Multivariate Cox Proportional Hazards Model Research Articles

Life's Essential 8 and Poor Brain Health Outcomes in Middle-Aged Adults.

Mounting evidence points to a strong connection between cardiovascular risk during middle age and brain health later in life. The American Heart Association's Life's Essential 8 (LE8) constitutes a research and public health construct capturing key determinants of cardiovascular health. However, the overall effect of the LE8 on global, clinically relevant metrics of brain health is still unknown. We tested the hypothesis that worse LE8 profiles are associated with higher composite risk of the most important clinical endpoints related to poor brain health. We conducted a two-stage (discovery and replication) prospective study using data from the UK Biobank (UKB) and All of Us (AoU), 2 large population studies in the United Kingdom and the United States, respectively. The primary exposure was the LE8 score, a validated tool that captures 8 modifiable cardiovascular risk factors (blood pressure, glucose, cholesterol, body mass index, smoking, physical activity, diet, and sleep duration), organized in 3 categories (optimal, intermediate, and poor). The primary outcome was a composite of stroke, dementia, or late-life depression. We evaluated associations using multivariable Cox proportional hazard models. The discovery stage included 316,127 UKB participants (mean age 56, 52% female). Over a mean (SD) follow-up time of 4.9 (0.4) years, the unadjusted risk of the composite outcome was 0.7% (95% CI 0.61-0.74), 1.2% (95% CI 1.11-1.22), and 1.8% (95% CI 1.70-1.91) in participants with optimal, intermediate, and poor cardiovascular health, respectively (p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health hazard ratio [HR], 1.37; 95% CI 1.24-1.52, and poor vs optimal cardiovascular health HR, 2.11; 95% CI 1.88-2.36, p trend <0.001). The replication stage included 68,407 AoU participants (mean age 56, 60% female). Over a mean (SD) follow-up time of 2.9 (1.41) years, the unadjusted risk of the composite outcome was 2.8% (95% CI 2.49-3.05), 6% (95% CI 5.76-6.22), and 9.7% (95% CI 9.24-10.24) in participants with optimal, intermediate, and poor cardiovascular health, respectively (p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health, HR 1.35; 95% CI 1.21-1.51, and poor vs optimal cardiovascular health, HR 1.94; 95% CI 1.72-2.18; p trend <0.001). Among middle-aged adults enrolled in 2 large population studies, poor cardiovascular health profiles were associated with two-fold higher risk of developing a composite outcome that captures the most important diseases related to poor brain health. Because the evaluated risk factors are all modifiable, our findings highlight the potential brain health benefits of using the Life's Essential 8 to guide cardiovascular health optimization.

Health-Related Behaviors and Risk of Common Age-Related Brain Diseases Across Severities of Genetic Risk.

The 21-point Brain Care Score (BCS) is an index that ranks behaviors and clinical measurements with the aim of encouraging lifestyle adjustments to lower the incidence of age-related brain disease, including stroke, late-life depression (LLD), and dementia. A higher BCS at baseline is associated with a lower risk of these outcomes. We aimed to investigate whether the associations between BCS and stroke, LLD, and dementia risks are independent of genetic predisposition for these conditions and quantify the effect of healthy lifestyle across genetic risk distributions for these outcomes. Using the UK Biobank (UKB) prospective cohort study, we computed baseline BCSs and polygenic scores to estimate genetic predisposition for stroke and LLD and APOE ε allele status to stratify dementia risk. As for outcomes again in UKB, we measured incidence of stroke, LLD, and dementia. We used multivariate Cox proportional hazard models to assess associations between BCS, genetic predisposition, and these outcomes. We also conducted stratified and interaction analyses to estimate the incidence of these outcomes across quartiles of genetic risk and BCS. We included 368,340 UKB participants (median age 58 years (interquartile range 51-63 years), 46.3% male). Independent of genetic risk, a 5-point increase in BCS corresponded to lowered hazards of stroke (hazard ratio [HR] 0.70, 95% CI 0.68-0.73), LLD (HR 0.65, 95% CI 0.63-0.67), and dementia (HR 0.82, 95% CI 0.78-0.85). Incidences of all 3 outcomes were higher among participants with high genetic risk of these outcomes. However, these increased risks were offset for individuals with a higher BCS (incidence rates per 1,000 person-years were 2.76 vs 1.19 for stroke, 7.34 vs 4.46 for LLD, and 3.64 vs 2.05 for dementia, when comparing low and high BCS). Across different genetic predispositions for stroke, LLD, and dementia, healthier lifestyle behaviors are protective for brain health, demonstrating the nondeterminism of genetic risk. Furthermore, differences in BCS behave as aggregate risk estimators of all 3 outcomes. Further work is needed to prospectively investigate the utility and performance of the BCS as a targeted intervention in populations at elevated genetic risk of age-related brain disease.

