Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Cryptococcal empyema treated with tube thoracostomy and intrapleural fibrinolysis.

A 55-year old woman with a history of relapsed T-cell ALL presented with right pleuritic chest pain and decreased breath sounds over the right hemithorax. Imaging of the chest showed loculated effusions. Tube thoracostomy was performed with intrapleural application of alteplase and dornase alpha over a 3-day period. Repeat imaging demonstrated a marked decrease in the volume of the effusion. In most prior published cases of pleural cryptococcosis, surgical drainage was required in addition to prolonged antifungal agents. More than 50% of patients with cryptococcal infection have severe underlying disease or immunodeficiency state making them high risk for surgery. This is the first case to our knowledge of cryptococcal empyema successfully treated with tube thoracostomy and intrapleural fibrinolysis.

Acute eosinophilic pneumonia triggered by secondhand cigarette smoke exposure in an elderly man.

The spectrum of eosinophilic lung diseases comprises a diverse group of pulmonary disorders associated with tissue or peripheral eosinophilia. [Acute eosinophilic pneumonia (AEP)] is an uncommon eosinophilic lung disease that can be idiopathic, but identifiable causes include medications, inhalational exposures and infections. Most cases in the literature are associated with first-time cigarette smoking or resuming smoking. Herein, we present a case of AEP in an elderly man triggered by exposure to secondhand tobacco smoke, in whom a transbronchial biopsy was diagnostic. The patient recovered fully with glucocorticoid therapy without recurrence after avoiding further secondhand smoke.

Transcriptomic evidence of immune activation in macroscopically normal-appearing and scarred lung tissues in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease manifested by overtly scarred peripheral and basilar regions and more normal-appearing central lung areas. Lung tissues from macroscopically normal-appearing (IPFn) and scarred (IPFs) areas of explanted IPF lungs were analyzed by RNASeq and compared with healthy control (HC) lung tissues. There were profound transcriptomic changes in IPFn compared with HC tissues, which included elevated expression of numerous immune-, inflammation-, and extracellular matrix-related mRNAs, and these changes were similar to those observed with IPFs compared to HC. Comparing IPFn directly to IPFs, elevated expression of epithelial mucociliary mRNAs was observed in the IPFs tissues. Thus, despite the known geographic tissue heterogeneity in IPF, the entire lung is actively involved in the disease process, and demonstrates pronounced elevated expression of numerous immune-related genes. Differences between normal-appearing and scarred tissues may thus be driven by deranged epithelial homeostasis or possibly non-transcriptomic factors.

Red Blood Cell-Derived Exosomal Oncogenic MicroRNA Promote Cancer Development and Progression.

The role of red blood cells (RBCs) in tumorigenesis is poorly understood. We previously identified RBC-microRNAs with aberrations linked to lung cancer, including miR-93-5p. Here we find that miR-93-5p levels are elevated in RBC-derived exosomes among lung cancer patients and are associated with their shorter survivals. RBC-derived miR-93-5p transfers to cancer cells primarily through the exosomal pathway. The transferred RBC-miR-93-5p can target PTEN in cancer cells, and hence increase cell proliferation, invasion, and migration. RBC-derived miR-93-5p accelerates, whereas targeting miR-93-5p diminishes tumor growth in xenograft models. These findings reveal a novel biological function of RBCs in tumorigenesis, where they facilitate cancer progression by transferring the oncomiR via exosomes, thereby offering new diagnostic and treatment strategies for lung cancer.

Dysregulation of lncRNA MALAT1 Contributes to Lung Cancer in African Americans by modulating the tumor immune microenvironment.

African American (AA) populations present with notably higher incidence and mortality rates from lung cancer in comparison to other racial groups. Here, we elucidate the contribution of long non-coding RNAs (lncRNAs) in the racial disparities and their potential clinical applications in both diagnosis and therapeutic strategies. AA patients had elevated plasma levels of MALAT1 and PVT1 compared with cancer-free smokers. Incorporating these lncRNAs as plasma biomarkers, along with smoking history, achieved 81% accuracy in diagnosis of lung cancer in AA patients. We observed a rise in MALAT1 expression, correlating with increased levels of monocyte chemoattractant protein-1 (MCP-1) and CD68, CD163, CD206, indicative of tumor-associated macrophages in lung tumors of AA patients. Forced MALAT1 expression led to enhanced growth and invasiveness of lung cancer cells, both in vitro and in vivo, accompanied by elevated levels of MCP-1, CD68, CD163, CD206, and KI67. Mechanistically, MALAT1 acted as a competing endogenous RNA to directly interact with miR-206, subsequently affecting MCP-1 expression and macrophage activity, and enhanced the tumorigenesis. Targeting MALAT1 significantly reduced tumor sizes in animal models. Therefore, dysregulated MALAT1 contributes to lung cancer disparities in AAs by modulating the tumor immune microenvironment through its interaction with miR-206, thereby presenting novel diagnostic and therapeutic targets.

