Novel Bronchoscopic Management of Bronchopleural Fistula Following Pneumonectomy.

Bronchopleural fistula (BPF) is a rare but significant cause of morbidity and mortality in cancer patients undergoing surgical lung resection. The mainstay of treatment for BPF is revision of surgical stump. We describe a case of persistent bronchopleural fistula treated with a novel combination of argon plasma coagulation and fibrin glue.

Needle-based confocal laser endomicroscopy for real-time granuloma detection.

BACKGROUND AND OBJECTIVE: Needle-based confocal laser endomicroscopy (nCLE) allows real-time microscopic imaging at the needle tip. nCLE malignancy criteria are used for tool-in-lesion confirmation during bronchoscopic lung nodule analysis. However, to date, nCLE criteria for granulomas are lacking. The aim was to identify and validate nCLE granuloma criteria and assess if blinded raters can distinguish malignant from granulomatous nCLE videos. METHODS: In patients with suspected sarcoidosis, nCLE-imaging of mediastinal lymph nodes was performed during endoscopic ultrasound procedures, followed by needle aspiration. nCLE granuloma criteria were identified by comparison with pathology and final diagnoses. Additionally, nCLE-videos of granulomatous lung nodules part of prospective trials and clinical care were compared to the proposed nCLE granuloma criteria. Blinded raters validated nCLE videos of sarcoid and reactive mediastinal lymph nodes and malignant and granulomatous lung nodules twice. RESULTS: Granuloma criteria were identified (brighter-toned, homogeneous and well-demarcated lesions) based on nCLE-imaging in 14 sarcoidosis patients. Raters evaluated 26 nCLE-videos obtained in lymph nodes (n = 15 sarcoidosis; n = 11 reactive and total of 260 ratings). Granuloma criteria were recognized with 88% accuracy. The inter-observer (κ = 0.63, 95% CI 0.54-0.72) and intra-observer reliability (κ = 0.70 ± 0.06) were substantial. Based on 12 nCLE-videos obtained in lung nodules (n = 4 granulomas, n = 6 malignancy, n = 2 malignancy + granulomas and total of 120 ratings) granuloma and malignancy criteria were recognized with 92% and 75% accuracy. CONCLUSION: nCLE imaging facilitates real-time granuloma visualization. Blinded raters accurately and consistently recognized granulomas on nCLE-imaging and distinguished nCLE granuloma criteria from malignancy. Our data show the potential of nCLE as a real-time bronchoscopic guidance tool for lung nodule analysis.

Robotic bronchoscopic needle-based confocal laser endomicroscopy to diagnose peripheral lung nodules.

BACKGROUND AND OBJECTIVE: Robotic bronchoscopy has demonstrated high navigational success in small peripheral lung nodules but the diagnostic yield is discrepantly lower. Needle based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging at the needle tip. We aim to assess feasibility, safety and needle repositioning based on real-time nCLE-guidance during robotic bronchoscopy in small peripheral lung nodules. METHODS: Patients with suspected peripheral lung cancer underwent fluoroscopy and radial EBUS assisted robotic bronchoscopy. After radial EBUS nodule identification, nCLE-imaging of the target area was performed. nCLE-malignancy and airway/lung parenchyma criteria were used to identify the optimal sampling location. In case airway was visualized, repositioning of the biopsy needle was performed. After nCLE tool-in-nodule confirmation, needle passes and biopsies were performed at the same location. MEASUREMENTS AND MAIN RESULTS: Twenty patients were included (final diagnosis n = 17 (lung) cancer) with a median lung nodule size of 14.5 mm (range 8-28 mm). No complications occurred. In 19/20 patients, good quality nCLE-videos were obtained. In 9 patients (45%), real-time nCLE-imaging revealed inadequate positioning of the needle and repositioning was performed. After repositioning, nCLE-imaging provided tool-in-nodule-confirmation in 19/20 patients. Subsequent ROSE demonstrated representative material in 9/20 patients (45%) and overall diagnostic yield was 80% (16/20). Of the three patients with malignant nCLE-imaging but inadequate pathology, two were diagnosed with malignancy during follow-up. CONCLUSION: Robotic bronchoscopic nCLE-imaging is feasible and safe. nCLE-imaging in small, difficult-to-access lung nodules provided additional real-time feedback on the correct needle positioning with the potential to optimize the sampling location and diagnostic yield.

Nodules, Navigation, Robotic Bronchoscopy, and Real-Time Imaging.

