Multivariate Cox Model Research Articles

The protective role of SGLT2 inhibitors on aortic aneurysm mediated by oxidative stress and inflammation in type 2 diabetes mellitus

BackgroundSodium-glucose transport protein 2 inhibitors (SGLT2i) have been widely used to treat patients with type 2 diabetes mellitus (T2DM) and have demonstrated protective effects against certain cardiovascular diseases. However, no clinical research has been conducted to explore the relationship between SGLT2i and the risk of aortic aneurysm (AA).MethodsWe extracted and analyzed the data of 4964 patients with T2DM from the First Affiliated Hospital of Zhengzhou University during July 2017 to January 2023. Multivariate Cox models, interaction analysis and Kaplan–Meier curves were performed to approximate the associations of SGLT2i therapy on the risk of AA. A sensitivity analysis was performed to test the robustness of results. Mediation analyses explored the roles of inflammatory (neutrophils, lymphocytes, C-reactive protein and alkaline phosphatase) and oxidative stress (gamma glutamyl transferase, total bilirubin, and uric acid) markers in the associations between SGLT2i and AA.ResultsA total of 1942 SGLT2 inhibitor (SGLT2i) users (39.12%) and 3022 non-SGLT2 inhibitor (NonSGLT2i) users were included in final analysis. After full adjustment for potential risk factors, SGLT2i patients were associated with a lower risk of aortic aneurysm (HR, 95% CI 0.91, 0.89–0.98, p = 0.001). Dapagliflozin showed the greatest difference for reduction of aortic aneurysm incidence (HR, 95% CI 0.84, 0.80–0.95, p = 0.011). Subgroup analysis indicated that use of SGLT2i lower the risk of aortic aneurysm in some subgroups of T2DM patients. The sensitivity analysis demonstrated the robustness of the results. CRP, lymphocytes, neutrophils, and uric acid were significantly associated with both SGLT2i and AA, with mediation proportions of 13.35%, 8.83%, 9.67% and 31.17%, respectively.ConclusionsOur study suggested that patients using SGLT2i may have a lower risk of aortic aneurysm, and this effect could potentially be mediated by inflammation and oxidative stress. Further mechanistic and prospective studies are required to verify this association.Graphical abstract

Outcomes of Pembrolizumab plus chemotherapy for patients with metastatic non-squamous NSCLC: Real-world evidence.

Pembrolizumab with chemotherapy (immunochemotherapy) has shown encouraging overall survival (OS) benefits in non-squamous mNSCLC, as demonstrated by the KEYNOTE-189 trial. However, randomised controlled trials may not fully capture the diversity of real-world patients. This study aims to evaluate immunochemotherapy outcomes in a real-world setting, including subgroups underrepresented in the KEYNOTE-189 trial. Patients diagnosed with non-squamous mNSCLC 2011-2022 and recorded in Cancer Registry Database of the German Federal State Baden-Württemberg (BWCR), were analysed. OS was assessed using Kaplan-Meier and multivariable Cox models, adjusted for major clinical parameters. Results were compared with KEYNOTE-189. Among 2630 eligible cases, 1314 patients received chemotherapy alone and 1316 received immunochemotherapy. Median OS (mOS) was 14.1 months (95%CI: 13.1-15.4) for immunochemotherapy and 10.4 months (95%CI: 9.7-11.2) for chemotherapy alone, with an HR of 0.7 (95%CI: 0.64-0.77). A significant benefit was seen in M1c stage (HR 0.7, 95%CI: 0.63-0.79). No significant OS improvement was observed in patients with ECOG 2-3 or bone metastases. This real-world evidence suggests that immunochemotherapy generally improves OS in mNSCLC. Subgroup analysis showed no survival benefit for patients with ECOG >1 or bone metastasis, but a benefit for patients with M1c stage.

18F-FDG PET/CT assessment of metabolic tumor burden predicts survival in patients with metastatic posterior uveal melanoma

The prognostic value of metabolic tumor burden parameters obtained from 18F-FDG PET/CT imaging was evaluated in this retrospective national multicenter study of patients with metastatic posterior uveal melanoma (PUM) and compared to the largest diameter of the largest metastatic lesion (LDLM) and the American Joint Committee on Cancer (AJCC) staging system. The Maximal Standard Uptake Value (SUVmax), Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) were obtained in 106 patients. Higher values of SUVmax (p = 0.007, log-rank), MTV (p < 0.001, log-rank), and TLG (p < 0.001, long-rank) were associated with shorter survival. The three parameters were also independent predictors in the multivariate Cox model, while the AJCC staging turned insignificant. Time-dependent positive predictive value (PPV) analysis and Receiver Operating Characteristics (ROC) curves showed that MTV (Area Under the Curve (AUC) = 0.78), TLG (AUC = 0.78), and LDLM (AUC = 0.76) were good predictors of 1-year survival. For the subset of 97 patients with liver metastases, the corresponding regional measurements in the liver tended to be even better predictors. In conclusion, MTV and TLG were found to be better predictors of survival in metastatic PUM than the AJCC staging system, but when LDLM was used as a continuous variable it showed an equally good prediction of 1-year survival.

