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Empyema necessitans should be suspected in any patient presenting with constitutional symptoms, pleural effusion, and a subcutaneous chest wall mass. Thoracic sonography is a readily available tool, which can expedite diagnosis and timely management.
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Introduction: This study aims to answer the question of whether adding mobile cone-beam computed tomography (mCBCT) imaging to shape-sensing robotic-assisted bronchoscopy (ssRAB) translates into a quantifiable improvement in the tool-lesion relationship. Methods: Data from 102 peripheral lung lesions with ≥2 sequential mCBCT orbital spins and from 436 lesions with 0-1 spins were prospectively captured and retrospectively analysed. The primary outcome was the tool-lesion relationship status across the first and the last mCBCT spins. Secondary outcomes included 1) the change in distance between the tip of the sampling tool and the centre of the lesion between the first and the last spins and 2) the per-lesion diagnostic yield. Results: Compared to lesions requiring 0-1 spins, lesions requiring ≥2 spins were smaller and had unfavourable bronchus sign and intra-operative sonographic view. On the first spin, 54 lesions (53%) were designated as non-tool-in-lesion (non-TIL) while 48 lesions (47%) were designated as TIL. Of the 54 initially non-TIL cases, 49 (90%) were converted to TIL status by the last spin. Overall, on the last spin, 96 out of 102 lesions (94%) were defined as TIL and six out of 102 lesions (6%) were defined as non-TIL (p<0.0001). The mean distance between the tool and the centre of the lesion decreased from 10.4 to 6.6â mm between the first and last spins (p<0.0001). The overall diagnostic yield was 77%. Conclusion: Targeting traditionally challenging lung lesions, intra-operative volumetric imaging allowed for the conversion of 90% of non-TIL status to TIL. Guidance with mCBCT resulted in a significant decrease in the distance between the tip of the needle to lesion centre.
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OBJECTIVE: Shape-sensing robotic-assisted bronchoscopy is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the shape-sensing robotic-assisted bronchoscopy learning curve at an academic center. METHODS: Shape-sensing robotic-assisted bronchoscopy procedures performed by 9 proceduralists at a single institution were analyzed. Cumulative sum analyses were performed to examine diagnostic sampling and procedure time over each operator's first 50 cases, with the acceptable yield threshold set to 73%. RESULTS: During the study period, 442 patients underwent sampling of 551 lesions. Each operator sampled 61 lesions (interquartile range, 60-63 lesions). Lesion size was 1.90 cm (interquartile range, 1.33-2.80 cm). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P < .001). The overall diagnostic yield was 72% (range, 58%-83%). Six of 9 operators achieved proficiency over the study period. An aggregated cumulative sum analysis of those who achieved competency demonstrated a steep improvement between lesions 1 and 21 and crossing of the competency threshold by lesion 25. Temporal analysis of yield-related lesion characteristics demonstrated that at approximately lesion 20, more challenging lesions were increasingly targeted, as evidenced by smaller target size, higher rates of unfavorable radial endobronchial ultrasound views, and a negative bronchus sign. CONCLUSIONS: Skills acquisition in shape-sensing robotic-assisted bronchoscopy is variable. Approximately half of proceduralists become facile with the technology within 25 lesions. After the initial learning phase, operators increasingly target lesions with more challenging features. Overall, these findings can inform certification and competency standards and provide new users with expectations related to performance over time.
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BACKGROUND AND OBJECTIVE: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. METHODS: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. RESULTS: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 µSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. CONCLUSION: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.
