader range of post-HT outcomes. Methods: Using the United Network for Organ Sharing (UNOS) database, we evaluated adult HT recipients between 2017 and 2022 and classified each according to race as either Black, non-Hispanic White and Other. The primary outcome was graft survival and secondary outcomes included rejection, renal dysfunction, and post-transplant diabetes. Chi-squared tests were used to compare baseline clinical factors and selected outcomes by racial group. Kaplan-Meier and Cox proportional hazards analyses were performed to compare risks of the primary outcome by race. Results: Among 15,873 recipients (63% non-Hispanic White, 23% Black, 14% Other), Black recipients were more often female, less often college educated, and more often had public (vs. private) insurance. Blacks had higher use of durable ventricular assist devices (VAD) and intra-aortic balloon pump (IABP) at the time of HT. Graft survival at one year did not differ by race (91.8% for Blacks vs. 91.1% for non-Blacks), but at three years was significantly lower for Blacks (83.4%) than non-Blacks (85.7%). Blacks had higher risk of graft failure after adjustment for baseline socioeconomic status (SES) and clinical variables (HR 1.28, CI 1.17 - 1.41). Blacks also had significantly higher prevalences of acute rejection (12.4% vs. 10.2%), diabetes (10.8% vs. 7.1%), and progression of renal dysfunction at 3-years post HT (40.9% vs. 37.1%; p < 0.05 for all). Conclusions: Racial disparities in graft survival after HT remain in the contemporary era but are only evident after longer-term follow-up. These survival disparities could be mediated by concurrent disparities in shorter term outcomes such as development of acute rejection, chronic kidney disease, and new onset diabetes.

Abstract 4134637: Impact of Glucagon-Like Peptide-1 Agonists on Cardiovascular Outcomes in Chronic Kidney Disease Stage 5: A Propensity Score-Matched Analysis

Background: Patients with chronic kidney disease stage 5 (CKD-5) face heightened risks of cardiovascular (CV) complications and mortality. Glucagon-like peptide-1 agonists (GLP-1a), primarily used in type 2 diabetes, are being investigated for potential CV benefits in this population. This study aims to evaluate the impact of GLP-1a treatment on CV outcomes and survival among CKD-5 patients. Methods: This retrospective cohort study utilized data of adult patients diagnosed with CKD-5 between January 2014 and August 2023 from the TriNetX global research network. A propensity score matching analysis of those treated with GLP-1a for at least six months versus those never exposed to GLP-1a therapy was conducted. Results: Our analysis showed significantly reduced odds for the composite primary outcome of acute myocardial infarction (AMI), stroke, and mortality (OR = 0.66, 95% CI: 0.57-0.78, p<0.001), and other CV outcomes such as cardiac arrest, hypertensive crisis, and hypertensive urgency, among the GLP-1a cohort compared with the non-GLP-1a cohort. Kaplan-Meier survival analysis revealed a significantly higher five-year incidence-free probability for the composite primary outcome (63.5% vs. 50.5%, p<0.001) and for other CV outcomes such as hypertensive events, AMI, cardiac arrest, and hemorrhagic stroke for the GLP-1a cohort. Conclusion: The study suggests that GLP-1a therapy in CKD 5 patients may confer certain CV benefits. Further investigations are warranted to elucidate the underlying mechanisms and confirm the therapeutic efficacy of GLP-1a in this patient population.

Comparison of iRoot BP Plus and mineral trioxide aggregate for pulpotomy in primary molars under general anesthesia: a 3-year retrospective study

Background Pulpotomy is a widely recommended treatment for deep caries and reversible pulpitis in primary teeth. However, there is a significant lack of large-scale clinical studies evaluating the long-term efficacy of pulpotomy in primary molars, especially in studies with follow-up periods extending beyond a two years. Aim This study aimed to evaluate the long-term efficacy of mineral trioxide aggregate (MTA) and iRoot BP Plus for pulpotomy in primary molars performed under general anesthesia and to investigate factors influencing the success rate. Methods In this retrospective study, a total of 942 primary molars from 422 children who met the inclusion criteria underwent pulpotomy. Propensity score matching method (PSM) was used to match the MTA and iRoot BP Plus groups in a 1:1 ratio based on covariates. Efficacy was assessed using the Zurn & Seale criteria. Kaplan-Meier survival analysis and Cox proportional hazards model were performed to analyze the outcomes. Results PSM resulted in 266 pairs of matched teeth from 532 teeth of 291 children (mean age: 4.64 ± 1.07 years, ranging from 2 to 8 years). Long-term clinical and radiographic evaluations revealed higher success rates for iRoot BP Plus (24-month: 99.54%/97.25%; 36-month: 97.22%/95.83%) compared to MTA (24-month: 94.76%/95.29%; 36-month: 92.50%/91.25%). Survival analysis indicated a statistically significant difference between two groups (P = 0.0042). Age, gender, tooth position, and decayed tooth surface showed no significant impact on pulpotomy success, whereas the choice of pulp capping materials significantly influenced the outcome (HR [95% CI]=0.3745[0.1857-0.7552], P = 0.006). Conclusion Clinical and radiographic evaluations support the use of iRoot BP Plus for pulpotomy in primary molars.