Impact of preoperative clinical and imaging factors on post-pericardiectomy outcomes in chronic constrictive pericarditis patients.

The present study was designed to identify the preoperative clinical and imaging findings influencing adverse clinical outcomes in patients with chronic constrictive pericarditis after pericardiectomy. Patients with constrictive pericarditis who underwent pericardiectomy between January 2009 and September 2023 were retrospectively analyzed. Preoperative evaluations included assessments of clinical symptoms, comorbidities, laboratory tests, cardiac computed tomography (CT), and transthoracic echocardiography. The volume of pericardial calcifications was quantified on calcium scoring CT. Adverse clinical events were defined as cardiovascular death or hospitalization due to cardiac causes, and all-cause mortality was assessed. Univariable and multivariable Cox proportional hazard model analysis were performed to find factors associated with adverse clinical events. Among the 91 patients with available preoperative CT scans, 26 (28.6%) experienced adverse clinical events after pericardiectomy, with 19 (20.9%) experiencing cardiovascular deaths. On multivariable Cox analysis, larger pericardial calcium volume hazard ratio [HR], 1.004 (95% confidence interval [CI], 1.001-1.006) per 1cm3 increase; p = 0.005), higher E/E' ratio (HR, 1.059, 95% CI, 1.015-1.105, p = 0.008), and lower albumin level (HR, 0.476, 95% CI, 0.229-0.986, p = 0.046) were significant factors associated with the adverse clinical events after pericardiectomy. The amount of pericardial calcification could be associated with the efficacy of pericardiectomy and potentially have implications for postoperative outcomes. Additionally, a high E/E ratio on echocardiography is indicative of unfavorable postoperative prognosis.

Is a higher body mass index associated with longer duration of survival with disability in frail than in non-frail older adults?

This study investigated the hitherto unclear association of body mass index (BMI) with age at overall, disability, and disability-free survival in older adults with and without frailty. This prospective cohort study enroled 10232 Japanese adults aged ≥65 years, who underwent follow-up for adverse events, from the Kyoto-Kameoka Study conducted from 2011-2016. BMI, calculated based on self-reported height and body weight, was classified into five categories: <18.5, 18.5-21.4, 21.5-24.9, 25.0-27.4, and ≥27.5 kg/m2. Frailty was assessed using the validated Kihon Checklist. The relationships between BMI and disability and mortality were analysed using multivariate Cox proportional hazards models and Laplace regression. During the 5.3-year median follow-up period (45472 person-years), 2348 (22.9%) incidences of disabilities occurred. After adjusting for confounders, including medical history and lifestyle, individuals in the lowest and highest BMI categories had a higher hazard ratio (HR) of disability [<18.5 kg/m2: HR: 1.31, confidence interval (CI): 1.16-1.49; ≥27.5 kg/m2: HR: 1.27, 95% CI: 1.08-1.49, p for non-linearity <0.001] compared with that of those with BMI = 21.5-24.9 kg/m2. In the 50th percentile differences in age at overall and disability-free survival, participants with BMI < 18.5 kg/m2 were more likely to die before disability incidence [survival with disability (overall survival - disability-free survival): -10.2 months]; those with BMI ≥ 27.5 kg/m2 had longer survival with disability (12.5 months). These relationships were more marked in the frailty-stratified model, where in the BMI ≥ 27.5 kg/m2 group, individuals with frailty survived longer with disability (27.2 months) than did individuals without frailty (6.2 months). Higher BMI is associated with a longer duration of survival with disability among older adults, especially in those with frailty. Therefore, reversing frailty should be prioritised because individuals with frailty have a shorter probability of disability-free survival than do individuals without frailty, regardless of BMI.

Relationship of serum calcium concentration with chronic kidney disease and mortality in type 2 diabetes mellitus patients: evidence from the NHANES 1999-2018.