The prognostic value of POD24 in relapsed/refractory follicular lymphoma-A SCHOLAR-5 analysis.

Follicular lymphoma (FL) has a heterogeneous prognosis. Progression within 24 months of starting front-line therapy (POD24) is prognostic of overall survival (OS). Despite its prognostic value in early lines, the role of POD24 in relapsed/refractory (R/R) patients initiating later lines of therapy (LoTs) is unknown. We analyzed the SCHOLAR-5 real-world cohort to investigate whether POD24 is prognostic in patients with R/R FL initiating ≥3rd LoT. Among the 128 SCHOLAR-5 patients, 34 patients experienced POD24. POD24 patients received their ≥3 LoT after a shorter time compared with non-POD24 patients (median 42.0 months [range: 8.8‒17.8] vs. 109.9 months [range: 29.6‒310.2]). Using a time-dependent multivariate Cox model, POD24 was predictive of shorter OS from initiation of ≥3rd LoT with a hazard ratio (HR) of 2.44 (95% confidence interval [CI]: 1.20‒4.96). For progression-free survival, using a multivariate repeated-measures Cox model, the effect was similar but not statistically significant (HR: 1.45; 95% CI: 0.94‒2.11). This study demonstrates that among patients with R/R FL initiating a ≥3rd LoT, POD24 patients reach these LoTs sooner after diagnosis and POD24 remains prognostic of subsequent OS. This suggests that POD24 status can inform clinical decision making in this population.

Retrospective analysis of HAIP therapy in metastatic colorectal cancer: Efficacy, safety, and prognostic factors.

126 Background: HAIP (hepatic arterial infusion pump) therapy is a promising intervention for metastatic colorectal cancer (mCRC) with liver metastases, addressing significant challenges in management and prognosis. It offers targeted treatment to maximize efficacy while minimizing systemic toxicity. We present a retrospective analysis of patients with metastatic colorectal adenocarcinoma treated with HAIP therapy at an academic center and safety net hospital. Methods: Patients with mCRC and hepatic metastasis who received at least one HAIP floxuridine (FUDR) cycle from 2013 to 2023 were included. Baseline data, including demographics, tumor characteristics, and treatment history, were collected pre-HAIP. The main outcome was overall survival (OS) post-pump placement, with secondary outcomes being real-world progression-free survival (rwPFS) and HAIP-related complications. Results: In total, 88 patients were evaluated for inclusion, of whom 63 met inclusion criteria and were included for analysis. The median age of included patients was 46 years (interquartile range (IQR) 41-57) and 54% were male. Prior to HAIP, 38 (60%) of patients received one line of systemic therapy, while 18 (29%) had two. The median OS from HAIP placement was 28.0 months (95% CI 21.9-NR) and median rwPFS was 11.2 months (95% CI 7.1-16.1). Baseline bilirubin, KRAS mutant status, and CEA were associated with OS in the multivariate cox model. The most common complication from HAIP placement was hematoma (n=4, 6.3%), followed by pump infection (n=2, 3.2%). Grade 3 toxicities from FUDR infusion were infrequent, involving alkaline phosphatase (n=6), AST or ALT elevation (n=3), bilirubin increase (n=2), and platelet count decrease (n=1). Conclusions: HAIP treatment is associated with durable responses and few complications, making it well-tolerated by patients. For individuals with colorectal cancer and hepatic metastases, HAIP chemotherapy using FUDR presents a viable and effective treatment option, potentially improving overall outcomes and quality of life. Further prospective and randomized work may establish the role for HAIP in mCRC with liver metastases.

Prognostic Impacts of Depression and Inflammatory Factors in Pancreatic Cancer Patients.

This study explores the potential connections between clinical depression, inflammation, and cancer progression in pancreatic cancer patients. Conducted from May 2021 to May 2023 at the National Cheng Kung University Hospital Clinical Data Warehouse, this prospective study involved 279 pancreatic cancer patients. The nine-item self-reported Patient Health Questionnaire (PHQ-9) was used to assess depressive symptoms. The study focused on the correlation between clinically significant depression (PHQ-9 scores >10), levels of inflammatory factors, and patient survival rates. At the time of diagnosis, 34.0% of the patients exhibited clinically significant depression. Analysis using Fixed Effects in Generalized Linear Mixed Models (GLMM) revealed a notable link between log-transformed C-reactive protein (ln CRP) levels with occurrence of depression (odds ratio [OR] = 1.274, p = .010). Furthermore, a univariate Cox proportional hazard model with time-varying covariates indicated a correlation between clinically significant depression and decreased overall survival (hazard ratio [HR] = 6.245, p < .001). A multivariate Cox model also showed significant associations of both ln CRP levels (HR = 1.966, p = .030) and clinically significant depression (HR = 3.611, p = .028) with survival outcomes. The findings highlight a complex interplay between inflammation, depression, and survival in pancreatic cancer patients. However, the study is limited by the lack of control over all potential confounders, such as chronic conditions, which could independently influence both depression and inflammatory biomarkers.

