Background Diagnostic evaluation of patients with diffuse parenchymal lung disease (DPLD) is best achieved by a multidisciplinary team correlating clinical, radiological, and pathologic features. ...Surgical lung biopsy remains the gold standard for histopathologic diagnosis of idiopathic interstitial pneumonias. Emerging data suggest an increasing role for transbronchial cryobiopsy (TBC) in DPLD evaluation. We describe our experience with TBC in patients with DPLD. Methods We retrospectively reviewed medical records of patients with radiographic features of DPLD who underwent TBC at Mayo Clinic in Rochester, Minnesota from June 2013 to September 2015. Results Seventy-four patients (33 women 45%) with a mean age of 63 years (SD, 13.8) were included. The mean maximal diameter of the samples was 9.2 mm (range, 2-20 mm SD, 3.9). The median number of samples per procedure was three (range, one to seven). Diagnostic yield was 51% (38 of 74 specimens). The most frequent histopathologic patterns were granulomatous inflammation (12 patients) and organizing pneumonia (OP) (11 patients), resulting in the final diagnoses of hypersensitivity pneumonitis (six patients), cryptogenic OP (six patients), connective tissue disease-associated OP (three patients), drug toxicity (three patients), infection-related OP (two patients), sarcoidosis (two patients), and aspiration (one patient). Other histopathologic patterns included respiratory bronchiolitis (three patients), acute fibrinous and organizing pneumonia (two patients), desquamative interstitial pneumonia (1 patient), diffuse alveolar damage (one patient), pulmonary alveolar proteinosis (one patient), amyloidosis (one patient), eosinophilic pneumonia (one patient), necrotizing vasculitis (one patient), bronchiolitis with food particles (one patient), and malignancy (three patients). Pneumothorax developed in one patient (1.4%), and bleeding occurred in 16 patients (22%). Conclusions Our single-center cohort demonstrated a 51% diagnostic yield from TBC; the rates of pneumothorax and bleeding were 1.4% and 22%, respectively. The optimal use of TBC needs to be determined.
In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from ...cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor.
We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV.
Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively.
A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1.
Diagnostic evaluation of patients with diffuse parenchymal lung disease (DPLD) is best achieved by a multidisciplinary team correlating clinical, radiological, and pathologic features. Surgical lung ...biopsy remains the gold standard for histopathologic diagnosis of idiopathic interstitial pneumonias. Emerging data suggest an increasing role for transbronchial cryobiopsy (TBC) in DPLD evaluation. We describe our experience with TBC in patients with DPLD.
We retrospectively reviewed medical records of patients with radiographic features of DPLD who underwent TBC at Mayo Clinic in Rochester, Minnesota from June 2013 to September 2015.
Seventy-four patients (33 women 45%) with a mean age of 63 years (SD, 13.8) were included. The mean maximal diameter of the samples was 9.2 mm (range, 2-20 mm SD, 3.9). The median number of samples per procedure was three (range, one to seven). Diagnostic yield was 51% (38 of 74 specimens). The most frequent histopathologic patterns were granulomatous inflammation (12 patients) and organizing pneumonia (OP) (11 patients), resulting in the final diagnoses of hypersensitivity pneumonitis (six patients), cryptogenic OP (six patients), connective tissue disease-associated OP (three patients), drug toxicity (three patients), infection-related OP (two patients), sarcoidosis (two patients), and aspiration (one patient). Other histopathologic patterns included respiratory bronchiolitis (three patients), acute fibrinous and organizing pneumonia (two patients), desquamative interstitial pneumonia (1 patient), diffuse alveolar damage (one patient), pulmonary alveolar proteinosis (one patient), amyloidosis (one patient), eosinophilic pneumonia (one patient), necrotizing vasculitis (one patient), bronchiolitis with food particles (one patient), and malignancy (three patients). Pneumothorax developed in one patient (1.4%), and bleeding occurred in 16 patients (22%).
Our single-center cohort demonstrated a 51% diagnostic yield from TBC; the rates of pneumothorax and bleeding were 1.4% and 22%, respectively. The optimal use of TBC needs to be determined.
The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of ...miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p < 0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p < 0.001; HR = 3.513 (CI: 1.818–6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p = 0.014; HR = 2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients' smoking history, and contributes to miR-486-5p repression.
•MiR-486-5p is commonly repressed in NSCLC but the mechanism is unclear.•MiR-486-5p is located within ANK1 intron and is co-expressed with its host gene.•Aberrant methylation of ANK1 promoter represses both ANK1 and miR-486-5p in NSCLC.•ANK1 is primarily methylated in lung adenocarcinoma from smokers.•ANK1/miR-486-5p co-repression contributes to smoking induced lung adenocarcinoma.
Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue ...macrophages by defining the impact of the Wnt/β-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of β-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, β-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted β-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This β-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by β-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.