This study aims to explore the relationship of serum calcium (Ca) concentration with diabetic kidney disease (DKD) and all-cause mortality among type 2 diabetes mellitus (T2DM) patients using National Health and Nutrition Examination Surveys (NHANES). Data of T2DM patients aged ≥ 40 years were screened from the NHANES database from 1999 to 2018. The outcomes were the risk of DKD diagnosed by urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 and the risk of all-cause mortality ascertained by linkage to National Death Index (NDI) records through 31 December 2019. The weighted univariate and multivariate logistic regression model and cox proportional hazard model were utilized to explore the relationships of serum Ca concentration with DKD and all-cause mortality, respectively, with odds ratios (ORs), hazard ratios (HRs) and 95% confidence interval. The relationships were further explored stratified by age, gender, body mass index (BMI), the duration of T2DM, and the history of cardiovascular disease (CVD), cancer and DKD. Totally, 6595 T2DM patients were included. Of these patients, 2441 (37.01%) had DKD and 1868 (28.32%) deaths occurred over a mean follow-up of 104.50 (± 1.61) months. In fully adjusted model, we observed high serum Ca concentration was associated with high risk of DKD (OR = 1.45, 95% CI 1.18-1.77) and high all-cause mortality risk (HR = 1.33, 95% CI 1.16-1.52). These relationships remained significant after performing subgroup analyses. The Restricted cubic spline curves shown that linear correlations were observed between serum Ca concentration and DKD as well as all-cause mortality (P < 0.05). Elevated serum Ca concentration may predict the high risk of DKD and poor prognosis in T2DM patients, and future large-scale and well-designed prospective cohort study is needed to explore the association of serum Ca concentration and DKD and prognosis in T2DM patients.

Proportion of Gleason Score ≥8 Prostate Cancer on Biopsy and Tumor Aggressiveness in Matched Cohorts of East Asian and Non-East Asian Men.

Historically, Asia had a lower prostate cancer (PCa) incidence and mortality compared with Western countries, but the gap is narrowing. Paradoxically, Asians have been reported to present with more advanced disease though more favorable outcomes. Despite PCa becoming an emerging health priority in East Asia, our knowledge remains limited. We compared the prevalence of high-grade PCa on biopsy and disease progression after radical prostatectomy (RP) in East Asian men from Asia and non-East Asian men from Western countries. This retrospective cohort study included men who underwent prostate biopsy and RP at academic centers in Shanghai, China, and Toronto, Canada (2014-2019). The expanded RP cohort included East Asian men from Singapore (n=282) and non-East Asians from Paris (n=192). Primary endpoints included the proportion of men with Gleason score (GS) ≥8 on biopsy and metastasis-free survival (MFS) after RP for GS ≥8. Multivariable logistic regression and Cox proportional hazard models were performed. Propensity score matching was used to reduce imbalances between cohorts. PCa was found on biopsy in 2,343 of 4,905 (48%) East Asians and 2,317 of 3,482 (67%) non-East Asians (P<.001). Prostate-specific antigen (PSA) levels at presentation and the proportion of men with GS ≥8 were higher in East Asians than non-East Asians (12.4 vs 6.6 ng/mL and 15.0% vs 8.8%, respectively; both P<.001). On multivariable analysis, there was no difference in the proportion of men with GS ≥8 between matched cohorts with PSA <20 ng/mL (n=3,572; odds ratio, 1.05 [95% CI, 0.77-1.43]; P=.76). No difference in MFS was found after RP between matched cohorts (hazard ratio, 0.97 [95% CI, 0.55-1.70]; P=.92). This contemporary study demonstrates that East Asian men are equally as likely to harbor aggressive PCa on biopsy as non-East Asian men at PSA levels observed in screening programs, with no difference in disease aggressiveness after RP. The assumption that unfavorable PCa at diagnosis is more common but less aggressive in East Asians should be revisited and viewed in the context of the expected increase in the PCa burden worldwide.

Association between sagittal abdominal diameter-to-height ratio and all-cause mortality among adults in the United States: a longitudinal study.

The global health crisis of obesity has prompted a need for better indicators of abdominal obesity than body mass index, with sagittal abdominal diameter emerging as a potential candidate. Nonetheless, the association between sagittal abdominal diameter-to-height ratio (SADHtR) and mortality remains inadequately established. Our objective was to contribute novel evidence to this association. This study encompassed 12,572 participants aged 18-80 years from the National Health and Nutrition Examination Survey 2011-2016. Mortality data were tracked until December 31, 2019. Weighted multivariable Cox proportional hazard models were employed to evaluate the association between SADHtR and all-cause mortality, with subgroup analyses conducted for result robustness. Following a median follow-up period of 69 months, each standard deviation (SD) increase in SADHtR was consistently associated with a higher risk of all-cause mortality across three models, yielding a hazard ratio (HR) and 95% confidence interval (CI) of 1.51(1.29,1.76) in model 3. Additionally, compared to the first tertile of SADHtR, the third tertile exhibited a higher risk for all-cause mortality, with HRs(95%CIs) of 1.58(1.25,2.01) in model 1, 2.01(1.33,3.02) in model 2, and 1.74(1.19,2.57) in model 3. Notably, subgroup analysis revealed persistent positive associations between SADHtR and all-cause mortality among subgroups based on age-at-risk (< 65, ≥ 65 years), sex, diabetes, hypertension, and hyperlipidemia. Elevated SADHtR was consistently associated with a higher risk of all-cause mortality in American adults. Regular SADHtR measurement should be considered to be integrated into clinical practice and healthcare examinations.

