Citations

Abstract TRIM29 (Tripartite Motif-Containing Protein 29), also known as ATDC (Ataxia-Telangiectasia Group D-Complementing Protein), is an E3 ubiquitin ligase frequently upregulated in muscle-invasive bladder cancer (MIBC). We have previously shown that TRIM29 overexpression in a genetically engineered mouse model (GEMM) is sufficient to drive development of MIBC. We have also shown that TRIM29 is enriched in basal bladder cancer subtypes and is part of a TP63-regulated program that promotes migration and invasive progression. Prior studies suggest that Keratin 5/14 (K5+/K14+) expressing basal-stem progenitor cells in the urothelium are the cells of origin for MIBC in mice. However, whether Trim29 expression in these basal urothelial cells is required for MIBC development has not been established. In this study, we find that Trim29 expression in K5+ basal cells is linked to the inflammatory response and is critical for bladder tumor formation and invasive progression. We show that urothelial TRIM29 expression is enhanced during inflammation in humans and under inflammatory and genotoxic stress in mice. Knockout (KO) of Trim29 in the K5+ basal urothelium of a GEMM exposed to a bladder-specific chemical carcinogen blocked MIBC development. Further, urothelial Trim29 KO enriches immune cell recruitment to the bladder and upregulates STING and inflammatory signaling in mouse and human bladder cancers. These data reveal a critical role for TRIM29 in immunomodulation of the bladder tumor microenvironment (TME), which may act in concert with pro-migratory basal gene programs to expedite MIBC development.

OBJECTIVE The objective was to evaluate the trajectories of hematoma resolution and functional improvement after middle meningeal artery embolization (MMAE) for chronic subdural hematoma (cSDH), model the temporal pattern of cSDH resolution, and identify factors associated with favorable outcomes. METHODS This real-world multicenter retrospective study included cSDH patients treated with MMAE at 24 centers between 2019 and 2024. Hematoma thickness was measured at baseline and at follow-up intervals (1–4 weeks, 1–3 months, 3–6 months, 6–12 months, and > 12 months after embolization). Resolution patterns were modeled using exponential decay functions. Modified Rankin Scale (mRS) scores assessed functional outcomes. Good functional outcome was defined as mRS score ≤ 2. Resolution patterns were modeled using exponential decay functions to estimate time to 50% and 80% reduction. Patients were categorized as complete resolution (≥ 99%) or by quartile of the remaining distribution (substantial [73%–98%], moderate [53%–73%], partial [27%–53%], minimal [< 27%]). The primary outcome was good functional status (mRS score ≤ 2). RESULTS The authors analyzed a total of 1781 patients with 2295 cSDHs who underwent MMAE. The mean ± SD age was 72.8 ± 12.4 years and 68.1% of patients were male. The initial mean hematoma thickness was 15.31 ± 6.53 mm, decreasing to 5.24 ± 5.91 mm at final follow-up (mean reduction 64.3% ± 42.1%). Resolution followed an exponential decay pattern, with an estimated time to 50% reduction of 1.8 months and to 80% reduction of 8.9 months. Complete resolution occurred in 1031 of 2224 patients (46.4%) with complete follow-up. The median (IQR) mRS score improved from 1 (0–3) at baseline to 0 (0–2) at > 12 months. Good functional outcomes were more common in patients with complete versus minimal resolution (68.9% vs 35.0%, p < 0.001). Achieving ≥ 73% resolution within 90 days was associated with better outcomes (good outcome in 76.9% of those with ≥ 73% resolution vs 67.3% in those without, p < 0.001). Neurological deterioration was the strongest predictor of lack of good outcome (23.7% in patients with neurological deterioration vs 82.4% without, p < 0.001). CONCLUSIONS After MMAE for cSDH, reduction in hematoma thickness follows a predictable exponential decay pattern. Greater extent (≥ 80%) and faster timing (within 90 days) of resolution are valuable prognostic indicators. Functional outcomes improve progressively through 6–12 months after the procedure. The relationship between resolution extent and functional outcomes provides quantitative benchmarks for evaluating treatment response.