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•Wnt-β-catenin signaling modulates AM inflammation and self-renewal through HIF-1α•AM β-catenin and HIF-1α signaling promotes host diseases and inhibits lung recovery•HIF-1α activity separates AM inflammatory activity from proliferative potential in vivo•β-Catenin and HIF-1α signaling may contribute to severe disease development in COVID-19
Zhu et al. examine the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt-β-catenin pathway, a regulator of self-renewal, in alveolar macrophages (AMs). Their findings reveal a β-catenin-HIF-1α signaling axis that promotes inflammatory AMs at the expense of proliferation. This axis is conserved in human AMs, with implications for the treatment of severe respiratory diseases.
SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, ...particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.
Diagnosis and treatment of peripheral pulmonary lesions (PPLs) currently require at least 2 procedures. An all-in-1 approach would require diagnosing malignancy with preliminary cytology results. ...This study investigated the concordance between preliminary cytology and final pathology results in biopsies of PPLs obtained by shape-sensing robotic-assisted bronchoscopy (ssRAB).
This study was a retrospective, consecutive, single-arm, single-center study of 110 ssRABs for PPLs. Concordance was defined as agreement between preliminary cytology and final pathology results. Accuracy, sensitivity, specificity, positive and negative predictive values, and safety outcomes were examined.
The concordance was 89% for needle biopsies, 85% for forceps biopsies, and 92% overall, with substantial agreement. There was no significant association of concordance with patients’ demographics or lesion characteristics. Preliminary cytology resulted in a malignant diagnosis in 70%, a nonmalignant diagnosis in 4%, and a nondiagnostic result in 26%, with accuracy of 86% and sensitivity of 84%. The total complication rate was 3.6%, with a pneumothorax rate of 1.8%.
This study compared the concordance of preliminary pathology results with final pathology results for ssRAB biopsies in PPLs. The results showed that preliminary samples have a high concordance with final pathology results and may enable management of PPLs with a single anesthetic procedure including biopsy, staging, and treatment.
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Objectives/Hypothesis
Idiopathic subglottic stenosis (ISS) is a rare type of airway stenosis of unclear etiology. Open resection, while effective, remains a complex surgery and requires a hospital ...stay. Endoscopic management is often preferred but has historically been associated with a high recurrence rate. We aimed to analyze our experience, consisting of a standardized endoscopic approach combined with an empiric medical treatment.
Study Design
Retrospective cohort study.
Methods
All patients with ISS managed with standardized endoscopic treatment at our institution between 1987 and 2012 were identified, and their electronic medical records were reviewed. The treatment consisted of CO2 laser resection without dilatation and local infiltration with steroids and application of mitomycin C. Patients were also treated with antireflux medications, inhaled corticosteroids, and occasionally trimethoprim‐sulfamethoxazole. The influence of medical management on annual recurrence rate was analyzed using negative binomial logistic regression.
Results
A total of 110 patients treated with standardized endoscopic management were included in our analysis. The procedure was well tolerated by all patients without complications. Recurrences were observed in approximately 60% of patients at 5 years. There was a trend suggesting an association between aggressive medical treatment and a reduction in the rate of recurrence/person/year (relative risk = 0.52, P = 0.051).
Conclusion
A standardized endoscopic management of ISS consisting of CO2 laser vaporization of the fibrotic scar appears effective in symptom control, with 40% of patients not requiring retreatment in the follow‐up period, and with recurrence noted in a majority of patients. Aggressive medical treatment may have a role, but further prospective studies are required to confirm these findings.
Level of Evidence
4. Laryngoscope, 124:498–503, 2014
Idiopathic subglottic stenosis (iSGS) is a localized airway disease that almost exclusively affects females. Understanding the molecular mechanisms involved may provide insights leading to ...therapeutic interventions. Next-generation sequencing was performed on tissue sections from patients with iSGS (n = 22), antineutrophil cytoplasmic antibody–associated vasculitis (AAV; n = 5), and matched controls (n = 9) to explore candidate genes and mechanisms of disease. Gene expression changes were validated, and selected markers were identified by immunofluorescence staining. Epithelial-mesenchymal transition (EMT) and leukocyte extravasation pathways were the biological mechanisms most relevant to iSGS pathogenesis. Alternatively activated macrophages (M2) were abundant in the subepithelium and perisubmucosal glands of the airway in iSGS and AAV. Increased expression of the mesenchymal marker S100A4 and decreased expression of the epithelial marker epithelial cell adhesion molecule (EPCAM) further supported a role for EMT, but to different extents, in iSGS and antineutrophil cytoplasmic antibody–associated subglottic stenosis. In patients with iSGS, high expression of prostate transmembrane protein, androgen induced 1 (PMEPA1), an EMT regulator, was associated with a shorter recurrence interval (25 versus 116 months: hazard ratio = 4.16; P = 0.041; 95% CI, 1.056–15.60). Thus, EMT is a key pathogenetic mechanism of subglottic stenosis in iSGS and AAV. M2 macrophages contribute to the pathogenesis of both diseases, suggesting a shared profibrotic mechanism, and PMEPA1 may be a biomarker for predicting disease recurrence in iSGS.
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