Renal tubular damage as an independent risk factor for all-cause and cardiovascular mortality in a community-based population: the Takahata study.

Renal tubular damage plays a crucial role in the development of end-stage kidney disease, a risk factor for cardiovascular events and mortality. However, the relationship between renal tubular damage and all-cause and cardiovascular mortality rates in the general population remains unclear. To address this gap, we conducted a cohort study in the general population using the urinary β2-microglobulin-creatinine ratio (UBCR) as a marker of renal tubular damage. This study included 3427 residents aged ≥ 40years in Takahata, Japan. We examined the association between the UBCR values in single-spot urine samples at enrollment and all-cause and cardiovascular mortality rates within a median follow-up of 9.2years. The participants were divided into two groups based on their UBCR levels (< 300μg/g and ≥ 300μg/g groups). Kaplan-Meier analysis showed a significantly higher incidence of all-cause and cardiovascular mortality rates in the high UBCR group (log-rank P < 0.01). Multivariable Cox proportional hazards model adjusted for age, sex, estimated glomerular filtration rate (eGFR), urine albumin level, smoking, and comorbidities showed a significantly higher hazard ratio of 1.49 (95% confidence interval (CI) 1.10-2.03, P = 0.01) for all-cause mortality and a hazard ratio of 1.73 (95% CI 1.00-2.98, P = 0.048) for cardiovascular mortality in the high-UBCR group. The net reclassification index was significantly improved by adding a high UBCR to the conventional risk factors. UBCR is an independent risk factor for all-cause and cardiovascular mortality in the general population, independent of eGFR and urinary albumin levels.

Recurrence-Free Survival Prediction for Anal Squamous Cell Carcinoma After Chemoradiotherapy using Planning CT-based Radiomics Model.

Approximately 30% of non-metastatic anal squamous cell carcinoma (ASCC) patients will experience recurrence after chemoradiotherapy (CRT), and currently available clinical variables are poor predictors of treatment response. We aimed to develop a model leveraging information extracted from radiation pretreatment planning CT to predict recurrence-free survival (RFS) in ASCC patients after CRT. Radiomics features were extracted from planning CT images of 96 ASCC patients. Following pre-feature selection, the optimal feature set was selected via step-forward feature selection with a multivariate Cox proportional hazard model. The RFS prediction was generated from a radiomics-clinical combined model based on an optimal feature set with five repeats of nested five-fold cross validation. The risk stratification ability of the proposed model was evaluated with Kaplan-Meier analysis. Shape- and texture-based radiomics features significantly predicted RFS. Compared to a clinical-only model, radiomics-clinical combined model achieves better performance in the testing cohort with higher C-index (0.80 vs 0.73) and AUC (0.84 vs 0.78 for 1-year RFS, 0.84 vs 0.79 for 2-year RFS, and 0.85 vs 0.81 for 3-year RFS), leading to distinctive high- and low-risk of recurrence groups (p < 0.001). A treatment planning CT based radiomics and clinical combined model had improved prognostic performance in predicting RFS for ASCC patients treated with CRT as compared to a model using clinical features only. The use of radiomics from planning CT is promising in assisting in personalized management in ASCC. The study outcomes support the role of planning CT-based radiomics as potential imaging biomarker.

HPB O06 - A computer tomography-based radiomics signature predicts overall survival following curative resection of colorectal liver metastasis: A multicentre, retrospective study

Abstract Background Colorectal cancer liver metastasis (CRLM) has a heterogeneous outcome and improved prognostic biomarkers are needed to aid patient-tailored management. Here, we assess the value of Computer Tomography (CT)-guided radiomics in the prognostication of post-resection CRLM using data from two large tertiary referral centres in the UK. Method Patient data was extracted from prospectively maintained databases of patients undergoing CRLM resection at two centres. CRLM and regions of interest from background normal liver were segmented. Radiomics features were extracted from portal venous phase CT images using open-source software. Feature selection techniques were applied. Machine learning models incorporating radiomic or clinical features, and their combination, were developed and assessed for mortality prediction at fixed time points. Cox proportional hazard regression was utilised for risk score generation to classify patients as high or low-risk for overall survival estimation. The models were evaluated on unseen testing data. Results Radiomics features (269) were generated from 959 metastases in 399 patients across the two sites. Models with combined clinical and radiomic features performed similarly to those with radiomic features alone, and often outperformed models with clinical features alone demonstrating good discrimination and risk prediction at 2 and 3 years. The computed radiomic scores allowed us to generate Kaplan–Meier curves which showed CRLM patients in the high-risk group had a lower overall survival vs the low-risk group(p&amp;lt;0.05). This risk-score independently predicted mortality in our multivariate Cox proportional-hazards model. Conclusion We demonstrate a robust combination of CT-based radiomics features can predict CRLM outcomes across two different hospital sites. Our radiomic risk-scores predicts overall survival and can prognosticate patients into high and low risk groups. These findings support the prognostic utility of CT-based radiomics in patients undergoing resection of CRLM and provide rationale for further investigation in a prospective, multi-centre setting.