Abstract The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre–CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post–CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

Abstract Introduction Sickle cell disease (SCD) disproportionately affects African Americans(AA), comprising over 90% of cases. Acute pulmonary embolism (APE) is a serious complication in SCD patients due to increased thromboembolic risk from chronic inflammation, endothelial dysfunction, and hypercoagulability. Although recent studies have demonstrated sex-based differences in APE outcomes, data remain limited for SCD patients. We evaluated sex-based differences in outcomes among AA SCD patients with APE. Methods AA adults with SCD hospitalized for APE were queried from the 2016-2022 National Inpatient Sample. COVID-19 positive patients, patients younger than 18 years, and cases missing data were excluded. Demographics, treatment patterns, and in-hospital outcomes were compared between males and females using appropriate statistical tests with survey-weighted analysis. Results We studied 3635 SCD patients who were treated for APE, consisting of 60.66% (3635)females and 39.34%(2205) males. The overall mean age was 38.40 years, with no differences between the two sexes(mean age of 38.71 in males and 38.20 years in females, p = 0.620). While males reported a higher comorbidity burden with a Charlson Comorbidity Index(CCI) score of 1.03 (vs. 0.92 in females), it was not statistically significant(p = 0.345). In total, 23.43% of males and 22.68% of females had a prior history of PE(p = 0.815). Medicare constituted 31.82% of primary payers among males and 38.36% among females, while Medicaid and private insurance accounted for 32.52% and 24.83% of males, and 32.19% and 25.11% of females, respectively(p = 0.015). After adjusting for confounders, we found that females demonstrated higher odds of receiving transfusion to males. No statistically significant differences were seen for mortality, major cardiovascular complications including cardiac arrest, acute kidney injury, acute liver injury, ventricular tachycardia, or cardiogenic shock. In addition, treatment modalities such as mechanical ventilation, vasopressors or thrombolytic interventions(systemic thrombolysis, catheter-directed thrombolysis, mechanical thrombectomy) were comparable between males and females. We further did not find any differences in sepsis, bleeding events, acute ischemic stroke, or acute myocardial infarction(Table 1). Similarly, although females stayed longer(mean: 5.46 days vs. 4.90 days, p = 0.121), and had higher inflation-adjusted charges($61106 vs. $58810, p = 0.688), they were comparable. Conclusion Our study revealed that sex-based differences in outcome disparities among AA SCD patients admitted for APE are limited, with female transfusion requirements differing significantly, which warrants further investigation. This abstract is funded by: None

Abstract Introduction Chronic Lymphocytic Leukemia(CLL) is the most common leukemia in adults in the United States. CLL patients are at higher risk of bacterial infections, and Pseudomonas aeruginosa is a notable pathogen. Limited data is available comparing the demographics and outcomes of pseudomonas sepsis in CLL. Our study aims to analyze the patient characteristics and mortality between intensive care unit (ICU) and non-ICU admissions for pseudomonas sepsis among CLL patients. Methods Adults with active CLL admitted with a primary diagnosis code of pseudomonas sepsis(ICD-10 code: A41.52) were identified via the National Inpatient Sample(NIS)(2016-2022), excluding COVID-19 cases. Admissions to ICU were estimated if the patients required mechanical ventilation , vasopressors or central venous catheter placement, as per prior NIS-based studies. The predictors of ICU admissions were identified using multivariable regression models, with further analyses focused on estimating the in-hospital mortality. All analysis incorporated adjustments for weight, cluster, and strata, as advised by the data source. Results A total of 1,650 admissions were identified, of which 335 (20.3%) required intensive care. The intensive care cohort was younger (mean age: 73.19 vs. 76.86 years), yet age was not a significant predictor for the need for intensive care. Significant racial disparities were observed, with Black patients demonstrating significantly higher odds of intensive care use than White patients. In contrast, Hispanic patients had comparable odds to White patients. Sex, weekend admission status, private insurance coverage versus Medicare, and income quartiles did not significantly impact intensive care utilization. Among comorbidities, liver cirrhosis and palliative care encounters predicted higher ICU admission rates. Paradoxically, hypertension was associated with lower odds. Other comorbidities showed no significant association with intensive care admission (Table 1). Intensive care patients demonstrated an in-hospital mortality rate of 40.91% versus 8.75% in non-intensive care patients (aOR: 6.690, 95% CI: 2.648-16.906, p &lt; 0.01). Furthermore, intensive care had a substantially greater resource utilization, longer stays (mean: 16.49 vs. 8.83 days, p &lt; 0.01) and markedly higher hospitalization charges (mean: $314,311 vs. $89,614, p &lt; 0.01). Conclusions Our study revealed that black race, comorbidities like liver cirrhosis and palliative care encounters were key predictors for ICU admissions. ICU utilization was associated with higher inpatient mortality, length of stay and hospitalization costs. These findings highlight the disparities and resource burden, and warrants strategic interventions to address them. This abstract is funded by: None