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Bronchoscopy , Cone-Beam Computed Tomography , Radiation Exposure , Robotic Surgical Procedures , Humans , Cone-Beam Computed Tomography/methods , Bronchoscopy/methods , Bronchoscopy/adverse effects , Male , Female , Radiation Exposure/adverse effects , Middle Aged , Robotic Surgical Procedures/adverse effects , Occupational Exposure/adverse effects , Aged , Radiation Dosage , Phantoms, Imaging , Adult , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/radiotherapyABSTRACT
RATIONALE: Serum amyloid A (SAA) is bound to high-density lipoproteins (HDL) in blood. Although SAA is increased in the blood of patients with asthma, it is not known whether this modifies asthma severity. OBJECTIVE: We sought to define the clinical characteristics of patients with asthma who have high SAA levels and assess whether HDL from SAA-high patients with asthma is proinflammatory. METHODS: SAA levels in serum from subjects with and without asthma were quantified by ELISA. HDLs isolated from subjects with asthma and high SAA levels were used to stimulate human monocytes and were intravenously administered to BALB/c mice. RESULTS: An SAA level greater than or equal to 108.8 µg/mL was defined as the threshold to identify 11% of an asthmatic cohort (n = 146) as being SAA-high. SAA-high patients with asthma were characterized by increased serum C-reactive protein, IL-6, and TNF-α; older age; and an increased prevalence of obesity and severe asthma. HDL isolated from SAA-high patients with asthma (SAA-high HDL) had an increased content of SAA as compared with HDL from SAA-low patients with asthma and induced the secretion of IL-6, IL-1ß, and TNF-α from human monocytes via a formyl peptide receptor 2/ATP/P2X purinoceptor 7 axis. Intravenous administration to mice of SAA-high HDL, but not normal HDL, induced systemic inflammation and amplified allergen-induced neutrophilic airway inflammation and goblet cell metaplasia. CONCLUSIONS: SAA-high patients with asthma are characterized by systemic inflammation, older age, and an increased prevalence of obesity and severe asthma. HDL from SAA-high patients with asthma is proinflammatory and, when intravenously administered to mice, induces systemic inflammation, and amplifies allergen-induced neutrophilic airway inflammation. This suggests that systemic inflammation induced by SAA-high HDL may augment disease severity in asthma.
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Asthma , Lipoproteins, HDL , Humans , Animals , Mice , Lipoproteins, HDL/metabolism , Lipoproteins, HDL/pharmacology , Serum Amyloid A Protein/analysis , Serum Amyloid A Protein/metabolism , Serum Amyloid A Protein/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6 , Inflammation/metabolism , Obesity , AllergensABSTRACT
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).
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Lung Transplantation , Humans , Lung Transplantation/adverse effects , Biopsy/methods , Hemorrhage/etiology , Hemorrhage/prevention & control , Hemorrhage/pathology , Lung/pathology , Epinephrine/therapeutic use , BronchoscopyABSTRACT
OBJECTIVE: Molecular diagnostic assays require samples with high nucleic acid content to generate reliable data. Similarly, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) requires samples with adequate tumor content. We investigated whether shape-sensing robotic-assisted bronchoscopy (ssRAB) provides adequate samples for molecular and predictive testing. METHODS: We retrospectively identified diagnostic samples from a prospectively collected database. Pathologic reports were reviewed to assess adequacy of samples for molecular testing and feasibility of PD-L1 IHC. Tumor cellularity was quantified by an independent pathologist using paraffin-embedded sections. Univariable and multivariable linear regression models were constructed to assess associations between lesion- and procedure-related variables and tumor cellularity. RESULTS: In total, 128 samples were analyzed: 104 primary lung cancers and 24 metastatic lesions. On initial pathologic assessment, ssRAB samples were deemed to be adequate for molecular testing in 84% of cases; on independent review of cellular blocks, median tumor cellularity was 60% (interquartile range, 25%-80%). Hybrid capture-based next-generation sequencing was successful for 25 of 26 samples (96%), polymerase chain reaction-based molecular testing (Idylla; Biocartis) was successful for 49 of 52 samples (94%), and PD-L1 IHC was successful for 61 of 67 samples (91%). Carcinoid and small cell carcinoma histologic subtype and adequacy on rapid on-site evaluation were associated with higher tumor cellularity. CONCLUSIONS: The ssRAB platform provided adequate tissue for next-generation sequencing, polymerase chain reaction-based molecular testing, and PD-L1 IHC in >80% of cases. Tumor histology and adequacy on intraoperative cytologic assessment might be associated with sample quality and suitability for downstream assays.