ECG-based machine learning model for AF identification in patients with first ischemic stroke.

The recurrence rate of strokes associated with atrial fibrillation (AF) can be substantially reduced through the administration of oral anticoagulants. However, previous studies have not demonstrated a clear benefit from the universal application of oral anticoagulants in patients with embolic stroke of undetermined source. Timely detection of AF remains a challenge in patients with stroke. This study aims to develop a convolutional neural network (CNN) model to accurately identify patients with AF using a 12-lead sinus-rhythm electrocardiogram (ECG) recorded around the time of the first ischemic stroke. Additionally, this study also evaluates the model's ability to predict future occurrence of AF. A CNN model was trained with ECG data from patients at Taipei Veterans General Hospital. External validation was performed on ischemic stroke patients from National Taiwan University Hospital. The model's performance was assessed for detecting AF at the stroke event and predicting future AF occurrences. The model demonstrated an area under curve (AUC) of 0.91 for internal validation and 0.69 for external validation in identifying AF at the stroke event, with sensitivity and negative predictive value both achieving 97%. Kaplan-Meier survival analysis of patients without a prior diagnosis of AF revealed a significant increase in future AF incidence among the high-risk group identified by the model (adjusted hazard ratio: 4.06; 95% confidence interval: 2.74-6.00). The CNN model effectively identifies AF in stroke patients using 12-lead ECGs and predicts future AF events, facilitating early anticoagulation therapy and potentially reducing recurrent stroke risk. Further prospective studies are warranted to confirm these findings.

Abstract 4137895: Serum High-density Lipoprotein-Associated Paraoxonase-1 Levels Predict Recurrent Cardiovascular Events after Stent Implantation in Patients with Stable Angina Pectoris

Background: Poor clinical outcomes for patients undergoing hemodialysis (HD) after drug-eluting stent (DES) implantation have been reported. High-density lipoprotein (HDL) cholesterol is well-established as a negative risk factor for coronary artery disease, and its anti-oxidant property has been attributed mainly to the HDL-bound enzyme paraoxonase-1 (PON-1). Myeloperoxidase (MPO), a pro-oxidant enzyme released from activated neutrophils, has been shown to alter the atheroprotective function of HDL to a dysfunctional form. The aim of this study was to investigate the relationship between plasma MPO and serum PON-1 levels after implantation of DES in patients with stable angina pectoris (SAP) with and without HD. Methods: Serum PON-1 concentrations and PON-arylesterase activity were measured in 183 patients with SAP after DES implantation (HD group, n=37; non-HD group, n=146) with a sandwich ELISA method. Cardiovascular events were defined as sudden cardiac death, fatal or non-fatal myocardial infarction, cerebral infarction and other non-fatal events including unstable angina pectoris or coronary revascularization. Results: Serum PON-1 concentrations and PON-arylesterase activity were significantly lower in the HD group than in the non-HD group (PON-1 concentrations, P<0.0001; PON-arylesterase activity, P<0.0001). In addition, plasma MPO in patients undergoing HD were significantly higher than in patients not undergoing HD (P<0.0001). Moreover, plasma MPO showed a significant inverse correlation with serum PON-1 concentrations and PON-arylesterase activity (concentration: R= -0.24, P=0.0013; arylesterase-activity: R=-0.24, P=0.0014). Cardiovascular event rates were significantly higher in the HD group than in the non-HD group (67.6% vs. 43.8%, P<0.01). Kaplan-Meier survival analysis showed that the low-PON-1 group (<58.0 mg/mL, median) had a significantly worse outcome than the high-PON-1 group ( P =0.013). Multivariate analysis showed that a low serum PON-1 concentration was the only independent predictor of cardiovascular events (odds ratio, 1.93; 95% confidence interval, 1.10 to 3.40, P =0.024). Conclusions: These findings demonstrate that plasma MPO have a significant inverse correlation with PON-1 in patients undergoing HD and suggest that an imbalance between pro-oxidants and anti-oxidants may contribute to the progression and destabilization of human coronary atherosclerotic lesions in patients with SAP who undergo HD following DES implantation.