Abstract 4138278: A Titin Missense Variant Causes Atrial Fibrillation

Background: Rare loss-of-function variants in TTN , the gene encoding the sarcomeric protein titin, have been causally associated with atrial fibrillation (AF). Missense TTN variants ( TTN mv) are generally regarded as benign in relation to dilated cardiomyopathy, but their role in AF is unknown. Hypothesis: TTN mv are associated with clinical outcomes and AF pathogenesis. Aims: We aimed to determine if TTN mv are associated with AF/heart failure (HF) hospitalizations and investigate if a rare missense variant ( TTN -T32756I) caused AF using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs). Methods: Whole exome sequencing was performed in 131 adults at an urban academic healthcare system who identified as non-Hispanic Black (NHB) or Hispanic/Latinx (HL). Multivariable Cox proportional hazard models were used to assess cumulative risk of AF/HF hospitalization. Isogenic TTN -T32756I iPSC-aCM mutants were generated using the CRISPR-Cas9 technique. We used confocal microscopy to assess sarcomeric integrity, MuscleMotion to assess contractility, and optical voltage mapping and patch-clamping to assess the electrophysiological (EP) properties. Results: We identified 137 TTN mvs in 76/131 (58.0%) of subjects, which were most commonly in the TTN A-band. 64 AF-related and 110 HF-related hospitalizations occurred after a median follow-up time of 4.16 years. Hospitalization risk was higher in TTN mv carriers (HR 1.81, Fig. 1A ). We also identified three patients with early-onset AF who shared a rare missense variant T32756I. TTN-T32756I -iPSC-aCMs displayed aberrant contractility ( Fig. 1B-D ), shortened action potential duration ( Fig. 1G-H ), increased activity of cardiac K + channel ( Fig. 1I ), and dysregulated Ca 2+ homeostasis ( Fig. 1J ) without compromising sarcomeric integrity ( Fig. 1E-F ). The titin-binding protein, Four-and-a-Half Lim domains 2 (FHL2), also has increased binding with KCNQ1 and its modulatory subunit KNCE1 in TTN-T32756I -iPSC-aCMs, which may enhance the slow delayed rectifier K + current ( I ks ). Suppression of FHL2 normalized I ks , supporting FHL2 as a mediator of the increased I ks ( Fig. 1K) . Conclusion: In a single-center multi-ethnic AF cohort, TTN mv were associated with increased AF/HF hospitalization, and the T32756I- TTN mv causes ion channel remodeling and an AF-like EP phenotype. These findings establish a mechanistic link between TTN mv, K + ion channels, and sarcomeric regulatory proteins that may represent a novel therapeutic target.

The prognostic importance of glioblastoma size and shape.

Extent of resection, MGMT promoter methylation status, age, functional level, and residual tumor volume are established prognostic factors for overall survival in glioblastoma patients. Preoperative tumor volume has also been investigated, but the results have been inconclusive. We hypothesized that the surface area and the shape were more representative of the tumor's infiltrative capacities, and thus, the purpose of this study was to assess the prognostic value of tumor size and shape in patients with glioblastoma. In total, 271 patients with primary, unifocal glioblastoma were included from two centers in Norway and Sweden, respectively. All tumors were automatically segmented on preoperative MRI scans and manually validated. Tumor volume was used as a measurement of size, whereas sphericity index and area-to-volume ratio defined the shape complexity of the tumor. Contact surface area of the tumor was considered a measurement of both size and shape. Multivariable Cox proportional hazards models were used to assess the prognostic value of the respective tumor measurements, with previously established prognostic factors as covariates. There were no associations between preoperative tumor volume and overall survival. Contact surface area (HR = 1.013, p = 0.002) and sphericity index (HR = 2.223, p = 0.001) were both significant independent prognostic factors for survival in the multivariable Cox models. Contact surface area was also associated with MGMT promoter methylation (p = 0.039) and extent of resection (p = 0.017). Tumor shape complexity appears to be an independent prognostic factor in glioblastoma patients and may also be associated with MGMT promoter methylation status and extent of surgical resection.