Deep Learning Model of Diastolic Dysfunction Risk Stratifies the Progression of Early-Stage Aortic Stenosis.

The development and progression of aortic stenosis (AS) from aortic valve (AV) sclerosis is highly variable and difficult to predict. The authors investigated whether a previously validated echocardiography-based deep learning (DL) model assessing diastolic dysfunction (DD) could identify the latent risk associated with the development and progression of AS. The authors evaluated 898 participants with AV sclerosis from the ARIC (Atherosclerosis Risk In Communities) cohort study and associated the DL-predicted probability of DD with 2 endpoints: 1) the new diagnosis of AS; and 2) the composite of subsequent mortality or AV interventions. Validation was performed in 2 additional cohorts: 1) in 50 patients with mild-to-moderate AS undergoing cardiac magnetic resonance (CMR) imaging and serial echocardiographic assessments; and 2) in 18 patients with AV sclerosis undergoing 18F-sodium fluoride (NaF) and 18F-fluorodeoxyglucose positron emission tomography (PET) combined with computed tomography (CT) to assess valvular inflammation and calcification. In the ARIC cohort, a higher DL-predicted probability of DD was associated with the development of AS (adjusted HR: 3.482 [95%CI: 2.061-5.884]; P< 0.001) and subsequent mortality or AV interventions (adjusted HR: 7.033 [95%CI: 3.036-16.290]; P< 0.001). The multivariable Cox model (incorporating the DL-predicted probability of DD) derived from the ARIC cohort efficiently predicted the progression of AS (C-index: 0.798 [95%CI: 0.648-0.948]) in the CMR cohort. Moreover, the predictions of this multivariable Cox model correlated positively with valvular 18F-NaF mean standardized uptake values in the PET/CT cohort (r=0.62; P = 0.008). Assessment of DD using DL can stratify the latent risk associated with the progression of early-stage AS.

The role of lymph node level ratio in predicting prognosis and the benefits of postoperative radiotherapy in patients with pathological N1 stage head and neck squamous cell carcinoma.

To analyze the role of lymph node level ratio (LNLR) in predicting prognosis and the benefits of postoperative radiotherapy (PORT) in patients with pathological N1 (pN1) head and neck squamous cell carcinoma (HNSCC). Patients with pN1 HNSCC from January 2011 to February 2021 were included. Patients were grouped by the LNLR, lymph node yield (LNY), and lymph node ratio (LNR) and were analyzed with the Kaplan-Meier method and multivariate Cox model. This study identified 310 patients. Time-dependent receiver operating characteristic analyses showed superior prognostic ability for LNLR in comparison with LNY and LNR. Patients with an LNLR ≤ 5.25 had the worst survival. Multivariate regressions demonstrated larger hazard ratios (HRs) and a higher concordance index for the LNLR model versus the LNY and LNR models. The HRs (95% confidence interval) for a LNLR ≤ 5.25 were 2.46 (1.71-3.54, p<0.001) for DFS, 1.95 (1.38-2.75, p<0.001) for OS, 2.25 (1.53-3.29, p<0.001) for DSS. Furthermore, postoperative radiotherapy-related significant improvement in survival was observed exclusively in the LNLR ≤ 5.25 subgroup. The LNLR is a more robust quality indicator for neck dissection. An LNLR of≤5.25 significantly compromises survival and indicates the need for PORT in patients with pN1 HNSCC.

Lp(a) concentration and polymorphic size are not associated with new onset diabetes in individuals with prediabetes.

Observational studies in the general population suggest that low concentrations of lipoprotein (a) [Lp(a)] are associated with an increased risk of type 2 diabetes. Here, we aim to determine whether Lp(a) plasma concentration and Kringle-IV (K-IV) repeat polymorphism were associated with new-onset diabetes (NOD) in individuals with prediabetes. IT-DIAB is an observational, prospective study including 303 participants with impaired fasting glucose (fasting plasma glucose [FPG]: 110-125 mg/dl) followed annually for 5 years. The primary endpoint was the development of NOD, defined as a first FPG value ≥ 126 mg/dl during follow-up. Lp(a) concentrations were measured by immunoturbidimetry, apo(a) concentrations and the number of K-IV domains by mass spectrometry. Survival analyses for NOD were modeled using Kaplan-Meier curves and a multivariable Cox model, after binarization on threshold values of Lp(a) or K-IV. Among the participants, 113 (37%) developed NOD during follow-up. The concentrations of Lp(a) and the number of K-IV domains were not significantly different according to NOD status. Similarly, the percentage of patients with a non-detectable (≤ 7 nmol/l) or elevated (>125 nmol/l) Lp(a) concentration was similar between those with or without NOD: 68.1 vs 63.7% (P = 0.46) and 8.8 vs 8.9% (P > 0.99), respectively. Kaplan-Meier curves and Cox models did not show any association between Lp(a) concentration (threshold 7 nmol/l and 125 nmol/l) or number of K-IV domain (threshold 23) and the risk of NOD. In a high-risk population, Lp(a) concentration or polymorphic size do not appear to be substantially associated with type 2 diabetes risk.