Abstract Introduction Interstitial lung disease-associated pulmonary hypertension (ILD-PH) is a clinically challenging entity that lies on a pathophysiologic spectrum between pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). We compared the metabolomes of patients with ILD-PH to those with PAH and ILD to characterize the PAH-ILD axis and determine whether ILD-PH patients can be phenotyped based on their metabolomic similarity to PAH. Methods Using untargeted metabolomics profiles from patients with PAH, ILD, and ILD-PH in the large, U.S.-based, NIH-funded, multi-center PVDOMICS cohort, we trained an anchor-based classifier on PAH and ILD metabolomes using supervised PLS-DA with a 75/25 train/test split. Primary and secondary PH or risk-group classifications in PVDOMICS were based on expert adjudication of clinical data including right heart catheterization hemodynamics, pulmonary function testing, chest imaging, and laboratory results. We then applied the trained model to each ILD-PH patient to assign a PAH similarity score. We classified patients as having a PAH-like or ILD-like metabolomic phenotype using an optimal PAH similarity score cutoff of 0.5 then compared PAH metabolomic similarity to expert-adjudicated primary and secondary WSPH classifications in PVDOMICS. We implemented FELLA, a network-based metabolomics enrichment method, to holistically characterize the biologic underpinnings of PAH, ILD-PH, and ILD metabolomes. Results We analyzed 244 patients with PAH, 54 with ILD, and 47 with ILD-PH. The anchor-based classifier demonstrated high train-test performance with a c-statistic of 0.81 and 78% agreement with expert-adjudicated diagnoses. Among the ILD-PH patients, 23 were classified as PAH-like and 24 as ILD-like (74% agreement with expert adjudication, Cohen’s kappa 0.49, Hedge’s g estimate of 0.86). FELLA enrichment revealed core glycolytic and bioenergetic pathways were enriched in both pure PAH and ILD-PH. Comparison of diffusion Z-scores between groups demonstrated subtle but biologically coherent differences in several reaction-level nodes, including lactate, NADPH oxidoreductase, and phosphofructokinase, which were enriched in ILD-PH. Conclusion Patients with ILD-PH demonstrate clinically relevant metabolomic phenotypes. Examination of the network biology underlying ILD-PH may point to potential therapeutic targets in this vulnerable subgroup with lagging clinical outcomes. This abstract is funded by: Pulmonary Fibrosis Foundation PFF Scholars Program

Abstract Introduction Catheter-directed thrombolysis (CDT) has emerged as a safer interventional option for acute pulmonary embolism (APE) compared to systemic thrombolysis, with reduced rates of hemorrhage and mortality. However, comparative outcomes between first-time and recurrent APE patients undergoing CDT remain inadequately documented. This study aims to compare complications, mortality, and readmissions following CDT in recurrent versus first-time PE to provide evidence-based guidance for treatment optimization. Methods We explored the 2016-2022 Nationwide Readmissions Database(NRD) for APE admissions treated with CDT and stratified our sample by history of prior pulmonary embolism. Our cases excluded patients with COVID-19 and those younger than 18 years. We compared differences in their demographics, in-hospital complications during the index admission, and 30-day readmission rates. Adjustments were made to account for the complex design of the NRD via STATA 18.0. Results Of 37,952 patients identified, 9.27% had a history of prior PE. The groups had comparable mean age, sex distribution, and hospital status, with varying comorbidities as shown in Tables 1a-1b. Patients with first-time PE were more likely to experience in-hospital complications including sepsis, transfusion requirement, invasive mechanical ventilation, shock, acute encephalopathy, acute kidney injury, and all-cause mortality during the index hospitalization(Table 2). However, hospital length of stay and charges were similar between groups(Table 1b). Following discharge, 30-day readmission rates were comparable (6.25% vs. 6.41% for first-time versus recurrent PE, respectively; hazard ratio 0.948, 95% CI 0.765-1.17, p = 0.626). Conclusion First-time APE patients who underwent CDT reported higher rates of various in-hospital complications, and all-cause mortality, despite having comparable 30-day readmission rates. There were certain limitations to our study, such as the lack of laboratory data, imaging findings, APE severity scores on admissions, and medication history. Prospective studies with detailed clinical parameters will help validate our findings and elucidate the different causes of death. This abstract is funded by: None