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Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Robotic Surgical Procedures , Thoracic Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/surgery , Carcinoma, Non-Small-Cell Lung/chemistry , Lung Neoplasms/genetics , Lung Neoplasms/surgery , Lung Neoplasms/chemistry , B7-H1 Antigen , Bronchoscopy , Retrospective Studies , Feasibility Studies , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysisABSTRACT
The emergence of spontaneous nonmalignant chylous effusions during treatment with various tyrosine kinase inhibitors (TKIs) has been previously described; however, there have been no prior reports for alectinib. Herein, we report a case of symptomatic bilateral chylothorax during alectinib therapy in a patient with ALK-rearranged lung adenocarcinoma. Although immediate control of symptoms was achieved by placement of bilateral tunneled pleural catheters, the chylothorax ultimately resolved only after alectinib discontinuation and transition to an alternative TKI. This case adds alectinib to the growing list of TKIs that may be associated with the rare emergence of spontaneous, nonmalignant chylous effusions.
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Timing of tracheostomy in patients with COVID-19 has attracted substantial attention. Initial guidelines recommended delaying or avoiding tracheostomy due to the potential for particle aerosolization and theoretical risk to providers. However, early tracheostomy could improve patient outcomes and alleviate resource shortages. This study compares outcomes in a diverse population of hospitalized COVID-19 patients who underwent tracheostomy either "early" (within 14 d of intubation) or "late" (more than 14 d after intubation). DESIGN: International multi-institute retrospective cohort study. SETTING: Thirteen hospitals in Bolivia, Brazil, Spain, and the United States. PATIENTS: Hospitalized patients with COVID-19 undergoing early or late tracheostomy between March 1, 2020, and March 31, 2021. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: A total of 549 patients from 13 hospitals in four countries were included in the final analysis. Multivariable regression analysis showed that early tracheostomy was associated with a 12-day decrease in time on mechanical ventilation (95% CI, -16 to -8; p < 0.001). Further, ICU and hospital lengths of stay in patients undergoing early tracheostomy were 15 days (95% CI, -23 to -9 d; p < 0.001) and 22 days (95% CI, -31 to -12 d) shorter, respectively. In contrast, early tracheostomy patients experienced lower risk-adjusted survival at 30-day post-admission (hazard ratio, 3.0; 95% CI, 1.8-5.2). Differences in 90-day post-admission survival were not identified. CONCLUSIONS: COVID-19 patients undergoing tracheostomy within 14 days of intubation have reduced ventilator dependence as well as reduced lengths of stay. However, early tracheostomy patients experienced lower 30-day survival. Future efforts should identify patients most likely to benefit from early tracheostomy while accounting for location-specific capacity.
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Herein we examine the need for minimally invasive mediastinal staging for patients with early-stage non-small cell lung cancer (NSCLC) using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Early NSCLC, stages 1 and 2, has a 5-year survival rate between 53 and 92%, whereas stages 3 and 4 have a 5-year survival of 36% and below. With more favorable outcomes in earlier stages, greater emphasis has been placed on identifying lung cancer earlier in its disease process. Accurate staging is crucial as it dictates both prognosis and therapy. Inaccurate staging can adversely impact surgical candidacy (if falsely "over-staged") or lead to inadequate treatment (if "under-staged"). Clinical staging utilizes noninvasive methods to evaluate the anatomic extent of disease; however, it remains controversial whether mediastinal staging of early NSCLC with radiological exams alone is sufficient. EBUS-TBNA has altered the landscape of invasive mediastinal staging and is a crucial component to improving confidence in lung cancer staging, specifically in early NSCLC. Radiographic occult lymph node metastasis identified upon review of surgical resection specimens of early NSCLC may support the argument to perform EBUS-TBNA in all cases of early-stage disease. Other data suggest that EBUS-TBNA could be spared in cases of peripheral cT1aN0 and cT1bN0 for which surgical resection with lymph node dissection is planned. By reviewing reported EBUS-TBNA outcomes in patients with early NSCLC, we aim to emphasize the necessity of staging with EBUS in this population.
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Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Small Cell Lung Carcinoma , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/pathology , Endosonography/methods , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Mediastinum/diagnostic imaging , Mediastinum/pathology , Small Cell Lung Carcinoma/pathologyABSTRACT
INTRODUCTION: Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs). METHODS: This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated. RESULTS: A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9). CONCLUSIONS: Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.