The effect of time from surgery to commencing adjuvant radiotherapy for patients with head and neck squamous cell carcinoma.

Studies reported inferior outcomes when radiotherapy starts >6-8weeks post-surgery for head and neck squamous cell carcinoma (HNSCC) but are limited due to time variable dichotomization. We assessed the relationship between survival and the time between surgery and radiotherapy as a continuous variable, hypothesising there would be no change in patients' survival at 6-8weeks post-surgery. Inclusion criteria: patients with HNSCC who underwent surgery and adjuvant (chemo)radiotherapy, Jan 2014-Dec 2020. A sub-cohort included patients with oral cavity squamous cell carcinoma (OCSCC) treated at the same institution, Jan 2016-Dec 2020. The primary endpoint was overall survival (OS); a multivariable Cox model was fitted. For the OCSCC sub-cohort, the endpoint of interest was progression-free survival (PFS); a multivariable competing risk regression model was fitted. 386 patients with HNSCC were included (main cohort). The median time between surgery and radiotherapy was 44days (IQR: 14days). Plotting time intervals vs log(hazard) did not demonstrate a threshold time where risk of death increases. The time interval between surgery and radiotherapy was not associated with OS (HR 1.00; 95% CI 0.99-1.02; p=0.4). In the sub-cohort of 208 patients with OCSCC, the time interval between surgery and radiotherapy was not associated with increased risk of cancer vs competing events (HR 1.01; 95% CI 0.99-1.03; p=0.5). Increasing time interval between surgery and radiotherapy was not associated with inferior survival outcomes. We suggest patients are considered for radiotherapy >6-8weeks post-surgery and that no threshold is considered for patient selection.

Individual patient data (IPD) pooled analysis on the optimal therapeutic management of patients with microsatellite instability-high (MSI) resectable gastroesophageal adenocarcinoma (GEA).

455 Background: Patients with resectable MSI/dMMR GEA showed improved survival and modest if any benefit from chemotherapy. Preoperative treatment with immune checkpoint inhibition (ICI) showed high rate of major-complete pathologic response in single arm trials possibly allowing the design of chemotherapy/surgery-free approaches. Methods: This was a multinational IPD analysis including patients with resectable GEA with MSI/dMMR status enrolled in INFINITY and NEONIPIGA phase II trials, with dual CTLA-4/PD-(L)1 ICI followed by surgery +/- adjuvant ICI; PROSECCO retrospective study, with perioperative FLOT chemotherapy and surgery, and the dataset of our previous IPD analysis on MAGIC, CLASSIC, ARTIST and ITACA-S randomized trials of patients treated with surgery alone or plus older perioperative/adjuvant chemo(radio)therapy regimen. Primary endpoint was the evaluation of rates of pathologic complete response (pCR) defined as TRG1a Becker and major-complete pathologic response (pCR/MPR) defined as TRG1a/b Becker according to preoperative treatment schedule in patients who underwent surgery. Univariable and multivariable analyses were conducted using a random effects logistic model adjusted with propensity score. Secondary endpoints were event-free survival (EFS) and overall survival (OS) according to the therapeutic strategy in the overall study population. Multivariable mixed-effects Cox models weighted with propensity score were performed. Results: The IPD included 197 patients. Of these, 49 received ICI +/- surgery, 27 FLOT chemotherapy plus surgery, 33 surgery alone and 88 older chemo(radio)therapy regimens plus surgery. In the 69 patients resected after neoadjuvant ICI or FLOT standard of care treatment, ICI demonstrated a higher rate of pathologic response compared to chemotherapy (pCR 61.9% vs 3.7%, OR 54.8 p=0.002; pCR/MPR 78.6% vs 10%, OR 39.3 p&lt;0.001). In ITT population, no significant difference in OS and EFS was shown in patients treated with ICI, FLOT plus surgery, old chemo(radio)therapy plus surgery or surgery alone. Conclusions: In resectable MSI/dMMR GEA, upfront ICI showed comparable survival outcomes to surgery alone, with limitations of study design and sample size. The impact on survival of ICI versus surgery alone should be investigated prospectively to avoid overtreatment or identify specific risk categories with benefit. The high rate of major-complete pathologic response may allow to study or perform organ sparing surgery procedures or non-operative management to reduce surgical morbidity/mortality and improve quality of life. OS EFS HR 2.5-97.5% CI p HR 2.5-97.5% CI p Ref: Surgery only - - - - - - Chemo+surgery 1.16 0.27-4.98 0.84 1.10 0.39-3.07 0.85 FLOT+surgery 1.10 0.19-6.22 0.92 2.38 0.90-6.27 0.08 ICI +/- surgery 1.97 0.43-8.96 0.38 1.39 0.51-3.77 0.52

Phenomapping the Response of Patients With Ischemic Cardiomyopathy With Reduced Ejection Fraction to Surgical Revascularization.