Abstract 4126650: Prognostic Value of Femoral-Ankle Pulse Wave Velocity for Cardiovascular Outcomes in Older Adults: The Atherosclerosis Risk in Communities (ARIC) study

Background: Carotid-femoral pulse wave velocity (cfPWV) is a representative measure of central arterial stiffness and an independent predictor of cardiovascular disease (CVD). Femoral-ankle PWV (faPWV) represents peripheral arterial stiffness, but its association with CVD has not been specifically studied. Aim: To compare faPWV and cfPWV regarding their associations with CVD outcomes. Methods: We analyzed 3,402 ARIC participants without prior heart failure (HF), coronary heart disease (CHD), or stroke at visit 5 (2011-13) (mean age 74.8 [SD 4.9] years, 36.1% male, and 78.0% White). faPWV and cfPWV were measured by Omron VP-1000 Plus. The outcomes of interest were composite and individual outcomes of CVD (HF, CHD, and stroke). We ran unadjusted and multivariable Cox proportional hazards models. Results: During a median follow-up of 9.0 years, there were 607 CVD events. Overall, faPWV showed an inverse association with CVD (Table). P-for-trend reached statistical significance in Models 1 and 2 and was borderline significant in Model 3 (p=0.077). In contrast, as anticipated, cfPWV was positively associated with CVD in all Models, although the association was somewhat attenuated in Model 3 (p-for-trend=0.045 and hazard ratio [HR] for top vs. bottom quartile 1.22 [95%CI 0.95-1.56]). Given their opposite patterns, we explored the ratio of cfPWV and faPWV (“cf/fa ratio”) and found that its association with CVD appeared stronger (p-for-trend=0.004 and HR for top vs. bottom quartile 1.37 [1.08-1.74]) than cfPWV. When each CVD subtype was examined separately, HF showed most consistent associations with our stiffness measures, and only the cf/fa ratio remained significant for HF up to Model 3 (p-for-trend=0.010 and HR for top vs. bottom quartile 1.40 [1.03-1.90]). Conclusions: faPWV was inversely associated with CVD, and cf/fa ratio appeared more strongly associated with CVD compared to cfPWV. Our findings indicate distinct prognostic implications of central vs. peripheral arterial stiffness and suggest cf/fa ratio as a new stiffness measure predicting CVD.

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 &lt; 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.

Abstract 4135517: Echocardiographic Biomarkers Enhance Mortality Predictions in Cirrhosis Patients

Introduction: Cirrhosis, a late-stage liver disease, is associated with numerous systemic complications, making long-term mortality prediction challenging. Traditional models like Child-Pugh and MELD are primarily designed for short-term (3-month) mortality. This study evaluates the impact of incorporating echocardiographic (echo) variables in predicting long-term mortality in cirrhosis patients. Methods: A retrospective cohort study was conducted using data from 60 patients with clinically diagnosed cirrhosis from Hippokration Hospital, Greece, spanning 2018 to 2022. Patients were followed for up to 52 months. Exclusion criteria included pre-existing cardiovascular diseases and significant co-morbidities. Patients were categorized into survived to end of study (n=31) and died during study (n=29) groups. Outcomes were analyzed using multivariate logistic regression and Cox proportional hazards models, and include parameters for age, blood pressure, lab-based biomarkers (potassium, pro-brain natriuretic peptide, hemoglobin, platelet count, aspartate transaminase, gamma-glutamyl transferase, uric acid), and echo/ecg measurements (QT interval, left ventricular (LV) ejection fraction, LV global longitudinal strain (GLS), left atrial GLS, annulus velocities, and E/A ratio). Results: The multivariate logistic regression model (MELD+) that included echo variables showed a 10% improvement in area under the curve (AUC: 0.901) compared to the MELD model alone (AUC: 0.817). MELD+ improved risk classification accuracy by nearly 10% with a conservative threshold. The Cox proportional hazards model with MELD+ also demonstrated superior performance (AUC: 0.923; C-index: 0.875; Brier Score: 0.097) compared to the MELD model alone (AUC: 0.892; C-index: 0.831; Brier Score: 0.134). The MELD+ model showed less variation in hazard ratio confidence intervals, indicating more consistent risk estimation. Conclusion: Incorporating echocardiographic measurements enhances the accuracy of long-term mortality predictions in cirrhosis patients. These findings suggest that cardiac imaging should be considered in risk assessments for cirrhosis patients, particularly for predicting survival beyond three months.

