Faculty Bibliography

Lung transplantation remains the only available therapy for many patients with end-stage lung disease. The number of lung transplants performed has increased significantly, but development of the field was slow compared with other solid-organ transplants. This delayed growth was secondary to the increased complexity of transplanting lungs; the continuous needs for surgical, anesthetics, and critical care improvements; changes in immunosuppression and infection prophylaxis; and donor management and patient selection. The future of lung transplant remains promising: expansion of donor after cardiac death donors, improved outcomes, new immunosuppressants targeted to cellular and antibody-mediated rejection, and use of xenotransplantation or artificial lungs.

Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting.

RATIONALE/BACKGROUND:Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. METHODS:Lower airway samples from 96 LT recipients with varying degrees of PGD were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS:Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference did not reach statistical significance (p=0.06). PGD severity associated with increased BAL neutrophil concentration (p=0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p<0.05). Furthermore, microbial signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p<0.05). C-SPT exhibited differential expression of TNF, SERPINE1 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. CONCLUSIONS:Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.

OBJECTIVE/UNASSIGNED:Anticoagulation monitoring in patients supported on extracorporeal membrane oxygenation is challenging given the risks of both bleeding and thrombotic complications. Based on our early clinical experience, we revised our heparin protocol by reducing our target anti-factor Xa assay from 0.3 to 0.7 U/mL to 0.15 to 0.5 U/mL, while instituting a partial thromboplastin time cutoff of 70 seconds. We evaluated the impact of this change on bleeding/thrombotic complications. METHODS/UNASSIGNED:A single-center retrospective study of adult patients on extracorporeal membrane oxygenation support was conducted from January 2015 to August 2022. Patients were stratified into groups based on protocol revision: Pre-Revision (2015-2018) or Post-Revision (2019-2022). Our primary end point was the incidence of bleeding/thrombotic complications. Time in therapeutic range was calculated to determine protocol adherence. Poisson regression was performed to correlate time in therapeutic range with the likelihood of complication. RESULTS/UNASSIGNED:008). CONCLUSIONS/UNASSIGNED:A modified heparin monitoring protocol defined by a lower therapeutic anti-factor Xa assay target and a set partial thromboplastin time cutoff correlated with decreases in bleeding/thrombotic complications in patients on extracorporeal membrane oxygenation.

OBJECTIVE:Early-stage lung adenocarcinoma is treated with local therapy alone, although patients with grade 3 stage I lung adenocarcinoma have a 50% 5-year recurrence rate. Our objective is to determine if analysis of the tumor microenvironment can create a predictive model for recurrence. METHODS:Thirty-four patients with grade 3 stage I lung adenocarcinoma underwent surgical resection. Digital spatial profiling was used to perform genomic (n = 31) and proteomic (n = 34) analyses of pancytokeratin positive and negative tumor cells. K-means clustering was performed on the top 50 differential genes and top 20 differential proteins, with Kaplan-Meier recurrence curves based on patient clustering. External validation of high-expression genes was performed with Kaplan-Meier plotter. RESULTS:There were no significant clinicopathologic differences between patients who did (n = 14) and did not (n = 20) have recurrence. Median time to recurrence was 806 days; median follow-up with no recurrence was 2897 days. K-means clustering of pancytokeratin positive genes resulted in a model with a Kaplan-Meier curve with concordance index of 0.75. K-means clustering for pancytokeratin negative genes was less successful at differentiating recurrence (concordance index 0.6). Genes upregulated or downregulated for recurrence were externally validated using available public databases. Proteomic data did not reach statistical significance but did internally validate the genomic data described. CONCLUSIONS:Genomic difference in lung adenocarcinoma may be able to predict risk of recurrence. After further validation, stratifying patients by this risk may help guide who will benefit from adjuvant therapy.

BACKGROUND/UNASSIGNED:The current gold standard of scoliosis correction procedures is still posterior spinal fusion, an extensively studied procedure. anterior vertebral body tethering is a newer surgical technique for the correction of scoliotic curves. Consequently, best practices have yet to be determined. METHODS/UNASSIGNED:A single-institution, retrospective, review of all patients diagnosed with adolescent idiopathic scoliosis who underwent two row anterior vertebral body tethering between June 2020 and April 2022 was performed. RESULTS/UNASSIGNED: = 4). CONCLUSIONS/UNASSIGNED:This early review of a 2-year two row vertebral body tethering postoperative experience provides a report of a safe and effective approach to chest tube management at a single academic center.