Coronary artery bypass grafting (CABG) has demonstrated long-term mortality benefits in patients with HFREF and obstructive coronary artery disease (CAD), but whether phenotypic heterogeneity influences the benefits of CABG is unknown. We applied clustering analysis to STICHES (Surgical Treatment for Ischemic Heart Failure Extension Study) to identify phenogroups with different long-term risk profiles and investigate differences in CABG benefits between phenogroups. STICHES was a randomized controlled trial evaluating the effect of CABG in addition to medical therapy versus medical therapy alone. We split the STICHES participants into derivation (n = 753) and validation (n = 459) cohorts. We phenomapped the derivation cohort using penalized model-based clustering. We fit multivariable Cox models to investigate long-term differences in all-cause mortality, cardiovascular (CV) mortality, and a composite of all-cause mortality/CV hospitalization between phenogroups and whether phenogroup assignment modified the effects of CABG on these outcomes. Findings were internally validated on the validation cohort. Four phenogroups were identified in the derivation cohort. The highest-risk group was at a twofold greater risk of death (HR: 2.0, 95% CI: 1.4-2.9, p < 0.001) and CV death (HR: 2.0, 95% CI: 1.3-3.1, p = 0.002), and a 1.5-fold greater risk for death/CV hospitalization (HR: 1.5, 95% CI: 1.1-2.1, p = 0.016). Phenogroup assignment did not modify the effects of CABG on the outcomes (p > 0.05 for all). Similar results were obtained in the validation cohort. The beneficial effects of CABG on all-cause mortality, CV mortality, and a composite of all-cause mortality and CV hospitalization persist despite phenotypic heterogeneity in HFREF and CAD.

FOLFIRI-ramucirumab (FOLFIRI-Ram) versus ramucirumab-paclitaxel (Ram-Pac) in the second line (2L) for patients with advanced upper gastrointestinal (UGI) cancer: A real-world propensity-score matched analysis of survival.

377 Background: The approach to 2L treatment of advanced UGI (gastric, esophageal, and gastroesophageal junction) cancers is guided primarily by the results of the RAINBOW trial, a global randomized phase III trial that demonstrated the benefit of Ram-Pac over paclitaxel. However, the onset of peripheral neuropathy limits its use in the palliative-intent setting. The RAMIRIS trial demonstrated the feasibility of 2L FOLFIRI-Ram compared to Ram-Pac, however it failed to meet the prespecified endpoint of ≥ 65% 6-month overall survival (OS). Despite this, FOLFIRI-Ram has emerged as an alternative 2L regimen and now endorsed in major society guidelines. Yet, comparative outcomes between FOLFIRI-Ram and Ram-Pac therapy in the real world are lacking. Methods: This study used the nationwide Flatiron Health electronic health record-derived deidentified database. During the study period (January 2011-June 2024), longitudinal patient-level data were derived from approximately 280 cancer clinics. Patients were eligible for inclusion if they had advanced unresectable or metastatic UGI cancer and received 2L treatment with either FOLFIRI-Ram or Ram-Pac. Demographics and lab values at the time of 2L initiation were extracted. Given anticipated imbalances in sample size, patients were matched 1:6 (FOLFIRI-Ram:Ram-Pac) for inclusion into the analytic dataset using a greedy match based on a logit model to predict propensity scores from key clinical and laboratory characteristics. The primary endpoint was OS from the start of 2L therapy, analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A hybrid approach was used to construct a multivariate Cox model. Results: A total of 15,908 patients were included in the database, of whom 5189 received a 2L treatment. Of these, 631 patients received 2L Ram-Pac and 40 received 2L FOLFIRI-Ram. After matching, the final sample size was 240 patients who received Ram-Pac and 40 who received FOLFIRI-Ram. Baseline clinical and laboratory characteristics were well-balanced. The median OS from initiation of 2L FOLFIRI-Ram was 9.7 months (95% CI 6.9-12.3) and 7.6 months with 2L Ram-Pac (95% CI 6.3-9.2 months). The hazard ratio (HR) for death with FOLFIRI-Ram was 0.77 (95% CI 0.52-1.15, log-rank P=0.20) in reference to Ram-Pac. The adjusted HR death for FOLFIRI-Ram after adjustment for baseline albumin and white blood cell count was 0.87 (95% CI 0.58-1.30, p=0.49) in the final multivariate model. Conclusions: This real-world propensity-score matched analysis of patients with advanced UGI cancers receiving FOLFIRI-Ram or Ram-Pac supports the ongoing use of FOLFIRI-Ram in the 2L as an alternative to Ram-Pac. These data are consistent with results from the RAMIRIS study, however further prospective study is needed.