OXPHOS mediators in acute myeloid leukemia patients: Prognostic biomarkers and therapeutic targets for personalized medicine.

Despite significant advances in comprehending its tumorigenic role, the prognostic and therapeutic potential of targeting oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) remain obscure. The prognostic value of ~ 200 mitochondrial/OXPHOS genes as candidate biomarkers was examined in AML patients over ~ 10 years follow-up using Kaplan-Meier and Cox regression analyses. Furthermore, the transcript levels of the assessed markers were inspected in healthy bone marrow tissues and the dependencies of AML cells on the assessed genes were examined. Elevated levels of NADH:ubiquinone oxidoreductase subunit A6 (NDUFA6), succinate dehydrogenase complex flavoprotein subunit A (SDHA), solute carrier family 25 member 12 (SLC25A12), electron transfer flavoprotein subunit beta (ETFB), carnitine palmitoyltransferase 1A (CPT1A) and glutathione peroxidase 4 (GPX4) were associated with poor overall survival of AML patients. SLC25A12, ETFB and CPT1A were overexpressed in AML compared to healthy tissues. Cytochrome B5 type A (CYB5A)high, SLC25A12high and GPX4high AML patients displayed higher levels of circulating and engrafted blasts compared to low-expressing cohorts. NPM1 and SRSF2 mutations were frequent in SDHAlow and CPT1Alow AML patients respectively. FLT3-ITD, NPM1 and IDH1 mutations were prevalent in CPT1Ahigh AML patients. FLT3-ITD AMLs were more dependent on OXPHOS. This study identifies NDUFA6 and SDHA as novel companion prognostic biomarkers which might present a rational strategy for personalized therapy of AML patients.

Abstract 4136677: High Visceral-to-Subcutaneous Fat Ratio is Correlated with Increased Cardiovascular Events in Patients with Low Waist Circumference Suspected of Coronary Artery Disease

Introduction: Waist circumference (WC) has been recognized as an appropriate index of obesity and is closely associated with the amount of abdominal fat. Although abdominal fat distribution (AFD), which is represented by the ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) area (V/S ratio), is possibly related to an increased risk of cardiovascular disease (CVD), few studies have explored the relationship between AFD and CVD outcomes. This study aimed to assess the influence of AFD based on the V/S ratio and physique categorized by WC on long-term clinical results in patients with suspected coronary artery disease (CAD). Methods: We evaluated 931 consecutive patients (mean age, 67 years; 42.4% women) with suspected CAD who underwent computed tomography (CT) angiography. The patients also underwent plain abdominal CT to assess and measure VAT and SAT areas; V/S ratio was calculated to assess AFD. The patients were divided into four groups based on the median V/S ratio (0.624) and reference values of WC for metabolic syndrome in Japan (85 cm for men, 90 cm for women). We assessed the relationship between the V/S ratio and long-term clinical outcomes in each WC group. The main outcome was major adverse cardiac events (MACEs, including cardiac death, any coronary revascularization, acute coronary syndrome, and emergency hospitalization due to cardiac cause). Results: Over a median follow-up of 1869 days, although the incidence of any cardiovascular event was not related to the V/S ratio among patients with high WC, a higher incidence of MACE and cardiac death was noted among patients with low WC in the high V/S ratio group than in the low V/S ratio group. Furthermore, Kaplan–Meier analysis revealed a significantly lower MACE-free survival rate among patients with low WC in the high V/S ratio group than in the low V/S ratio group, despite of no differences being noted among high WC patients in both the V/S ratio groups (Figure). Conclusion: Only in patients with low WC, a high V/S ratio was linked to increased risks of MACE. Thus, high V/S ratio may be an essential risk factor for CVD, specifically in patients with low WC. However, AFD did not influence CVD prognosis in patients with high WC.

