Citations

Diagnosing pulmonary rheumatoid nodules (RN) is challenging because they are rare and share clinical, radiologic, and histopathologic features with other necrotizing granulomatous diseases such as infectious granulomas (IG) and granulomatosis with polyangiitis (GPA). Herein, we revisit the histopathologic features of RN and the findings in the adjacent lung tissue, in comparison with IG and GPA, to identify distinguishing features. Twenty-eight cases with surgically resected RN evaluated at our institution (1991 to 2024), 33 IG (10 mycobacterial infection, 10 histoplasmosis, 13 coccidiomycosis), and 10 GPA cases were included in the study. All available slides with H&E and special stains were reviewed for various histologic parameters within the nodules and in surrounding lung tissue. Many histopathologic features of RN overlap with the necrotizing granulomas seen in infections and GPA. However, some findings in the adjacent lung tissue showed significant differences. The lack of airspace granulomas/non-necrotizing granuloma and the absence of necrotizing vasculitis in the setting of RN can help to differentiate between infection cases and GPA, respectively. Given their considerable overlap, correlation with clinical context, serologic and microbiologic studies, as well as careful evaluation of special stains is crucial in the diagnosis of RN.

Background: The safety and cost of concomitant atrial fibrillation (AF) ablation and left atrial appendage occlusion (LAAO) procedure remain unknown. Objective: The study sought to determine real-world outcomes of AF patients who underwent LAAO with ablation. Methods: The National Inpatient Sample and International Classification of Diseases–Tenth Revision codes were used to identify patients who underwent LAAO with and without AF ablation during the years 2016-2022. The outcomes assessed included procedural complications and resource utilization. Results: LAAO with AF ablation was associated with a higher rate of overall complications (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.37-1.74), major complications (OR 1.38, 95% CI 1.18-1.60), non-home discharge (OR 1.55, 95% CI 1.23-1.96), prolonged length of stay >1 day (OR 3.21, 95% CI 2.92-3.52), and increased hospitalization costs as defined by median cost >$25,926 (OR 19.42, 95% CI 16.21-23.25) when compared to LAAO alone after adjustment for potential confounding variables. Patients who underwent LAAO with ablation were also more likely to receive pacemaker implantation (3.6 % vs 0.2%, P < 0.001) and experience acute kidney injury (3.9% vs 2.1%, P < 0.001) and non-ST elevation myocardial infarction (3.7% vs 1.5%, P < 0.001). Conclusion: In a large, contemporary, real-world study of LAAO procedures in the United States, concomitant AF ablation was associated with a higher rate of overall and major complications and an increased resource utilization.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P &lt; .0001) and worse OS (HR, 2.09; P &lt; .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.