Weight and Blood-Based Markers of Cachexia Predict Disability, Hospitalization and Worse Survival in Cancer Immunotherapy Patients.

Cancer-associated cachexia can inhibit immune checkpoint inhibitor (ICI) therapy efficacy. Cachexia's effect on ICI therapy has not been studied in large cohorts of cancer patients aside from lung cancer. We studied associations between real-world routinely collected clinical cachexia markers and disability-free, hospitalization-free and overall survival of cancer patients. A retrospective study was conducted of electronic health records (EHR) of patients with lung, renal cell, melanoma and other cancers treated with ICI therapy at Northwestern Medicine of Chicago, IL, United States, between March 2011 and January 2022. Weight, body mass index, absolute neutrophil and lymphocyte counts, albumin and C-reactive protein (CRP) measures were analysed to calculate the Fearon consensus criteria for cachexia, weight loss grading system (WLGS) score, neutrophil-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI) and modified Glasgow Prognostic Score (mGPS) at ICI therapy initiation. Kaplan-Meier and Cox proportional hazards analyses were used to determine associations between these metrics and disability-free, hospitalization-free and overall survival. EHR analysis uncovered 3285 cancer patients on ICI therapy (54% > 65 years of age, 50.7% male, 77.7% White). At ICI therapy initiation, 1282 (39.0%) patients had cachexia (consensus criteria), 1641 (50.0%) had a WLGS score ≥ 2, 1806 (55.0%) had an NLR > 3, 1087 (33.1%) had albumin < 3.5 g/dL and 1318 (40.1%) had a PNI < 44. Missing measurements included CRP missing for 98.2% and mGPS missing for 98.6% of patients. Disability-free (n = 1373), hospitalization-free (n = 2374) and overall survival (n = 1599) events were analysed with 1-year rates of 65% (64%-67%), 35% (34%-37%) and 65% (63%-66%), respectively. Multivariate Cox model analyses showed hazard ratios (HR) for cachexia at 1.58 (95% CI 1.38-1.80), 1.47 (95% CI 1.33-1.63) and 1.97 (95% CI 1.75-2.23) for disability, hospitalization and death, respectively. HRs for WLGS ≥ 2 were 1.45 (95% CI 1.28-1.66), 1.37 (95% CI 1.24-1.51) and 1.91 (95% CI 1.69-2.17). HRs for NLR > 3 were 1.57 (95% CI 1.35-1.83), 1.40 (95% CI 1.25-1.58) and 1.95 (95% CI 1.67-2.27). HRs for albumin < 3.5 g/dL were 1.33 (95% CI 1.15-1.54), 1.67 (95% CI 1.50-1.86) and 2.09 (95% CI 1.84-2.36). HRs for PNI < 44 were 1.60 (95% CI 1.39-1.84), 1.46 (95% CI 1.31-1.63) and 2.07 (95% CI 1.80-2.37). Fearon consensus criteria, WLGS, NLR, albumin and PNI were routinely collected at ICI initiation in regular clinical practice and predictive of worse disability-free, hospitalization-free and overall survival in cancer patients receiving ICI therapy. These routine clinical measures may aid prognostication and decision-making in cancer patients with cachexia.

Critical Time Intervals in Door-to-Balloon Time Linked to One-Year Mortality in ST-Elevation Myocardial Infarction

Background: Timely activation of primary percutaneous coronary intervention (PCI) is crucial for patients with ST-segment elevation myocardial infarction (STEMI). Door-to-balloon (DTB) time, representing the duration from patient arrival to balloon inflation, is critical for prognosis. However, the specific time segment within the DTB that is most associated with long-term mortality remains unclear. In this study we aimed to identify the target time segment within the DTB that is most associated with one-year mortality in STEMI patients. Methods: We conducted a retrospective cohort study at a tertiary teaching hospital. All patients diagnosed with STEMI and activated for primary PCI from the emergency department were identified between January 2013–December 2021. Patient demographics, medical history, triage information, electrocardiogram, troponin-I levels, and coronary angiography reports were obtained. We divided the DTB time into door-to-electrocardiogram (ECG), ECG-to-cardiac catheterization laboratory (cath lab) activation, activation-to-cath lab arrival, and cath lab arrival-to-balloon time. We used Kaplan-Meier survival analysis and multivariable Cox proportional hazards models to determine the independent effects of these time intervals on the risk of one-year mortality. Results: A total of 732 STEMI patients were included. Kaplan-Meier analysis revealed that delayed door-to-ECG time (&amp;gt;10 min) and cath lab arrival-to-balloon time (&amp;gt;30 min) were associated with a higher risk of one-year mortality (log-rank test, P &amp;lt; .001 and P = 0.01, respectively). In the multivariable Cox models, door-to-ECG time was a significant predictor for one-year mortality, whether it was analyzed as a dichotomized (&amp;gt;10 min vs ≤10 min) or a continuous variable. The corresponding adjusted hazard ratios (aHR) were 2.81 (95% confidence interval [CI] 1.42–5.55) for the dichotomized analysis, and 1.03 (95%CI 1.00–1.06) per minute increase, respectively. Cath lab arrival-to-balloon time also showed an independent effect on one-year mortality when analyzed as a continuous variable, with an aHR of 1.02 (95% CI 1.00–1.04) per minute increase. However, ECG-to-cath lab activation and activation-to-cath lab arrival times did not show a significant association with the risk of one-year mortality. Conclusion: Within the door-to-balloon interval, the time from door-to-ECG completion is particularly crucial for one-year survival after STEMI, while cath lab arrival-to-balloon inflation may also be relevant.