Abstract 4138253: Reintervention Burden of Single and Biventricular Palliation of Pulmonary Atresia with Intact Ventricular Septum

Introduction: Pulmonary atresia with intact ventricular septum (PAIVS) patients may proceed down a single (SV) or biventricular (BV) pathway. We evaluated the total interventional burden of both pathways including after either end-state was reached. Hypothesis: SV patients will have more interventions in comparison to BV patients. Goals: Assess the nature of interventions in PAIVS. Methods: Retrospective review of PAIVS patients from 1995-2020 who achieved SV (Fontan completion) or BV (normal saturations with no significant shunts) end-state. Demographic, procedural, and follow-up details were collected. Descriptive statistics were used and Kaplan-Meier analysis of freedom from reintervention was performed. Results: Of 79 patients who reached end-state, 40 (51%) were SV and 39 (49%) were BV. Total median in-hospital time was 48 [31-78] days and 18 [12-35] days for SV and BV (p<0.01). The ratio of in-hospital days to total follow-up was a median of 1.7% [0.9-2.7] for SV and 0.4% [0.3-0.8] for BV (p<0.01). SV and BV cohorts had an overall median of 4 [3-5] and 3 [2-4] interventions, respectively (p<0.01). Interventions and their relationship to end-state are shown in Table 1 . The SV and BV groups achieved end-state at a median of 2.9 [2.3-3.6] and 2.1 [0.2-8.8] years (p=0.01) ( Figure 1A ). Median follow up in years after achieving end-state was similar between groups {7 [2.7-15.8] in SV and 7.4 [4.2-13.4] for BV (p=0.11)}. After end-state, there was no difference in the proportion of patients requiring reinterventions (17 (43%) SV and 12 (31%) BV, p>0.05). Freedom from reintervention at 15-years was 44.1% in the SV group and 64.3% in the BV group (p=0.11) ( Figure 1B) with one late SV death. Conclusions: PAIVS therapy requires multiple interventions to achieve both SV and BV repair. While SV patients undergo more interventions and spend more days in the hospital, reinterventions and 15-year freedom from reintervention were comparable between groups with equivalent follow up.

Abstract 4134273: Low 5-hydroxytryptamine levels are associated with adverse outcomes in patients with heart failure with preserved ejection fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome and its pathophysiology is not fully understood. A monoamine, 5-hydroxytryptamine (5-HT), is involved in diverse biological functions and suggested to play a role in cardiovascular diseases. However, the clinical relevance of 5-HT in HFpEF remains unclear. Aims: This study aimed to elucidate the clinical significance and prognostic value of 5- HT in patients with HFpEF. Methods: We conducted a prospective study involving 240 consecutive hospitalized patients with HFpEF (mean age 72 years, 52% male). We measured circulating blood 5-HT levels using the enzyme-linked immunosorbent assay method. Clinical and outcome data were collected. Results: Correlation analysis revealed that 5-HT levels were negatively correlated with blood B-type natriuretic peptide concentration and tricuspid regurgitation pressure gradient. When patients were stratified into two groups based on the median 5-HT levels (90.5 ng/mL), Kaplan-Meier analysis showed that HFpEF patients with low blood 5-HT levels had lower event-free survival rates from the composite event of cardiac death and worsening heart failure over a median follow-up period of 725 days (Figure). In a multivariable Cox proportional hazard model adjusting for confounding variables, low levels of 5-HT were independently associated with increased risks of the composite of cardiac events (hazard ratio, 3.25; P < 0.01). Conclusion: Low 5-HT levels are associated with adverse outcomes in patients with HFpEF and 5-HT may serve as a useful biomarker for predicting prognosis in such patients.

CNSC-35. TEMOZOLOMIDE POTENTIALLY POSTPONES THE DEVELOPMENT OF SUBSEQUENT METASTASES IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PATIENTS

Abstract OBJECTIVE Surgical intervention is thought to increase the likelihood of subsequent dissemination in diffuse intrinsic pontine glioma (DIPG) patients. However, there is no study evaluating the factors influencing the timing of metastasis development. Hence, the present analysis was conducted to shed light on factors associated with subsequent dissemination timing. METHODS This analysis included 28 pediatric (age≤12) DIPG cases with metastasis treated at Sanjiu Brain Hospital between June 1, 2017 and June 30, 2023. The clinical data were retrospectively collected following the initial diagnosis. The diagnosis was established by typical imaging features of DIPG. The same three radiologists analyzed the imaging data independently. Time to subsequent metastasis was estimated using Kaplan–Meier analysis, and a log-rank test evaluated the differences between groups. RESULTS Of 28 patients, 13 (46.4%) were males and 15 were females. 23 (82.1%) underwent surgical intervention, while 5 (17.9%) did not receive surgery. The patients’ median age was 7 years (2-12 yrs.). The Kaplan-Meier method showed that the median time to metastasis was 5.8 months (95%CI 4.2-9.1). The log-rank test demonstrated that adjuvant temozolomide was the only variable that could significantly delay metastasis in the pediatric DIPG population (P=0.03). The median time to metastasis from the day of initial diagnosis for those who received adjuvant temozolomide was 6.8 months (95%CI 5-10.7) vs. 3 months for those who did not receive adjuvant temozolomide (95%CI 2.3-NA). Sex, age, surgical intervention, and concurrent irradiation and temozolomide were not associated with metastasis timing. CONCLUSION Adjuvant temozolomide administration might benefit DIPG patients by delaying metastasis, especially in those who are at higher risk for subsequent metastasis, such as those who underwent surgical intervention. However, prospective studies are warranted to confirm these results.