Dysregulation of lncRNA MALAT1 Contributes to Lung Cancer in African Americans by Modulating the Tumor Immune Microenvironment.

African American (AA) populations present with notably higher incidence and mortality rates from lung cancer in comparison to other racial groups. Here, we elucidated the contribution of long non-coding RNAs (lncRNAs) in the racial disparities and their potential clinical applications in both diagnosis and therapeutic strategies. AA patients had elevated plasma levels of MALAT1 and PVT1 compared with cancer-free smokers. Incorporating these lncRNAs as plasma biomarkers, along with smoking history, achieved 81% accuracy in diagnosis of lung cancer in AA patients. We observed a rise in MALAT1 expression, correlating with increased levels of monocyte chemoattractant protein-1 (MCP-1) and CD68, CD163, CD206, indicative of tumor-associated macrophages in lung tumors of AA patients. Forced MALAT1 expression led to enhanced growth and invasiveness of lung cancer cells, both in vitro and in vivo, accompanied by elevated levels of MCP-1, CD68, CD163, CD206, and KI67. Mechanistically, MALAT1 acted as a competing endogenous RNA to directly interact with miR-206, subsequently affecting MCP-1 expression and macrophage activity, and enhanced the tumorigenesis. Targeting MALAT1 significantly reduced tumor sizes in animal models. Therefore, dysregulated MALAT1 contributes to lung cancer disparities in AAs by modulating the tumor immune microenvironment through its interaction with miR-206, thereby presenting novel diagnostic and therapeutic targets.

Differential Non-Coding RNA Profiles for Lung Cancer Early Detection in African and White Americans.

Introduction: Lung cancer leads in cancer-related deaths. Disparities are observed in lung cancer rates, with African Americans (AAs) experiencing disproportionately higher incidence and mortality compared to other ethnic groups. Non-coding RNAs (ncRNAs) play crucial roles in lung tumorigenesis. Our objective was to identify ncRNA biomarkers associated with the racial disparity in lung cancer. Methods: Using droplet digital PCR, we examined 93 lung-cancer-associated ncRNAs in the plasma and sputum samples from AA and White American (WA) participants, which included 118 patients and 92 cancer-free smokers. Subsequently, we validated our results with a separate cohort comprising 56 cases and 72 controls. Results: In the AA population, plasma showed differential expression of ten ncRNAs, while sputum revealed four ncRNAs when comparing lung cancer patients to the control group. In the WA population, the plasma displayed eleven ncRNAs, and the sputum had five ncRNAs showing differential expression between the lung cancer patients and the control group. For AAs, we identified a three-ncRNA panel (plasma miRs-147b, 324-3p, 422a) diagnosing lung cancer in AAs with 86% sensitivity and 89% specificity. For WAs, a four-ncRNA panel was developed, comprising sputum miR-34a-5p and plasma miRs-103-3p, 126-3p, 205-5p, achieving 88% sensitivity and 87% specificity. These panels remained effective across different stages and histological types of lung tumors and were validated in the independent cohort. Conclusions: The ethnicity-related ncRNA signatures have promise as biomarkers to address the racial disparity in lung cancer.

Spray Cryotherapy for Benign Large Airway Stenosis: A Multicenter Retrospective Cohort Study of Safety and Practice Patterns.

BACKGROUND: Benign airway stenosis (BAS) represents a significant burden on patients, providers, and healthcare systems. Spray cryotherapy (SCT) has been proposed as an adjunctive treatment to reduce BAS recurrence. We sought to examine safety and practice variations of the latest SCT system when used for BAS. METHODS: We conducted a retrospective multicenter cohort study in seven academic institutions within the Interventional Pulmonary Outcomes Group. All patients who underwent at least one SCT session with a diagnosis of BAS at the time of procedure at these institutions were included. Demographics, procedure characteristics, and adverse events were captured through each center's procedural database and electronic health record. RESULTS: A total of 102 patients underwent 165 procedures involving SCT from 2013 to 2022. The most frequent etiology of BAS was iatrogenic (n = 36, 35%). In most cases, SCT was used prior to other standard BAS interventions (n = 125; 75%). The most frequent SCT actuation time per cycle was five seconds. Pneumothorax complicated four procedures, requiring tube thoracostomy in two. Significant post-SCT hypoxemia was noted in one case, with recovery by case conclusion and no long-term effects. There were no instances of air embolism, hemodynamic compromise, or procedural or in-hospital mortality. CONCLUSION: SCT as an adjunctive treatment for BAS was associated with a low rate of complications in this retrospective multicenter cohort study. SCT-related procedural aspects varied widely in examined cases, including actuation duration, number of actuations, and timing of actuations relative to other interventions.