Efficient estimation for the multivariate Cox model with missing covariates

Efficient estimation for the multivariate Cox model with missing covariates

385. Sepsis-Associated Encephalopathy and Dementia Outcome: A Retrospective Cohort Study of 30,378 Adult Sepsis Inpatient Survivors at a Tertiary Medical Center in Taiwan

Abstract Background Sepsis-associated encephalopathy (SAE) is commonly observed in critically ill patients without identifiable causes, potentially leading to neurological sequelae. Prior studies have associated the long-term risk of dementia with sepsis or in-hospital infections, or the short-term risk of mortality with SAE, rather than the short-term dementia risk with SAE. We aimed to assess the association between SAE and the 1-year risk of dementia among sepsis survivors.Figure 1.Flowchart of the selection process of adult sepsis inpatient survivors (n = 30,378). Methods This cohort included inpatients aged ≥ 18 years with first-time sepsis during 2010-2019, no prior dementia or central nervous system (CNS) infections, Glasgow Coma Scale (GCS) measurements within 7 days of sepsis, and who survived the index hospitalization (Figure 1). Sepsis was identified using Sepsis-3 criteria. SAE was defined as having at least two GCS measurements of either &amp;lt; 7 for patients with endotracheal tubes, tracheostomies, or aphasia, or &amp;lt; 12 for the remaining patients within the 7 days of sepsis. Dementia at 3 months and 1 year was defined by the presence of ICD-9 and ICD-10 diagnosis codes from 7 days to 3 months, and from 3 months to 1 year post-sepsis onset, respectively. Multivariable Cox models were used, considering death as the competing risk. Demographic, clinical characteristics, and outcomes of adult sepsis inpatient survivors, stratified by SAE status. Results Of 30,378 eligible sepsis inpatient survivors, 6.4% developed SAE within 7 days of sepsis onset. Patients with SAE tended to be older, female, and have more comorbidities compared to those without SAE (Table 1). Dementia occurred more frequently in patients with SAE than those without (10.9% vs 3.9% within 3 months; 3.6% vs 2.1% within 1 year). Similar patterns were observed in mortality rate. SAE was significantly associated with an increased risk of dementia for 3-month (adjusted hazard ratio [aHR] 1.81; 95% confidence interval [CI] 1.55-2.12) and for 1-year (aHR 1.54; 95% CI 1.18-2.01), compared to patients without SAE (Table 2). This association was significantly stronger among patients without chronic pulmonary disease, stroke, and with a qSOFA &amp;lt; 2, regarding the 3-month dementia risk (Figure 2). Risk of dementia and all-cause mortality associated with SAE among adult sepsis inpatient survivors. Conclusion Determining whether SAE is a trigger for the disease itself or merely triggers more intensive dementia surveillance requires more studies with standardized SAE diagnostic criteria and post-sepsis follow-up strategies. Subgroup analyses of the risk of dementia and all-cause mortality associated with SAE. Disclosures All Authors: No reported disclosures

P-877. Effectiveness of Oral Step-down Antibiotic Therapy in Uncomplicated Enterococcus faecalis Bloodstream Infection