BIOM-11. PROGNOSTIC VALUE OF H3K27ME3 AND EZH2 IN ASTROCYTOMA, IDH-MUTANT

Abstract BACKGROUND H3K27 trimethylation (H3K27me3), catalyzed by EZH2, regulates gene expression through epigenetic mechanisms. H3K27me3 is used as a surrogate marker in pathology for diffuse midline glioma, ependymoma. However, the clinical value of H3K27me3 and EZH2 in astrocytoma, IDH-mutant has not been reported. The aim of this study was to evaluate the clinical significance of H3K27me3 and EZH2 in astrocytoma, IDH-mutant. METHODS A total of 30 patients with astrocytoma, IDH-mutant treated at our institute were included. The patients were divided into 2 groups according to the expression of immunohistochemistry (IHC) for H3K27me3. The following factors were analyzed; age, WHO grade, IHC for EZH2, CDKN2A status, ki67-index and extent of resection. The CDKN2A status was diagnosed by IHC for MTAP and was confirmed by NGS-based CGP test in some cases. Kaplan–Meier analysis and Cox regression analysis were performed to analyze overall survival (OS) and progression-free survival (PFS). RESULTS According to WHO classification 2021, astrocytomas were classified as follows: WHO grade2: 20 cases, grade 3: 2 cases, grade 4: 8 cases. Seventeen patients were identified as H3K27me3 positive, while fourteen patients were classified as H3K27me3 negative. The proportion of WHO grade 3 or 4 and ki-67 index were significantly higher in the H3K27me3 positive group (p=0.0011, 0.0036, respectively). OS and PFS were significantly longer in H3K27me3 positive group (p=0.0379, 0.0025). Furthermore, in the analysis of WHO grade 2/3, double-positive expression of H3K27me3 and EZH2 showed significantly shorter PFS and OS than the other group (p=0.0114 and 0.0068, respectively). In Cox regression analysis, H3K27me3 showed the highest likelihood ratio for OS (p=0.01061). CONCLUSIONS In Astrocytoma, IDH-mutant, the H3K27me3 positive group showed poor prognosis than H3K27me3 negative group. In addition, patients with double-positive expression of H3K27me3 and EZH2 demonstrated more unfavorable prognosis. H3K27me3 and EZH2 could be prognostic markers for astrocytoma, IDH-mutant.

The impact of new onset diabetes on cardiovascular risks in orthotopic liver transplant recipients: findings from the COLT study.

Orthotopic liver transplantation (OLT) has greatly improved short-term survival for end-stage liver disease. However, cardiovascular events (CVE) still pose a significant threat to long-term post-transplant health. Aim of this study is to assess the occurrence of long-term cardiovascular events and whether it relates to new-onset diabetes after liver transplantation (NODALT). We conducted a multicentric retrospective analysis of adult OLT recipients with regular follow-up visits spanning from January 1995 to December 2020. Data collection included anamnestic, clinical, anthropometric, and laboratory data from two centers. NODALT was diagnosed following ADA guidelines. The primary outcome was incident CVE (a composite of fatal and non-fatal stroke and myocardial infarction). CVE occurrence was analyzed in relation to NODALT diagnosis, along with clinical characteristics associated with its development. Ninety-three eligible Caucasian patients, with a median age of 57.0 years (IQR: 49.0-62.0, 69.9% male), were enrolled. Over the median follow-up period of 100.5 months, 29 patients (31.2%) developed NODALT, and 14 patients (15.1%) developed any CVE, with 9 being in the NODALT group. A significant association between NODALT and cardiovascular complications was confirmed by both generalized estimating equation (OR 5.31; 95% CI 1.59-17.72, p = 0.006) and Kaplan-Meier analysis (log-rank = 0.046). Metabolic syndrome and impaired fasting glucose were identified as baseline risk factors for the incident NODALT (OR 5.75; 95% CI 1.44-22.92, p = 0.013 and OR 7.29; 95% CI 1.46-36.41, p = 0.015, respectively). Post-OLT cardiovascular events are less frequent than previously reported but are notably linked to NODALT, highlighting the interplay between metabolic syndrome and impaired fasting glucose.