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Chylothorax , Chylous Ascites , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Retrospective StudiesABSTRACT
BACKGROUND: The landscape of guided bronchoscopy for the sampling of pulmonary parenchymal lesions is evolving rapidly. Shape-sensing robotic-assisted bronchoscopy (ssRAB) recently was introduced as means to allow successful sampling of traditionally challenging lesions. RESEARCH QUESTION: What are the feasibility, diagnostic yield, determinants of diagnostic sampling, and safety of ssRAB in patients with pulmonary lesions? STUDY DESIGN AND METHODS: Data from 131 consecutive ssRAB procedures performed at a US-based cancer center between October 2019 and July 2020 were captured prospectively and analyzed retrospectively. Definitions of diagnostic procedures were based on prior standards. Associations of procedure- and lesion-related factors with diagnostic yield were examined by univariate and multivariate generalized linear mixed models. RESULTS: A total of 159 pulmonary lesions were targeted during 131 ssRAB procedures. The median lesion size was 1.8 cm, 59.1% of lesions were in the upper lobe, and 66.7% of lesions were beyond a sixth-generation airway. The navigational success rate was 98.7%. The overall diagnostic yield was 81.7%. Lesion size of ≥ 1.8 cm and central location were associated significantly with a diagnostic procedure in the univariate analysis. In the multivariate model, lesions of ≥ 1.8 cm were more likely to be diagnostic compared with lesions < 1.8 cm, after adjusting for lung centrality (OR, 12.22; 95% CI, 1.66-90.10). The sensitivity and negative predictive value of ssRAB for primary thoracic malignancies were 79.8% and 72.4%, respectively. The overall complication rate was 3.0%, and the pneumothorax rate was 1.5%. INTERPRETATION: This study was the first to provide comprehensive evidence regarding the usefulness and diagnostic yield of ssRAB in the sampling of pulmonary parenchymal lesions. ssRAB may represent a significant advancement in the ability to access and sample successfully traditionally challenging pulmonary lesions via the bronchoscopic approach, while maintaining a superb safety profile. Lesion size seems to remain the major predictor of a diagnostic procedure.
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Bronchoscopy/methods , Lung Neoplasms/diagnosis , Robotics , Aged , Feasibility Studies , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Endobronchial ultrasound (EBUS) bronchoscopy is an established minimally-invasive modality for visualization, characterization, and guidance of sampling of paratracheal and parabronchial structures and tissues. In the intensive care unit (ICU), rapidly obtaining an accurate diagnosis is paramount to the management of critically ill patients. In some instances, diagnosing and confirming terminal illness in a critically ill patient provides needed closure for patients and their loved ones. Currently available data on feasibility, safety, and yield of EBUS bronchoscopy in critically ill patients is based on single center experiences. These data suggest that in select ICU patients convex and radial probe-EBUS bronchoscopy can serve as useful tools in the evaluation of mediastinal lymphadenopathy, central airway obstruction, pulmonary embolism, and peripheral lung lesions. Barriers to the use of EBUS bronchoscopy in the ICU include: (I) requirement for dedicated equipment, prolonged procedure time, and bronchoscopy team expertise that may not be available; (II) applicability to a limited number of patients and conditions in the ICU; and (III) technical difficulty related to the relatively large outer diameter of the convex probe-EBUS bronchoscope and an increased risk for adverse cardiopulmonary consequences due to intermittent obstruction of the artificial airway. While the prospects for EBUS bronchoscopy in critically ill patients appear promising, judicious patient selection in combination with bronchoscopy team expertise are of utmost importance when considering performance of EBUS bronchoscopy in the ICU setting.
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Background: The impact of the coronavirus disease (COVID-19) pandemic extends beyond the realms of patient care and healthcare resource use to include medical education; however, the repercussions of COVID-19 on the quality of training and trainee perceptions have yet to be explored. Objective: The purpose of this study was to determine the degree of interventional pulmonology (IP) fellows' involvement in the care of COVID-19 and its impact on fellows' clinical education, procedure skills, and postgraduation employment search. Methods: An internet-based survey was validated and distributed among IP fellows in North American fellowship training programs. Results: Of 40 eligible fellows, 38 (95%) completed the survey. A majority of fellows (76%) reported involvement in the care of patients with COVID-19. Fellows training in the Northeast United States reported involvement in the care of a higher number of patients with COVID-19 than in other regions (median, 30 [interquartile range, 20-50] vs. 10 [5-13], respectively; P < 0.01). Fifty-two percent of fellows reported redeployment outside IP during COVID-19, mostly into intensive care units. IP procedure volume decreased by 21% during COVID-19 compared with pre-COVID-19 volume. This decrease was mainly accounted for by a reduction in bronchoscopies. A majority of fellows (82%) reported retainment of outpatient clinics during COVID-19 with the transition from face-to-face to telehealth-predominant format. Continuation of academic and research activities during COVID-19 was reported by 86% and 82% of fellows, respectively. After graduation, all fellows reported having secured employment positions. Conclusion: Although IP fellows were extensively involved in the care of patients with COVID-19, most IP programs retained educational activities through the COVID-19 outbreak. The impact of the decrease in procedure volume on trainee competency would be best addressed individually within each training program. These data may assist in focusing efforts regarding the education of medical trainees during the current and future healthcare crises.