Abstract Background The transition from intravenous (IV) to oral antibiotic therapy is a common strategy in the management of uncomplicated bloodstream infection (BSI). However, the role of oral step-down therapy in uncomplicated Enterococcus faecalis BSI has not been defined. This retrospective cohort study examines the effectiveness of oral step-down antibiotics compared to standard IV therapy in uncomplicated E. faecalis BSI. Risk factors for treatment failure in uncomplicated Enterococcus faecalis bloodstream infection (BSI) *Early clinical failure criteria include systolic blood pressure &amp;lt;100 mmHg or vasopressor use, heart rate &amp;gt;100 beats/minute, respiratory rate ≥ 22 breaths/minute or mechanical ventilation, altered mental status, white blood cell count &amp;gt;12,000/mm3. Methods Adults with uncomplicated E. faecalis BSI admitted to 10 Prisma Health hospitals in South Carolina from January 2021 to June 2023 were evaluated. Clinically insignificant positive blood cultures, polymicrobial, recurrent, persistent, and complicated BSI were excluded. Deaths within 7 days were excluded to mitigate immortal time bias. Multivariate Cox proportional hazards regression examined the risk of treatment failure (all-cause mortality or recurrence) within 90-day. Wilcoxon rank sum test compared hospital length of stay (HLOS) between the two groups. Results Of 476 screened patients, 131 with uncomplicated E. faecalis BSI were included in the analysis. The median age was 70 years, 84 (64%) were men, and 46 (35%) had a urinary source of infection. Eighty-seven patients (66%) received standard IV therapy and 44 (34%) were transitioned to oral step-down therapy. Median antibiotic treatment durations were 15 and 14 days, respectively. Patients in the oral step-down group received 6 days of IV antibiotics followed by 8 days of oral therapy, most commonly oral aminopenicillins (33/44; 75%). In the multivariate Cox model, oral step-down therapy was not associated with increased risk of treatment failure compared to standard IV therapy (hazard ratio 0.91, 95% confidence intervals 0.31-2.63; Table). HLOS was 7 days in the oral step-down group and 11 days in the standard IV group (p&amp;lt; 0.001). Conclusion Transitioning patients with uncomplicated E. faecalis BSI from IV to oral step-down antibiotic therapy appears to be a promising strategy with shorter HLOS and no significant increase in the risk of treatment failure. These results should be confirmed in larger multicenter studies prior to routine implementation in clinical practice. Disclosures All Authors: No reported disclosures

Metaphyseal comminution in distal radius fractures: a predictor of secondary fragility fractures and the role of osteoporosis treatment.

Distal radius fractures (DRFs) are common in patients with osteoporosis and associated with increased risks for subsequent fractures. Metaphyseal comminution in patients with DRFs may indicate severe osteoporosis and heightened bone fragility. However, its relationship with the risk of secondary fragility fractures remains unclear. This study aimed to evaluate the incidence of secondary fractures in patients with DRFs involving metaphyseal comminution and assess the effectiveness of osteoporosis treatment in reducing this risk. In this retrospective cohort study, 134 patients aged ≥ 50years underwent DRF surgery at a single institution from July 2018 to December 2022. The patients were allocated into groups by the presence (n = 45) or absence (n = 89) of metaphyseal comminution. The primary outcome was secondary fracture incidence. A multivariate Cox model was used, adjusting for age, sex, body mass index, bone mineral density, osteoporosis treatment type, and dementia. Secondary fractures were significantly more frequent in the comminution group (17.8%) than in the non-comminution group (3.4%) (p = 0.004). Metaphyseal comminution was associated with 5.2-fold increased secondary fracture risk (hazards ratio: 5.2, 95% confidence interval: 1.4-10.7, p = 0.004). The patients administered combination therapy (active vitamin D plus bisphosphonates or anabolic agents) had notably lower secondary fracture rate than did those receiving vitamin D alone (5.6% vs. 15.4%, p = 0.046). Metaphyseal comminution in patient with DRFs significantly elevated secondary fracture risk; combination osteoporosis therapy might mitigate this risk. These findings underscore the need for robust osteoporosis management in high-risk patients, suggesting metaphyseal comminution should be crucial for fracture risk stratification.

Risk of Cancers According to the Use of Biological Agents in Patients With Radiographic Axial Spondyloarthritis: A Nationwide Population-Based Cohort Study.

As the duration of use of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with radiographic axial spondyloarthritis (r-axSpA) accumulates over time, long-term real-world safety data on cancer risk are needed. This study assessed the association between tumor necrosis factor inhibitors (TNFis) and interleukin 17 inhibitors (IL-17is) exposures and cancer risk in patients with r-axSpA. From the Korean nationwide database, we assembled 41,889 patients without prior history of cancer who were diagnosed with r-axSpA from 2010 onwards. Patients were followed up through 2021. Multivariable time-varying Cox models were performed to estimate the adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs) of (1) overall cancers and (2) cancer subtypes according to TNFis exposure versus bDMARDs nonexposure, IL-17is exposure versus bDMARDs nonexposure, and IL-17is exposure versus TNFis exposure. The incident rates of overall cancers during bDMARDs nonexposure, TNFis exposure, and IL-17is exposure were 53.8, 37.6, and 67.3 per 10,000 person-years, respectively. TNFis exposure versus bDMARDs nonexposure was not associated with an increased risk of overall cancers (aHR = 0.9, 95% CI = 0.8-1.1). IL-17is exposure was not associated with an increased risk of overall cancers compared with bDMARDs nonexposure (aHR = 1.2, 95% CI = 0.5-3.0) or TNFis exposure (aHR = 1.3, 95% CI = 0.6-3.3). Similarly, no significant associations were observed between bDMARDs exposures and the risk of cancer subtypes. In patients with r-axSpA, there was no evidence of increased cancer risk with TNFis and IL-17is exposures compared with bDMARDs nonexposure, suggesting that the use of bDMARDs is safe with respect to cancer risk in patients with r-axSpA.