SURG-30. SURVIVAL AND OUTCOMES ANALYSIS OF PATIENTS TREATED WITH LASER INTERSTITIAL THERMAL THERAPY FOR LARGE-VOLUME GLIOBLASTOMA

Abstract INTRODUCTION Laser interstitial thermal therapy (LITT) has shown increased patient survival and outcomes in glioblastoma multiforme (GBM). However, its safety and survival in large-volume GBM tumors has been poorly elucidated. OBJECTIVE To evaluate the use of LITT in large-volume GBMs. METHODS A retrospective cohort of adult patients with grade IV IDH-wt GBM measuring ≥ 10 cm3 who were treated with LITT was compared to a control group with volumes <10 cm3. A Kaplan-Meier analysis, followed by a Cox-proportional hazards model with overall survival (OS) as the timeline and death as the event, were performed with volume group, mFI-11 score, 30-day readmission, age at surgery (AOS), recurrent vs. primary lesions, and EOA as covariates. RESULTS The cohort consisted of 46 large-volume patients (mean: 22.0 cm3, STD: 10.8) with a mean age of 63 years and 57% male predominance, compared to 41 controls (mean: 4.4 cm3, STD: 2.8). Lesions were primary in 78% and 60%, and recurrent in 22% and 40%, of the large and small-volume groups, respectively. Kaplan-Meier analysis showed no significant survival difference between the large (OS=245 days) and small-volume (OS=358 days) groups (p=0.261). No covariate showed significant risk of hazard in the large compared to small-volume cohorts (p>0.05). Across the entire cohort, mFI-11 score, recurrent lesions, and EOA showed no significance as individual predictors of death (p>0.25). AOS (p<0.005) and 30-day readmission (p<0.005) showed significantly increased hazard for the entire cohort. Importantly, volume group did not significantly increase hazard (1.16 [0.68, 1.98], p=0.60). CONCLUSION This is the first study evaluating the safety and efficacy of LITT in large-volume GBMs, specifically, with a larger cohort than any existing analysis sub-grouped by volume. We show LITT can be safe and efficacious, without significantly increased mortality compared to in small-volume GBMs.

Clinical values of nuclear morphometric analysis in fibroepithelial lesions.

Fibroepithelial lesions (FELs) of the breast encompass a broad spectrum of lesions, ranging from commonly encountered fibroadenomas (FAs) to rare phyllodes tumors (PTs). Accurately diagnosing and grading these lesions is crucial for making management decisions, but it can be challenging due to their overlapping features and the subjective nature of histological assessment. Here, we evaluated the role of digital nuclear morphometric analysis in FEL diagnosis and prognosis. A digital nuclear morphometric analysis was conducted on 241 PTs and 59 FAs. Immunohistochemical staining for cytokeratin and Leukocyte common antigen (LCA) was used to exclude non-stromal components, and nuclear area, perimeters, calipers, circularity, and eccentricity in the stromal cells were quantified with QuPath software. The correlations of these features with FEL diagnosis and prognosis was assessed. All nuclear features, including area, perimeter, circularity, maximum caliper, minimum caliper and eccentricity, showed significant differences between FAs and benign PTs (p ≤ 0.002). Only nuclear area, perimeter, minimum caliper and eccentricity correlated significantly with PT grading (p ≤ 0.022). For differentiation of FAs from benign PTs, the model integrating all differential nuclear features demonstrated a specificity of 90% and sensitivity of 70%. For PT grading, the nuclear morphometric score showed a specificity of 78% and sensitivity of 96% for distinguishing benign/borderline from malignant PTs. In addition, a relationship of nuclear circularity was found with PT recurrence. The Kaplan-meier analysis, using the best cutoff determined by ROC curve, showed shorter event free survival in benign PTs with high circularity (chi-square = 4.650, p = 0.031). Our data suggested the digital nuclear morphometric analysis could have potentials to objectively differentiate different FELs and predict PT outcome. These findings could provide the evidence-based data to support the development of deep-learning based algorithm on nuclear morphometrics in FEL diagnosis.