NCOG-21. ADJUVANT RADIATION THERAPY IN ATYPICAL MENINGIOMA TREATMENT DOES NOT IMPROVE PROGRESSION FREE SURVIVAL OR OVERALL SURVIVAL: A RETROSPECTIVE COHORT STUDY

Abstract Treatment of atypical meningiomas (AMs) presents a challenge due to their aggressive nature and tendency to recur. While there is clear evidence for the role of surgical resection of AMs, the use of adjuvant radiation therapy (ART) is a topic of ongoing debate. The aim of this study is to explore the impact of ART following surgical resection of AMs. The primary outcomes of interest are progression free survival (PFS) and overall survival (OS). Records were reviewed for all patients treated for Ams at our institution between January 1, 2014 and January 1, 2024. Patients were grouped into two cohorts, those who were initially treated with surgical resection only and those who also received adjuvant RT. PFS and OS were compared between the two groups using Kaplan Meier curves and Log Rank test. Additionally, multivariable cox proportional hazard models were used to adjust for age, MIB, and resection Simpson grading. There were 76 patients who were initially treated with surgery only and 23 patients who had surgery and ART. No significant difference in PFS or OS was observed between the groups (p=0.3522 and p=0.3636, respectively); including after adjusting for age, MIB, and Simpson grading (HR= 1.55 [0.64-3.76], p= 0.330; and HR = 0.95 [0.31-2.93] p= 0.934, respectively). On multivariate analysis, MIB &amp;gt;10 was associated with a significant difference in PFS (HR=2.76 [1.15-6.59], p=0.023). With ART, PFS was 91% at 12 and 60% at 36 months (versus 89% and 57%, respectively, with surgery only). OS was 95% at 12 and 88% at 36 months (versus 91% and 85%, respectively, with surgery only). In this series, ART was not observed to significantly improve PFS or OS compared to surgery alone. Larger series are needed to determine if there is a subset of patients who benefit from ART.

TMIC-16. SPECIFIC TARGETING OF THE MRNA EXPRESSION OF TGFB2 LIGAND TO POTENTIALLY ENHANCE IMMUNE THERAPIES IN LOW-GRADE GLIOMAS

Abstract Low-grade glioma (LGG) tumors are characterized by a low infiltration of immune cells, requiring therapies augmenting the immune response in the tumor microenvironment (TME). The Transforming Growth Factor beta (TGFB) pathway contributes to an immunosuppressive environment. We propose targeting the specific inhibition of Transforming Growth Factor Beta 2, TGFB2 mRNA, as an attractive therapeutic strategy using antisense oligonucleotides. We conducted a bioinformatic-led investigation highlighting the ratio of TGFB2:TGFB1 mRNA expression levels in the cohort of 513 TCGA patients, revealing the TGFB2 ratio as a negative prognostic indicator through utilizing a multivariate Cox proportional hazards model that included the TGFB2 ratio and age at diagnosis as linear covariates to predict overall survival (OS). The model showed a 1.8-fold higher TGFB2 ratio relative to TGFB1 mRNA expression correlated to worse OS. Furthermore, the impact of the TGFB2 ratio was significantly affected by the age at diagnosis, in which older patients exhibited worse OS at increased TGFB2 ratios. Increasing the ratio of TGFB2 relative to TGFB1, TGFB3, TGFBR1, or TGFBR2 in LGG patients led to significant increases in multivariate Cox model determined hazards ratios, HR (HR (95% CI range)) of 1.372 (1.224-1.539), 1.434 (1.288-1.560), 1.327 (1.195-1.473), and 1.381 (1.233-1.547) respectively (P&amp;lt;0.0001 for all comparisons). Correlation of TGFB2:TGFB1/TGFB3/TGFBR1/TGFBR2 ratio across 1330 Reactome pathways using Gene Set Enrichment Analysis showed the most positively correlated genes were members of TME pathways including PD-1 signaling, Syndecan interactions, Non-integrin membrane-ECM interactions, EPH-Ephrin signaling, and Collagen biosynthesis and modifying enzymes. These results suggest that the specific targeting TGFB2 in LGG can remodel the TME for immune therapies to improve OS outcomes.

Subclinical hypothyroidism as an independent predictor of cardiovascular prognosis in left ventricular thrombus patients.

Left ventricular thrombus (LVT) is associated with an increased risk of adverse cardiovascular events, and thyroid hormones are known to affect the cardiovascular system in various ways. However, subclinical thyroid dysfunction still deserves to be emphasized, and its impact on the prognosis of patients with LVT is rare but needs to be investigated. We used retrospective data from patients diagnosed with LVT at Fuwai Hospital over the past 10 years to assess the relationship between thyroid functional status and prognosis of LVT using multivariate Cox proportional hazards models, and validated the improved predictive effect of including thyroid function in the prognostic assessment of LVT using receiver operating characteristic (ROC) curves. Subclinical hypothyroidism was significantly associated with a higher incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) (HR 1.774, 95% CI: 1.053-2.989; p = 0.031) and cardiovascular death (HR 1.986, 95%CI: 1.110-3.553; p = 0.021) in LVT patients, whereas no significant correlation was observed in the subclinical hyperthyroidism group. In addition, including thyroid function in the prognostic consideration of LVT patients would contribute to the predictive effect of MACCEs (AUC for 1 year: 0.715; AUC for 2 years: 0.745; AUC for 3 years: 0.684). Subclinical hypothyroidism can be used as an independent predictor of MACCEs in patients with LVT, and there is a clinical value in using subclinical hypothyroidism as an important factor suggesting a poor prognosis in patients with LVT.