The process of detection, diagnosis, and management of lung nodules is complex due to the heterogeneity of lung pathology and a relatively low malignancy rate. Technological advances in bronchoscopy have led to less-invasive diagnostic procedures and advances in imaging technology have helped to improve nodule localization and biopsy confirmation. Future research is required to determine which modality or combination of complimentary modalities is best suited for safe, accurate, and cost-effective management of lung nodules.

Robotic Navigational Bronchoscopy Combined with Needle-Based Confocal Laser Endomicroscopy: Case Report of a Novel Approach to Diagnose Small Lung Nodules.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Advancements in navigational bronchoscopy have shown encouraging results but the diagnostic yield of small lung nodules by bronchoscopic techniques is still below that of transthoracic needle aspiration. The development of robotic bronchoscopy has demonstrated a significantly improved navigational success but the diagnostic yield is regularly limited by near-miss of the target nodule. Needle-based confocal laser endomicroscopy is a novel imaging technique that allows for the real-time visualization of individual cells and structures with microscopic resolution at the tip of the needle. We present the first reported case of confocal laser endomicroscopy guided robotic bronchoscopy for the real-time diagnosis of a small, partially cystic lung nodule.

Prospective randomized trial to compare the safety, diagnostic yield and utility of 22-gauge and 19-gauge endobronchial ultrasound transbronchial needle aspirates and processing technique by cytology and histopathology.

INTRODUCTION: Endobronchial ultrasound (EBUS)-guided transbronchial needle aspirate (TBNA) is a widely used method of minimally invasive lymph node sampling. The benefit of processing samples by cytologic methods versus "core biopsy" is unclear. It is unknown if safety or diagnostic yield varies by needle gauge. MATERIALS AND METHODS: Between June 2018 and July 2019, 40 patients (56 lesions) undergoing EBUS TBNA lymph node evaluation were enrolled in this single-center prospective trial. Patients were chosen by permuted block randomization to undergo EBUS TBNA starting with 22-gauge (22g) or 19-gauge (19g) needles. Separate samples were sent for processing by cytologic methods and histopathology. Surgical pathologists and cytopathologists were blinded to needle size. The primary endpoint was diagnostic yield. Secondary endpoints compared specimen adequacy by rapid onsite evaluation (ROSE), sample adequacy for molecular testing, sample quality, and safety. RESULTS: Diagnostic yield for histopathologic examination was 87.5% and 83.9% for 19g and 22g respectively (P = 0.625). There was no significant difference in diagnostic yield by cytologic examination based on needle size. There was no significant difference in slide quality. Molecular adequacy for core-biopsy was 77% and 80% for 22g and 19g needles, respectively. Molecular adequacy for cytology cell block was 77% and 80% for 22g and 19g needles, respectively. There were no significant procedural complications. CONCLUSION: Both the 22g and 19g EBUS TBNA needles provided a similar diagnostic yield and clinical utility for ancillary testing. Processing techniques by cytologic methods or "core biopsy" showed no significant impact in diagnostic yield or utility of molecular testing.

Safety of Laser and Thermal Therapy During Rigid Bronchoscopy Using Manual Hand Jet Ventilation.

INTRODUCTION: Thermal ablative therapies (laser, radiofrequency ablation, electrocautery, argon plasma coagulation) are often used during rigid bronchoscopy for the treatment of central airway obstructions (CAO). An airway fire is a feared complication that can occur during endobronchial thermal ablation. MATERIALS AND METHODS: This was a single-center, retrospective, observational study. A total of 175 patients were reviewed undergoing rigid bronchoscopy in the operating room and bronchoscopy suite requiring manual hand jet ventilation and thermal therapy between September 2014 and September 2018. The study objective was to determine the safety of manual hand jet ventilation during endobronchial thermal therapies with rigid bronchoscopy. RESULTS: Over a five-year period, 175 patients underwent endobronchial thermal therapy during rigid bronchoscopy with manual hand jet ventilation for the treatment CAOs. Immediately prior to thermal therapy activation, jet ventilation was paused. No incidences (0/175) of airway fires occurred despite immediate delivery of thermal energy following a jet ventilation hold. CONCLUSIONS: Results of our study show that performing thermal ablative therapy during rigid bronchoscopy with jet ventilation using a breath-hold technique is safe.

In vivo assessment of changes to canine airway smooth muscle following bronchial thermoplasty with OR-OCT.