Sustained Clinical Benefits of Spiration Valve System in Patients with Severe Emphysema: 24-Month Follow-Up of EMPROVE.

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.

PURPOSE: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM. EXPERIMENTAL DESIGN: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico. RESULTS: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations. CONCLUSIONS: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM.

Laying the Foundation for a Mesothelioma Patient Registry: Development of Data Collection Tools.

Mesothelioma, a cancer of mesothelial cells that line the chest, lungs, heart, and abdomen, is a relatively rare disease. In the United States, approximately 3000 individuals are diagnosed with mesothelioma annually. The primary risk factor for mesothelioma is occupational asbestos exposure which can occur decades prior to disease development, though in approximately 20% of cases, known asbestos exposure is lacking. While several other countries have developed mesothelioma registries to collect key clinical and exposure data elements to allow better estimation of incidence, prevalence, and risk factors associated with disease development, no national mesothelioma registry exists in the U.S. Therefore, as part of a larger feasibility study, a patient exposure questionnaire and a clinical data collection tool were created using a series of key informant interviews. Findings suggest that risk factor and clinical data collection via an on-line questionnaire is feasible, but specific concerns related to confidentiality, in the context of employer responsibility for exposure in the unique U.S. legal environment, and timing of enrollment must be addressed. Lessons learned from piloting these tools will inform the design and implementation of a mesothelioma registry of national scope.

Operative Management of Aerodigestive Injuries: Improved Survival Over two Decades.

INTRODUCTION: Non-iatrogenic aerodigestive injuries are infrequent but potentially fatal. We hypothesize that advances in management and adoption of innovative therapies resulted in improved survival. METHODS: Trauma registry review at a university Level 1 center from 2000 to 2020 that identified adults with aerodigestive injuries requiring operative or endoluminal intervention. Demographics, injuries, operations, and outcomes were abstracted. Univariate analysis was performed, P < .05 was statistically significant. RESULTS: 95 patients had 105 injuries: 68 tracheal and 37 esophageal (including 10 combined). Mean age 30.9 (± 14), 87.4% male, 82.1% penetrating, and 28.4% with vascular injuries. Median ISS, chest AIS, admission BP, Shock Index, and lactate were 26 (16-34), 4 (3-4), 132 (113-149) mmHg, .8 (.7-1.1), and 3.1 (2.4-5.6) mmol/L, respectively. There were 46 cervical and 22 thoracic airway injuries; 5 patients in extremis required preoperative ECMO. 66 airway injuries were surgically repaired and 2 definitively managed with endobronchial stents. There were 24 cervical, 11 thoracic, 2 abdominal esophageal injuries-all repaired surgically. Combined tracheoesophageal injuries were individually managed and buttressed. 4 airway complications were successfully managed, and 11 esophageal complications managed conservatively, stented, or resected. Mortality was 9.6%, half from intraoperative hemorrhage. Specific mortality: tracheobronchial 8.8%, esophageal 10.8%, and combined 20%. Mortality was significantly associated with higher ISS (P = .01), vascular injury (P = .007), blunt mechanism (P = .01), bronchial injury (P = .01), and years 2000-2010 (P = .03), but not combined tracheobronchial injury. CONCLUSION: Mortality is associated with several variables, including vascular trauma and years 2000-2010. The use of ECMO and endoluminal stents in highly selected patients and institutional experience may account for 97.8% survival over the past decade.

Prophylactic epinephrine attenuates severe bleeding in lung transplantation patients undergoing transbronchial lung biopsy: Results of the PROPHET randomized trial.

BACKGROUND: Severe hemorrhage is an uncommon yet potentially life-threatening complication of transbronchial lung biopsy. Lung transplantation recipients undergo multiple bronchoscopies with biopsy and are considered to be at an increased risk for bleeding from transbronchial biopsy, independent of traditional risk factors. We aimed to evaluate the efficacy and safety of endobronchial administration of prophylactic topical epinephrine in attenuating transbronchial biopsy-related hemorrhage in lung transplant recipients. METHODS: The Prophylactic Epinephrine for the Prevention of Transbronchial Lung Biopsy-related Bleeding in Lung Transplant Recipients study was a 2-center, randomized, double blind, placebo-controlled clinical trial. Participants undergoing transbronchial lung biopsy were randomized to receive 1:10,000-diluted topical epinephrine vs saline placebo administered prophylactically into the target segmental airway. Bleeding was graded based on a clinical severity scale. The primary efficacy outcome was incidence of severe or very severe hemorrhage. The primary safety outcome was a composite of 3-hours all-cause mortality and an acute cardiovascular event. RESULTS: A total of 66 lung transplantation recipients underwent 100 bronchoscopies during the study period. The primary outcome of severe or very severe hemorrhage occurred in 4 cases (8%) in the prophylactic epinephrine group and in 13 cases (24%) in the control group (p = 0.04). The composite primary safety outcome did not occur in any of the study groups. CONCLUSIONS: In lung transplantation recipients undergoing transbronchial lung biopsy, prophylactic administration of 1:10,000-diluted topical epinephrine into the target segmental airway before biopsy attenuates the incidence of significant endobronchial hemorrhage without conveying a significant cardiovascular risk. (ClinicalTrials.gov identifier: NCT03126968).

Seizure-Induced Hemoptysis in a Pediatric Patient.

Hemoptysis can complicate seizures, albeit rarely. This unfamiliar presentation, reported infrequently in adults, can also affect children. This remains a rare clinical entity in pediatrics and we report one such case and its association with sterol carrier protein (SCP) gene mutation. We present a case of a 16-year-old male with recurrent episodes of hemoptysis following seizures. The diagnostic workup for etiology of the hemoptysis was unrevealing and he was ultimately treated for neurogenic pulmonary edema as a diagnosis of exclusion. He achieved complete resolution with supportive care and diuretics. Our case report describes the clinical and radiological presentation and overall management of post-ictal pulmonary hemorrhage and edema in a pediatric patient. In addition, it reports a new finding of possible association with sterol carrier protein (SCP2) carrier status. It also highlights a rare but potentially life-threatening consequence of inadequate seizure control in pediatric patients.

A Retrospective Analysis of Respiratory Complications under General Anesthesia during EBUS-TBNA.

Background: EBUS-TBNA is an established technique for diagnostically sampling intrathoracic masses and lymph nodes. While the procedure is commonly conducted under general anesthesia (GA), little is known regarding the association between anesthetic management and perioperative respiratory complications. Here, we aim to evaluate this association among patients presenting for EBUS-TBNA. Methods: 586 patients receiving GA for EBUS-TBNA between 2012 and 2018 were retrospectively evaluated. The primary endpoint was the occurrence of perioperative respiratory complications and the secondary endpoint was procedure end to OR exit time (minutes). Respiratory complications were defined as episodes of severe (SpO2 <85%) or prolonged (SpO2<90% for >5 min) hypoxemia, bronchospasm, and postoperative ventilation that could not be directly attributed to procedural invasiveness. Results: Among all patients, 79 (13.5%) had respiratory complications. Four patient characteristics were associated with respiratory complications: home oxygen use (OR 2.39; 95% CI 1.26-4.45; P = 0.007), pre-existing respiratory disease (OR 2.01; CI 1.21-3.29; P = 0.005), ASA class (P = 0.03), and albuterol administration intra-operatively (OR 2.22; CI 1.23-3.92; P = 0.007). No anesthetic factors were found to be statistically significant. Procedures with respiratory complications had a longer duration (mean time 88.7 min vs. 111.8 min; P = 0.00009), prolonged time to extubation (mean time 11.9 min vs. 14.2 min; P = 0.039), and stayed in the room longer after extubation (mean time 18.4 min vs. 23.1 min; P = 0.0016). When comparing types of GA, there were no significant differences between volatile anesthetics versus TIVA (12.7% vs. 14.6%, P = 0.54). Conclusions: Pre-existing patient characteristics, as opposed to anesthetic factors, are associated with respiratory complications during EBUS-TBNA.

A Multicenter Study Assessing Interventional Pulmonary Fellow Competency in Electromagnetic Navigation Bronchoscopy.

Background: Current medical society guidelines recommend a procedural number for obtaining electromagnetic navigational bronchoscopy (ENB) competency and for institutional volume for training. Objective: To assess learning curves and estimate the number of ENB procedures for interventional pulmonology (IP) fellows to reach competency. Methods: We conducted a prospective multicenter study of IP fellows in the United States learning ENB. A tool previously validated in a similar population was used to assess IP fellows by their local faculty and two blinded independent reviewers using virtual recording of the procedure. Competency was determined by performing three consecutive procedures with a competency score on the assessment tool. Procedural time, faculty global rating scale, and periprocedural complications were also recorded. Results: A total of 184 ENB procedures were available for review with assessment of 26 IP fellows at 16 medical centers. There was a high correlation between the two blinded independent observers (rho = 0.8776). There was substantial agreement for determination of procedural competency between the faculty assessment and blinded reviewers (kappa = 0.7074; confidence interval, 0.5667-0.8482). The number of procedures for reaching competency for ENB bronchoscopy was determined (median, 4; mean, 5; standard deviation, 3.83). There was a wide variation in the number of procedures to reach competency, ranging from 2 to 15 procedures. There were six periprocedural complications reported, four (one pneumomediastinum, three pneumothorax) of which occurred before reaching competence and two pneumothoraces after achieving competence. Conclusion: There is a wide variation in acquiring competency for ENB among IP fellows. Virtual competency assessment has a potential role but needs further studies.