NCOG-48. CT SCAN COMPOSITE SCORE CAN IDENTIFY GLIOBLASTOMA PATIENTS WITH WORSE OUTCOMES

Abstract OBJECTIVE Obesity is a risk factor for many cancer types including glioblastoma multiforme (GBM). We used CT body composition analyses to construct a sex-specific composite score that would optimally predict overall survival in GBM. METHODS Using a retrospective institutional cohort, we performed single slice (L3) and volumetric (L1-L5) automated body segmentation analyses on abdominal and pelvic computed tomography (CT) scans performed within 1 month of diagnosis of GBM. Multivariable Cox proportional hazards models were then used to identify variables that were independently associated with GBM overall survival. Lastly, a learning-tree algorithm was implemented to identify the relative importance of body composition metrics using a XGBoost-powered learning model. These weights were used to create sex-specific composite CT scan scores of protective and predisposing factor with relation to GBM survival. A log-rank pairwise t-test was used to compared GBM survival across patient groups stratified based on these CT composite scores. RESULTS Higher relative inter/intramuscular adipose tissue volume (HR(95%CI):1.9(1.01-3.06), p=0.02), visceral adipose tissue volume (HR(95%CI):2.1(1.04-4.1), p=0.04) and aortic calcification volume (HR(95%CI):2.6(1.2-5.5), p&amp;lt;0.001) were associated with lower GBM overall survival, while higher subcutaneous adipose tissue volume (HR(95%CI):0.4(0.2-0.8), p=0.02), iliopsoas muscle volume (HR(95%CI):0.4(0.2-0.9), p&amp;lt;0.001), and trabecular bone density (HR(95%CI):0.4(0.1-0.8), p=0.003) were predictive of higher GBM OS (p-value of all tests &amp;lt;0.05). Using quartiles of the CT scan composite predisposing and protective scores, we were able to stratify male and female participants with significantly different outcomes with regards to GBM OS (Figure). Male and female participants with higher burden of predisposing factors had significantly lower chances of survival compared to those with lower cumulative burden of these factors (Figure, p-value Q4 vs. Q1 males&amp;lt; 0.01 and 0.001 in females) CONCLUSION Using automated body segmentation analysis we optimized a CT scan composite score that was able to stratify GBM patients with worse overall survival.

RADT-17. FRACTIONATED REIRRADIATION OF RECURRENT IDH WILDTYPE GLIOBLASTOMA: HIGHER REIRRADIAITON DOSE AND SAFETY

Abstract The optimal regimen, normal tissue tolerances, and appropriate indications for reirradiation for recurrent glioblastoma (GBM) are uncertain. We evaluate outcomes and toxicity after fractionated reirradiation. Patients with recurrent IDH wildtype GBM after prior standard radiotherapy during 2007-2022 were retrospectively reviewed. All patients initially received conventionally fractionated radiotherapy. Radiation necrosis (RN) was determined by imaging or pathology. Overall survival (OS) was estimated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazard models for OS were constructed. Bivariable associations with RN were estimated using fisher exact tests. 99 patients (median age 56 yrs, median KPS 80) were treated with reirradiation (median followup 7.4 mo). Median time between initial and reirradiation was 20 months (range, 2 – 214 mo). Median received dose at reirradiation was 41.4 Gy (30.6 – 60 Gy) to a median planning target volume (PTV) of 183 cc (16 – 825 cc). Median cumulative maximum dose to the optics and brainstem were 54 Gy (4 – 103 Gy) and 76 Gy (5 – 146 Gy), respectively. Median OS was 9 mo (95% CI 6.2 – 10.6 mo). On univariate analysis, time between initial and reirradiation ≥24 mo (HR 0.58, CI 0.36 – 0.94) and reirradiation dose ≥41.4 Gy (HR 0.56, CI 0.35 – 0.88) were associated with longer OS. On multivariate analysis, interval between radiation sessions (HR 0.56, CI 0.34 – 0.91) and higher reirradiation dose (HR 0.55, CI 0.35 – 0.87) remained associated with OS. No cases of radiation injury to the optics or brainstem were reported. 10% of patients experienced RN. Reirradiation dose ≥41.4 Gy, reirradiation PTV ≥200 cc and interval between radiation sessions &amp;lt; 24 mo were not significantly associated with RN. These data support the safety and efficacy of fractionated reirradiation for recurrent GBM including for large tumors. This study suggests that higher reirradiation dose may be feasible, including for large treatment volumes.