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We performed the midpoint transverse process to pleura (MTP) block in a patient with a recurrent pleural effusion requiring medical thoracoscopy, drainage of pleural effusion, talc poudrage, and placement of tunneled pleural catheter under sedation while in the left lateral decubitus position. Forty milliliters of a combination of bupivacaine hydrochloride and lidocaine, with dexamethasone and clonidine as adjuvants, was injected at the T6 level under ultrasound guidance with satisfactory intra- and postoperative analgesia.
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Breast Neoplasms/secondary , Pleura/innervation , Pleural Effusion/surgery , Thoracoscopy/methods , Breast Neoplasms/complications , Catheters/standards , Drainage/methods , Female , Humans , Middle Aged , Nerve Block/instrumentation , Pleura/drug effects , Pleura/pathology , Pleural Effusion/etiology , Talc/administration & dosage , Treatment Outcome , Ultrasonography, Interventional/methodsABSTRACT
The primary function of APOE (apolipoprotein E) is to mediate the transport of cholesterol- and lipid-containing lipoprotein particles into cells by receptor-mediated endocytosis. APOE also has pro- and antiinflammatory effects, which are both context and concentration dependent. For example, Apoe-/- mice exhibit enhanced airway remodeling and hyperreactivity in experimental asthma, whereas increased APOE levels in lung epithelial lining fluid induce IL-1ß secretion from human asthmatic alveolar macrophages. However, APOE-mediated airway epithelial cell inflammatory responses and signaling pathways have not been defined. Here, RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). Neutralizing antibodies directed against TLR4 (Toll-like receptor 4), but not TLR2, attenuated APOE-mediated CXCL5 secretion by human asthmatic SAECs. Inhibition of TAK1 (transforming growth factor-ß-activated kinase 1), IκKß (inhibitor of nuclear factor κ B kinase subunit ß), TPL2 (tumor progression locus 2), and JNK (c-Jun N-terminal kinase), but not p38 MAPK (mitogen-activated protein kinase) or MEK1/2 (MAPK kinase 1/2), attenuated APOE-mediated CXCL5 secretion. The roles of TAK1, IκKß, TPL2, and JNK in APOE-mediated CXCL5 secretion were verified by RNA interference. Furthermore, RNA interference showed that after APOE stimulation, both NF-κB p65 and TPL2 were downstream of TAK1 and IκKß, whereas JNK was downstream of TPL2. In summary, elevated levels of APOE in the airway may activate a TLR4/TAK1/IκKß/NF-κB/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma.
Subject(s)
Apolipoproteins E/metabolism , Asthma/metabolism , Chemokine CXCL5/metabolism , Epithelial Cells/metabolism , Respiratory System/metabolism , Signal Transduction/physiology , Toll-Like Receptor 4/metabolism , Chemokines/metabolism , Humans , Inflammation/metabolism , Neutrophils/metabolism , RNA, Messenger/metabolismABSTRACT
A 74-year-old woman presented with chest pain and dyspnoea following endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) for presumed malignancy. Computed tomography angiography revealed a left-sided pleural effusion with hypertrophied and tortuous bronchial arteries (BAs) with contrast blush into the left lung hilum. Tube thoracostomy and pleural fluid analysis confirmed the diagnosis of haemothorax. The mechanism of injury was determined to be BA laceration during EBUS-TBNA and drainage led to rapid improvement in the patient's symptoms. This is the first reported case of haemothorax due to BA injury during EBUS-TBNA.