The inability to assess and measure changes to the airway smooth muscle (ASM) in vivo is a major challenge to evaluating asthma and its clinical outcomes. Bronchial thermoplasty (BT) is a therapy for asthma that aims to reduce the severity of excessive bronchoconstriction by ablating ASM. Although multiple long-term clinical studies of BT have produced encouraging results, the outcomes of BT treatment in practice have been variable, and questions remain regarding the selection of patients. Previously, we have demonstrated an imaging platform called orientation-resolved optical coherence tomography that can assess ASM endoscopically using an imaging catheter compatible with bronchoscopy. In this work, we present results obtained from a longitudinal BT study performed using a canine model (n = 8) and with the goal of investigating the use of orientation-resolved optical coherence tomography (OR-OCT) for measuring the effects of BT on ASM. We demonstrate that we are capable of accurately assessing ASM both before and in the weeks following the BT procedure using blinded matching to histological samples stained with Masson's trichrome (P < 0.0001, r2 = 0.79). Analysis of volumetric ASM distributions revealed significant decreases in ASM in treated airways (average cross-sectional ASM area: 0.245 ± 0.145 mm2 pre-BT and 0.166 ± 0.112 mm2 6 wk following BT). These results demonstrate that OR-OCT can provide clinicians with the feedback necessary to better evaluate ASM and its response to BT, and may potentially play an important role in phenotyping asthma and predicting which patients are most likely to respond to BT treatment.NEW & NOTEWORTHY The inability to assess ASM in vivo is a significant hurdle in advancing our understanding of airway diseases such as asthma, as well as evaluating potential treatments and therapies. In this study, we demonstrate that endoscopic OR-OCT can be used to accurately measure changes to ASM structure following BT. Our results demonstrate how this technology could occupy an important role in asthma treatments targeting ASM.

Treatment of Recurrent Respiratory Papillomatosis: Case Series and Review of Technique.

Adult Recurrent Respiratory Papillomatosis (RRP) is a rare disease caused by the human papilloma virus in which papilloma grows from the respiratory epithelium. Patients can suffer from significant respiratory distress secondary to tracheal or bronchial obstruction by papilloma and the mainstay of treatment is bronchoscopic debridement. There are a variety of techniques to resect the endoluminal tumor, including CO2 or YAG laser, argon plasma coagulation, microdebrider and cold forceps. There have been documented cases of healthcare workers contracting HPV after exposure to surgical smoke during ablation of papilloma and measures should be taken to avoid inhalation of the smoke plume. For proximal lesions that are accessible to a microdebrider, this appears to be a safe and effective technique that does not generate heat or surgical smoke. The rate of recurrence of adult-onset respiratory papilloma after initial debulking varies and adjuvant medical therapy including intralesional cidofovir, interferon, or oral indole-3-carbinol has been used to slow recurrence. Malignant transformation of adult-onset RRP to squamous cell carcinoma has been reported to occur in 3-7% of cases. Therefore, ongoing surveillance is needed to monitor for disease progression and malignant transformation. Here we describe three patients whose tracheal disease was managed with an Nd-YAG laser and microdebrider. One patient was treated with adjuvant systemic indole-3 carbinol and another was maintained with serial debridement only. The third patient presented with obstructing squamous cell carcinoma of the trachea and was treated with definitive chemoradiation. She presented with a new left mainstem lesion 6 months later which was diagnosed as RRP. She was started on indole-3 carbinol, but unfortunately it transformed to squamous cell carcinoma 8 months later.

Robot-assisted bronchoscopy for pulmonary lesion diagnosis: results from the initial multicenter experience.

BACKGROUND: The Robotic Endoscopic System (Auris Health, Inc., Redwood City, CA) has the potential to overcome several limitations of contemporary guided-bronchoscopic technologies for the diagnosis of lung lesions. Our objective is to report on the initial post-marketing feasibility, safety and diagnostic yield of this technology. METHODS: We retrospectively reviewed data on consecutive cases in which robot-assisted bronchoscopy was used to sample lung lesions at four centers in the US (academic and community) from June 15th, 2018 to December 15th, 2018. RESULTS: One hundred and sixty-seven lesions in 165 patients were included in the analysis, with an average follow-up of 185 ± 55 days. The average size of target lesions was 25.0 ± 15.0 mm. Seventy-one percent were located in the peripheral third of the lung. Pneumothorax and airway bleeding occurred in 3.6 and 2.4% cases, respectively. Navigation was successful in 88.6% of cases. Tissue samples were successfully obtained in 98.8%. The diagnostic yield estimates ranged from 69.1 to 77% assuming the cases of biopsy-proven inflammation without any follow-up information (N = 13) were non-diagnostic and diagnostic, respectively. The yield was 81.5, 71.7 and 26.9% for concentric, eccentric and absent r-EBUS views, respectively. Diagnostic yield was not affected by lesion size, density, lobar location or centrality. CONCLUSIONS: RAB implementation in community and academic centers is safe and feasible, with an initial diagnostic yield of 69.1-77% in patients with lung lesions that require diagnostic bronchoscopy. Comparative trials with the existing bronchoscopic technologies are needed to determine cost-effectiveness of this technology.

OSA and pulmonary hypertension: time for a new look.

OSA is a common yet underdiagnosed disorder encountered in everyday practice. The disease is a unique physiologic stressor that contributes to the development or progression of many other disorders, particularly cardiovascular conditions. The pulmonary circulation is specifically affected by the intermittent hypoxic apneas associated with OSA. The general consensus has been that OSA is associated with pulmonary hypertension (PH), but only in a minority of OSA patients and generally of a mild degree. Consequently, there has been no sense of urgency to screen for either condition when evaluating the other. In this review, we explore available evidence describing the interaction between OSA and PH and seek to better understand underlying pathophysiology. We describe certain groups of patients who have a particular preponderance of OSA and PH. Failure to recognize the mutual additive effects of these disorders can lead to suboptimal patient outcomes. Among patients with PH and OSA, CPAP, the mainstay treatment for OSA, may ameliorate pulmonary pressure elevations, but has not been studied adequately. Conversely, among patients with OSA, PH significantly limits functional capacity and potentially shortens survival; yet, there is no routine screening for PH in patients with OSA. We think it is time to study the interaction between OSA and PH more carefully to identify high-risk subgroups. These would be screened for the presence of combined disorders, facilitating earlier institution of therapy and improving outcomes.

Palladium-catalyzed preparation of Weinreb amides from boronic acids and N-methyl-N-methoxycarbamoyl chloride.

A simple protocol for the synthesis of Weinreb benzamides and alpha,beta-unsaturated Weinreb amides through a palladium-catalyzed cross-coupling reaction between organoboronic acids and N-methoxy-N-methylcarbamoyl chloride has been developed. The method is also applicable to the use of potassium organotrifluoroborates.

Ca2+ sparks and cellular distribution of ryanodine receptors in developing cardiomyocytes from rat.

Although abundant ryanodine receptors (RyRs) exist in cardiomyocytes from newborn (NB) rat and despite the maturity of their single-channel properties, the RyR contribution to excitation-contraction (E-C) coupling is minimal. Immature arrangement of RyRs in the Ca(2+) release site of the sarcoplasmic reticulum and/or distant RyRs location from the sarcolemmal Ca(2+) signal could explain this quiescence. Consequently, Ca(2+) sparks and their cellular distribution were studied in NB myocytes and correlated with the formation of dyads and transverse (T) tubules. Ca(2+) sparks were recorded in fluo-4-loaded intact ventricular myocytes acutely dissociated from adult and NB rats (0-9 days old). Sparks were defined/compared in the center and periphery of the cell. Co-immunolocalization of RyRs with dihydropyridine receptors (DHPR) was used to estimate dyad formation, while the development of T tubules was studied using di-8-ANEPPS and diIC12. Our results indicate that in NB cells, Ca(2+) sparks exhibited lower amplitude (1.7+/-0.5 vs. 3.6+/-1.7 F/F(0)), shorter duration (47+/-3.2 vs. 54.1+/-3 ms), and larger width (1.7+/-0.8 vs. 1.2+/-0.4 microm) than in adult. Although no significant changes were observed in the overall frequency, central sparks increased from approximately 60% at 0-1 day to 82% at 7-9 days. While immunolocalization revealed many central release sites at 7-8 days, fluorescence labeling of the plasma membrane showed less abundant internal T tubules. This could imply that although during the first week, release sites emerge forming dyads with DHPR-containing T tubules; some of these T tubules may not be connected to the surface, explaining the RyR quiescence during E-C coupling in NB.

A new chemical tool for exploring the physiological function of the PDE2 isozyme.

Oxindole (2) is a potent and selective PDE2 inhibitor with a favorable ADME, physiochemical and pharmacokinetic profile to allow for use as a chemical tool in elucidating the physiological role of PDE2.