Clinical validation and utility of Percepta GSC for the evaluation of lung cancer.

The Percepta Genomic Sequencing Classifier (GSC) was developed to up-classify as well as down-classify the risk of malignancy for lung lesions when bronchoscopy is non-diagnostic. We evaluated the performance of Percepta GSC in risk re-classification of indeterminate lung lesions. This multicenter study included individuals who currently or formerly smoked undergoing bronchoscopy for suspected lung cancer from the AEGIS I/ II cohorts and the Percepta Registry.

Percepta Genomic Sequencing Classifier and decision-making in patients with high-risk lung nodules: a decision impact study.

Background: Incidental and screening-identified lung nodules are common, and a bronchoscopic evaluation is frequently nondiagnostic. The Percepta Genomic Sequencing Classifier (GSC) is a genomic classifier developed in current and former smokers which can be used for further risk stratification in these patients. Percepta GSC has the capability of up-classifying patients with a pre-bronchoscopy risk that is high (> 60%) to "very high risk" with a positive predictive value of 91.

The Impact of the Envisia Genomic Classifier in the Diagnosis and Management of Patients with Idiopathic Pulmonary Fibrosis.

The diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and can result in delayed or misdiagnosis. IPF diagnosis is based on the presence of either a radiographic or histologic usual interstitial pneumonia (UIP) pattern in the absence of an identifiable etiology. The Envisia Genomic Classifier is a clinically validated molecular diagnostic test that identifies UIP in transbronchial biopsies.

Utility of a Molecular Classifier as a Complement to High-Resolution Computed Tomography to Identify Usual Interstitial Pneumonia.

Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP.

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.

The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects.

Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis.

Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6.

Clinical Risk Factors and Prognostic Model for Primary Graft Dysfunction after Lung Transplantation in Patients with Pulmonary Hypertension.

Rationale: Pulmonary hypertension from pulmonary arterial hypertension or parenchymal lung disease is associated with an increased risk for primary graft dysfunction after lung transplantation.

Objective: We evaluated the clinical determinants of severe primary graft dysfunction in pulmonary hypertension and developed and validated a prognostic model.

Methods: We conducted a retrospective cohort study of patients in the multicenter Lung Transplant Outcomes Group with pulmonary hypertension at transplant listing.

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution.

Reliability of diagnostic criteria for bronchiolitis obliterans syndrome after lung transplantation: a survey.

Background: Long-term outcomes after lung transplantation are limited due to chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS) is the most common form of obstructive CLAD and its definition derives from spirometric measurements. Given the importance of this diagnosis, both the accuracy and reliability of the definition of CLAD are crucial in understanding the pathophysiology of this disease to develop therapeutic options and influence outcome after lung transplantation.

Association of soluble HLA-G with acute rejection episodes and early development of bronchiolitis obliterans in lung transplantation.

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of bronchiolitis obliterans syndrome (BOS). Soluble HLA-G, a mediator of adaptive immunity that modulates regulatory T cells and certain classes of effector T cells, may be a useful marker of survival free of BOS.

MicroRNAs Implicated in Dysregulation of Gene Expression Following Human Lung Transplantation.

Background: Lung transplantation remains the only viable treatment option for the majority of patients with advanced lung diseases. However, 5-year post-transplant survival rates remain low primarily secondary to chronic rejection. Novel insights from global gene expression profiles may provide molecular phenotypes and therapeutic targets to improve outcomes after lung transplantation.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

Background: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database.

Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.

Background: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies.

Clinical risk factors for primary graft dysfunction after lung transplantation.

Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.

Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.

Elevated plasma angiopoietin-2 levels and primary graft dysfunction after lung transplantation.

Introduction: Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability.

Monitoring of nonsteroidal immunosuppressive drugs in patients with lung disease and lung transplant recipients: American College of Chest Physicians evidence-based clinical practice guidelines.

Objectives: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome.

Conventional and novel approaches to immunosuppression.

Immunosuppressive therapy has contributed significantly to improved survival after solid organ transplantation. Nevertheless, treatment-related adverse events and persistently high risk of chronic graft rejection remain major obstacles to long-term survival after lung transplantation. The development of new agents, refinements in techniques to monitor immunosuppression, and enhanced understanding of transplant immunobiology are essential for further improvements in outcome.

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine.

Background: While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of bronchiolitis obliterans syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role.

Early readmission is a predictor of overall survival following isolated lung transplantation.

Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival.