A rare case of straight-back syndrome causing airway obstruction.

Straight-back syndrome is a rare congenital condition involving the loss of the normal dorsal curvature of the upper thoracic spine. This leads to flattening of the upper thoracic cavity, resulting in compression of the underlying vasculature and airways. In this case report, we discuss the management of an 18-year-old male with straight-back syndrome who was referred to our interventional pulmonary clinic for further management of his stridor and apneic events. A trial of airway stenting was done which resolved the patient's respiratory symptoms. Definitive surgical correction was not applicable due to other significant medical conditions, but tracheostomy provided a sustainable alternative treatment. Tracheostomy tube placement and airway stenting are reasonable alternatives to surgery for patients who experience airway obstruction due to straight-back syndrome. Stent placement may also relieve respiratory symptoms but is associated with a higher rate of complications.

Exhaled breath condensate contains extracellular vesicles (EVs) that carry miRNA cargos of lung tissue origin that can be selectively purified and analyzed.

Lung diseases, including lung cancer, are rising causes of global mortality. Despite novel imaging technologies and the development of biomarker assays, the detection of lung cancer remains a significant challenge. However, the lung communicates directly with the external environment and releases aerosolized droplets during normal tidal respiration, which can be collected, stored and analzsed as exhaled breath condensate (EBC). A few studies have suggested that EBC contains extracellular vesicles (EVs) whose microRNA (miRNA) cargos may be useful for evaluating different lung conditions, but the cellular origin of these EVs remains unknown. In this study, we used nanoparticle tracking, transmission electron microscopy, Western blot analyses and super resolution nanoimaging (ONi) to detect and validate the identity of exhaled EVs (exh-EVs). Using our customizable antibody-purification assay, EV-CATCHER, we initially determined that exh-EVs can be selectively enriched from EBC using antibodies against three tetraspanins (CD9, CD63 and CD81). Using ONi we also revealed that some exh-EVs harbour lung-specific proteins expressed in bronchiolar Clara cells (Clara Cell Secretory Protein [CCSP]) and Alveolar Type II cells (Surfactant protein C [SFTPC]). When conducting miRNA next generation sequencing (NGS) of airway samples collected at five different anatomic levels (i.e., mouth rinse, mouth wash, bronchial brush, bronchoalveolar lavage [BAL] and EBC) from 18 subjects, we determined that miRNA profiles of exh-EVs clustered closely to those of BAL EVs but not to those of other airway samples. When comparing the miRNA profiles of EVs purified from matched BAL and EBC samples with our three tetraspanins EV-CATCHER assay, we captured significant miRNA expression differences associated with smoking, asthma and lung tumor status of our subjects, which were also reproducibly detected in EVs selectively purified with our anti-CCSP/SFTPC EV-CATCHER assay from the same samples, but that confirmed their lung tissue origin. Our findings underscore that enriching exh-EV subpopulations from EBC allows non-invasive sampling of EVs produced by lung tissues.

Bronchoscopic deployment and implantation of Diffusing alpha-emitters Radiation Therapy into the lung and mediastinum for treatment of lung cancer: a pre-clinical safety and feasibility study.

Background: Radiotherapy is a standard treatment modality in cancer therapy, particularly for lung cancer. Diffusing alpha-emitters Radiation Therapy sources (hereafter, "Alpha DaRTs") are fixed with Ra-244 (half-life =3.6 days) that releases alpha-emitting atoms into the tumor tissue to an effective range of a few millimeters. Methods: The feasibility, usability, and safety of Alpha DaRTs deployment and implantation via bronchoscopy into the lung parenchyma and mediastinum in a big animal model of healthy swine was studied in two phases: (I) inert and (II) active Alpha DaRTs deployment. The Alpha DaRTs were inserted in both individual and cluster patterns based on a predefined plan. Swine health was monitored throughout the study. The usability of bronchoscopic deployment and implantation was evaluated using a user questionnaire. The movement and migration of the Alpha DaRTs were assessed. Necropsy was performed, and lungs were evaluated via gross pathology and histopathology. Results: A total of 158 Alpha DaRTs were inserted successfully in the lung parenchyma and mediastinum of five swine in two phases. It was possible to deliver and place the Alpha DaRTs in clusters of no more than 4 mm distance between the Alpha DaRTs. No adverse event or change in the health and general condition of animals was observed. Hematologic evaluation did not show any clinically significant abnormality related to the Alpha DaRTs. Histopathology demonstrated local mild inflammatory changes, minimal fibrosis, and dystrophic mineralization with giant cells. Minimal movement and no migration of Alpha DaRTs were observed. Conclusions: Bronchoscopic deployment of Alpha DaRTs in the lung parenchyma and mediastinum of the porcine animal is feasible, precise, and safe.

Inter- and intra-observer variability of radial-endobronchial ultrasound image interpretation for peripheral pulmonary lesions.

Background: Radial probe endobronchial ultrasound (R-EBUS) is often utilized in guided bronchoscopy for the diagnosis of peripheral pulmonary lesions. R-EBUS probe positioning has been shown to correlate with diagnostic yield, but overall diagnostic yield with this technology has been inconsistent across the published literature. Currently there is no standardization for R-EBUS image interpretation, which may result in variability in grading concentricity of lesions and subsequently procedure performance. This was a survey-based study evaluating variability among practicing pulmonologists in R-EBUS image interpretation. Methods: R-EBUS images from peripheral bronchoscopy cases were sent to 10 practicing Interventional Pulmonologists at two different time points (baseline and 3 months). Participants were asked to grade the images as concentric, eccentric, or no image. Cohen's Kappa-coefficient was calculated for inter- and intra-observer variability. Results: A total of 100 R-EBUS images were included in the survey. There was 100% participation with complete survey responses from all 10 participants. Overall kappa-statistic for inter-observer variability for Survey 1 and 2 was 0.496 and 0.477 respectively. Overall kappa-statistic for intra-observer variability between the two surveys was 0.803. Conclusions: There is significant variability between pulmonologists when characterizing R-EBUS images. However, there is strong intra-rater agreement from each participant between surveys. A standardized approach and grading system for radial EBUS patterns may improve inter-observer variability in order to optimize our clinical use and research efforts in the field.

Digital Tomosynthesis: Review of Current Literature and Its Impact on Diagnostic Bronchoscopy.

Bronchoscopy has garnered increased popularity in the biopsy of peripheral lung lesions. The development of navigational guided bronchoscopy systems along with radial endobronchial ultrasound (REBUS) allows clinicians to access and sample peripheral lesions. The development of robotic bronchoscopy improved localization of targets and diagnostic accuracy. Despite such technological advancements, published diagnostic yield remains lower compared to computer tomography (CT)-guided biopsy. The discordance between the real-time location of peripheral lesions and anticipated location from preplanned navigation software is often cited as the main variable impacting accurate biopsies. The utilization of cone beam CT (CBCT) with navigation-based bronchoscopy has been shown to assist with localizing targets in real-time and improving biopsy success. The resources, costs, and radiation associated with CBCT remains a hindrance in its wider adoption. Recently, digital tomosynthesis (DT) platforms have been developed as an alternative for real-time imaging guidance in peripheral lung lesions. In North America, there are several commercial platforms with distinct features and adaptation of DT. Early studies show the potential improvement in peripheral lesion sampling with DT. Despite the results of early observational studies, the true impact of DT-based imaging devices for peripheral lesion sampling cannot be determined without further prospective randomized trials and meta-analyses.

Initial development and testing of an exhaled microRNA detection strategy for lung cancer case-control discrimination.

For detecting field carcinogenesis non-invasively, early technical development and case-control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically "fingerprinted", using paired EBC, upper and lower airway donor sample sets. A clinic-based case-control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case-control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1-2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e-04)); former smokers 2.5% (p = 3.6e-05); early stage 1.2% (p = 9.0e-03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment.

Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking.

Although lung cancer risk among smokers is dependent on smoking dose, it remains unknown if this increased risk reflects an increased rate of somatic mutation accumulation in normal lung cells. Here, we applied single-cell whole-genome sequencing of proximal bronchial basal cells from 33 participants aged between 11 and 86 years with smoking histories varying from never-smoking to 116 pack-years. We found an increase in the frequency of single-nucleotide variants and small insertions and deletions with chronological age in never-smokers, with mutation frequencies significantly elevated among smokers. When plotted against smoking pack-years, mutations followed the linear increase in cancer risk until about 23 pack-years, after which no further increase in mutation frequency was observed, pointing toward individual selection for mutation avoidance. Known lung cancer-defined mutation signatures tracked with both age and smoking. No significant enrichment for somatic mutations in lung cancer driver genes was observed.

Mobile 3D Intraprocedural Fluoroscopy in Combination With Ultrathin Bronchoscopy for Biopsy of Peripheral Lung Nodules.

Despite development of multiple technologies, distinguishing benign from malignant lung nodules when they are still small in size is challenging. A high yield and minimally invasive bronchoscopic technology with low cost for diagnosis of small lung lesions is needed in pulmonary and lung cancer clinical practice. Peripheral airway bronchoscopy using thin and most recently ultrathin bronchoscopes improve visualization of small airways. The novel mobile 2D/3D C-Arm fluoroscopy system is a complementary tool along with radial endobronchial ultrasound in detecting small lung nodules with real-time high-quality multidimensional image confirmation during bronchoscopy. This combined technology can be easily acquired in any bronchoscopy room, and potentially affect lung nodule practice significantly.

Preemptive non-selective bronchial artery angioembolization to reduce recurrence rate of hemoptysis.

BACKGROUND: Massive hemoptysis which is presented in advanced lung diseases is a life-threatening condition. Bronchial artery embolization as a minimally invasive procedure is the treatment of choice either in first or recurrent hemoptysis. This study aimed to assess the early and late efficacy of bronchial angioembolization (BAE) without microcatheter. METHODS: In this prospective cohort study, all patients with hemoptysis who had undergone BAE from August 2018 to March 2019 were included. Angiographic patterns including bleeding sources, number of involved vessels, the underlying etiology, and recurrence rate were evaluated in a one-year follow up. RESULTS: 153 patients were included with mean age of 55 ±16 years. 68% of them were male and 58% had life-threatening massive hemoptysis. Three distinct angiographic patterns were recognized. The culprit bleeding vessel was bronchial in 126 (92%), intercostal in 4 (3%), and both vessels in 7 (5%) of cases (p<0.05). One vessel involvement was seen in 56 patients; however it was observed in 69% of non-cystic fibrosis lobar bronchiectasis patients. In 1, 3 and 12 months follow up, recurrent hemoptysis was reported in 15 (11%), 4 (2.5%), and 24 (15.5%), respectively. In 52% of cases, no abnormal vessels were observed during aorta injection, but culprit bronchial or intercostal arteries were found in selective investigational angiography. CONCLUSION: BAE was successful in the control of hemoptysis and resulted in a low rate of recurrence in different types of lung diseases. This could be due to the embolization of all pathological arteries found during angiography which might have prevented recurrent bleeding.

Use of selective serotonin reuptake inhibitors and outcomes in pulmonary arterial hypertension.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have been suggested to offer therapeutic benefit in patients with pulmonary arterial hypertension (PAH). We conducted two analyses to explore the association between SSRI use and PAH outcomes using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry). METHODS: First, new users (SSRI-naive patients who initiated treatment after enrollment, incident use analysis, n = 220) were matched (1:2) with non-SSRI users (nonusers, n = 440) by enrollment center, sex, date of most recent visit, age, and 6-min walk distance. Second, a cross-sectional design was used to compare nonusers (n = 2,463), high-affinity SSRI users (n = 430), and non-high-affinity SSRI users (n = 125) at enrollment. Mortality and a composite end point defined by events indicative of clinical worsening were evaluated. RESULTS: New users had a higher risk of death (unadjusted hazard ratio [HR], 1.74; 95% CI, 1.19-2.54; P = .004) and were less likely to be free from the composite end point 2 years after enrollment vs nonusers (25.7% vs 43.2%, respectively; P < .001). Similarly, among prevalent SSRI users (patients with a history of SSRI use at enrollment), high-affinity SSRI users were less likely to be free from the composite end point vs nonusers (unadjusted HR, 1.20; 95% CI, 1.07-1.36; P = .003). In both analyses, differences in outcome were maintained after adjustment for clinical variables previously associated with PAH outcomes. CONCLUSIONS: In a large population of patients with PAH, incident SSRI use was associated with increased mortality and a greater risk of clinical worsening, although we could not adjust for all potential confounders.

Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a devastating disease leading to progressive hypoxemia, right ventricular failure, and death. Hypoxia can play a pivotal role in PH etiology, inducing pulmonary vessel constriction and remodeling. These events lead to increased pulmonary vessel wall thickness, elevated vascular resistance and right ventricular hypertrophy. The current study examined the association of the inflammatory cytokine macrophage migration inhibitory factor (MIF) with chronic lung disease and its role in the development of hypoxia-induced PH. We found that plasma MIF in patients with primary PH or PH secondary to interstitial lung disease (ILD) was significantly higher than in the control group (P = 0.004 and 0.007, respectively). MIF involvement with hypoxia-induced fibroblast proliferation was examined in both a human cell-line and primary mouse cells from wild-type (mif⁺/⁺) and MIF-knockout (mif⁻/⁻) mice. In vitro, hypoxia-increased MIF mRNA, extracellular MIF protein accumulation and cell proliferation. Inhibition of MIF inflammatory activity reduced hypoxia-induced cell proliferation. However, hypoxia only increased proliferation of mif⁻/⁻ cells when they were supplemented with media from mif⁺/⁺ cells. This growth increase was suppressed by MIF inhibition. In vivo, chronic exposure of mice to a normobaric atmosphere of 10% oxygen increased lung tissue expression of mRNA encoding MIF and accumulation of MIF in plasma. Inhibition of the MIF inflammatory active site, during hypoxic exposure, significantly reduced pulmonary vascular remodeling, cardiac hypertrophy and right ventricular systolic pressure. The data suggest that MIF plays a critical role in hypoxia-induced PH, and its inhibition may be beneficial in preventing the development and progression of the disease.

The conversion in application of percutaneous coronary intervention following the introduction of drug eluting stents.

In order to determine the changes in the pattern of techniques applied during elective coronary intervention, data from 688 patients prior to Sirolimus. Drug-Eluting Stents (DES) approval was compared to 438 patients who underwent coronary intervention after DES approval. There was increased intervention to higher risk lesions, including smaller vessels and re-stenotic lesions after DES approval. Total number of stents per patient significantly decreased, despite longer stent length per patient or per lesion after DES approval. No significant difference was found in multivessel interventions.