Abstract Introduction Sedation is routinely administered to facilitate comfort and tolerance of life support for critically ill adults dependent on invasive mechanical ventilation. Isoflurane, a widely used anesthetic during surgery, has properties that may also benefit ICU patients requiring continuous sedation. However, efficacy as a sedative and safety in this population is not well established. Methods We conducted two identically designed multicenter randomized trials, INSPIRE ICU1 and INSPIRE ICU2, at hospitals across the US. Ventilator-dependent adults were randomly assigned in a 1.5:1 ratio to receive either inhaled isoflurane or intravenous propofol as the first-line sedative for up to 48 ± 6 hours, targeting a sedation depth between Richmond agitation-sedation scale (RASS) -1 (drowsy) to -4 (responsive only to physical stimuli). Isoflurane was administered via an anesthetic conserving device (Sedaconda ACD-S). In both arms, opioids were permitted at the lowest dose required to achieve freedom from pain. The primary outcome was the percentage of time at target sedation level, assessed as a noninferiority outcome with pre-specified margin of 15%. Secondary outcomes included opioid exposure, wake-up time after end of treatment, time to extubation, and proportion of time with spontaneous breathing effort. Results A total of 470 combined participants were included in the two trials. In each trial, 142 patients were randomly assigned to isoflurane and 93 to propofol. In INSPIRE ICU1, percentage of time within target sedation depth was 77.1 [53.2, 89.9] % with isoflurane and 80.9 [58.2, 96.4] % with propofol (difference -1.5 [-8.9, &gt;99] %; p &lt; 0.01 for noninferiority). In INSPIRE ICU2, percentage of time within target sedation depth was 72.6 [66.4, 78.9] % with isoflurane and 74.5 [67.5, 81.5] % with propofol (difference -1.9 [-9.4, &gt;99] %; p &lt; 0.01 for noninferiority). In both trials, patients assigned to isoflurane received significantly less opioid, measured as fentanyl equivalents, during the treatment period. In INSPIRE ICU2, participants receiving isoflurane were significantly likelier to exhibit spontaneous breathing efforts, but this finding was not replicated in INSPIRE ICU1. There were no significant differences in time to wake-up or time to extubation between groups in either trial. No episodes of malignant hyperthermia or propofol infusion syndrome were reported. Adverse events were comparable in type and frequency between groups. Conclusions In two US multicenter trials, isoflurane was noninferior to propofol for maintaining target sedation depth in adults undergoing invasive ventilation, and was associated with significantly lower opioid exposure. (NCT05327296, NCT05312385) This abstract is funded by: Sedana Medical

Abstract Introduction Pneumocystis jirovecii pneumonia (PJP) is a significant opportunistic infection in immunocompromised patients. While cancer patients experience significant immunosuppression that increases their susceptibility to PJP, outcomes of this infection stratified by specific tumor types remain poorly characterized. Methods This retrospective study identified adults with PJP and either solid or hematologic malignancies using the National Inpatient Sample (2016-2022). Exclusion criteria included age &lt;18 years, COVID-19 positivity, concurrent solid and hematologic malignancies, HIV positivity, or missing data. Baseline characteristics were compared between the two cancer groups. Multivariable regression analyses, adjusting for potential confounders, were conducted to estimate adjusted odds ratios for adverse events, treatments, and mortality. All analyses accounted for the complex survey design of the dataset. Results We found 11565 admissions involving PCP matching our selection, with 55.6%(6430) liquid and 44.4%(5135) solid cancers. Both groups contained an elderly population (mean age in solid: 64.25 years, vs. mean age in liquid: 63.36 years, p = 0.139), and mostly males( 51.32% of solid and 66.33% of liquid cancers, p &lt; 0.01). The adjusted Deyo Charlson Comorbidity Index Scores were also comparable(1.65 in solid vs. 1.55 in liquid cancers, p = 0.195). Majority of patients in both groups (73.97% of solid and 72.55% of liquid) were Whites(p = 0.155), insured via Medicare(52.98% of solid and 54.60% of liquid,p=0.580), and hospitalized at urban teaching centers(85.69% of solid and 87.17% of liquid, p = 0.341). Among patients with solid tumors, 32.03% were respiratory/thoracic cancers, 11.88% were breast cancers, 11.10% were gastrointestinal cancers. Among patients with hematologic malignancies, the most common diagnoses were lymphoma (48.4%) followed by leukemia (37.2%). Patients with hematologic malignancies recorded reduced rates of acute respiratory failure, mechanical ventilation requirements, and intubation. In contrast, no significant differences were observed between groups for cardiovascular complications including cardiac arrest and septic shock. Acute kidney injury odds were similarly comparable between the two cohorts(Table 1). Our analysis demonstrated significantly lower mortality in hematologic malignancy patients compared to solid tumor patients, but with longer lengths of stay (15.4 days vs 13.2 days) and higher hospital charges ($234,616 vs $188,792). Conclusions Our findings demonstrate that solid malignancies may pose a bigger threat to PJP outcomes as compared to hematological cancers, warranting further investigation to set up appropriate preventive strategies and treatment protocols. This abstract is funded by: None