Asthmatic patients with high serum amyloid A have proinflammatory HDL: Implications for augmented systemic and airway inflammation.

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.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

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.

Mediastinal Staging with Endobronchial Ultrasound in Early-Stage Non-Small Cell Lung Cancer: Is It Necessary?

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.

Apolipoprotein E Signals via TLR4 to Induce CXCL5 Secretion by Asthmatic Airway Epithelial Cells.

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.

The Spectrum of Hepatic Involvement in Patients With Telomere Disease.

Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity in telomere diseases, but very few studies have characterized the nature and extent of liver involvement in affected patients. We report the prevalence and characteristics of liver involvement in a large cohort of patients with telomere disease evaluated serially at the National Institutes of Health. One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included in the current study. Median follow-up was 2.4 years. Data were collected regarding their demographic information, laboratory analysis, imaging, and histopathology. Forty patients (40% of the cohort) with a median age of 42 years were found to have liver involvement. Liver enzyme elevation was cholestatic in pattern; 8 (21%) had drug-related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% (9) of patients, followed by hepatomegaly in 26% (6). Biopsies were infrequent because of risk associated with thrombocytopenia, but in 6 patients, there were varying findings: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. Almost half the cohort had pulmonary diffusion abnormalities, and 25% died during the follow-up period. Conclusion: In patients with telomere disease, hepatic involvement is common and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities. Liver disease has important implications for morbidity and mortality in patients with telomere disease.

Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1ß secretion by bronchoalveolar fluid macrophages from asthmatic subjects.

BACKGROUND: House dust mite (HDM)-challenged Apoe-/- mice display enhanced airway hyperreactivity and mucous cell metaplasia. OBJECTIVE: We sought to characterize the pathways that induce apolipoprotein E (APOE) expression by bronchoalveolar lavage fluid (BALF) macrophages from asthmatic subjects and identify how APOE regulates IL-1ß secretion. METHODS: Macrophages were isolated from asthmatic BALF and derived from THP-1 cells and human monocytes. RESULTS: HDM-derived cysteine and serine proteases induced APOE secretion from BALF macrophages through protease-activated receptor 2. APOE at concentrations of less than 2.5 nmol/L, which are similar to levels found in epithelial lining fluid from healthy adults, did not induce IL-1ß release from BALF macrophages. In contrast, APOE at concentrations of 25 nmol/L or greater induced nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) 3 and pro-IL-1ß expression by BALF macrophages, as well as the caspase-1-mediated generation of mature IL-1ß secreted from cells. HDM acted synergistically with APOE to both prime and activate the NLRP3 inflammasome. In a murine model of neutrophilic airway inflammation induced by HDM and polyinosinic-polycytidylic acid, APOE reached a concentration of 32 nmol/L in epithelial lining fluid, with associated increases in BALF IL-1ß levels. APOE-dependent NLRP3 inflammasome activation in macrophages was primarily mediated through a potassium efflux-dependent mechanism. CONCLUSION: APOE can function as an endogenous, concentration-dependent pulmonary danger signal that primes and activates the NLPR3 inflammasome in BALF macrophages from asthmatic subjects to secrete IL-1ß. This might represent a mechanism through which APOE amplifies pulmonary inflammatory responses when concentrations in the lung are increased to greater than normal levels, which can occur during viral exacerbations of HDM-induced asthma characterized by neutrophilic airway inflammation.

[THE ROLE OF CLOSED PLEURAL BIOPSY IN THE DIAGNOSIS OF TUBERCULOUS PLEURISY IN A POPULATION AT-RISK].

BACKGROUND: Tuberculous pleurisy is the most common form of extrapulmonary tuberculosis, and a common cause of exudative pleural effusion. Closed pleural biopsy can be used for diagnosis. In recent years, more invasive methods are used for the diagnostic process in the western world. Contrary to the global trend, physicians at the Pulmonary Institute of the Soroka University Medical Center still perform a closed pleural biopsy as the first diagnostic step. In this article, we report our experience in the diagnosis of tuberculous pleurisy by closed pleural biopsy. METHODS: A retrospective cohort analysis, conducted among patients, who were admitted for investigation of pleural effusion between 2008 and 2013, and underwent closed pleural biopsy with an Abrams needle in the evaluation of tuberculous pleurisy (n=25). Histopathological evidence of tuberculosis bacterium infection included a positive staining for acid-fast bacteria, identification of Langerhans giant cells, demonstration of chronic granulomatous inflammation or demonstration of granulomas with central necrosis in samples of pleural fluid or pleural biopsy. RESULTS: Closed pleural biopsy was performed in 22/25 (88%) of patients. In 15/22 subjects (68%) histopathotogical evidence of tuberculous pleurisy was found. No significant complications were evident after the procedure. In addition, it was found that acid-fast bacteria in sputum samples, gastric fluid and pleural fluid is of very low diagnostic yield for the diagnosis of tuberculous pleurisy, while in cultures of sputum, gastric fluid or pleural fluid infection it was diagnosed in 27, 28 and 28% of subjects respectively. CONCLUSIONS: In subjects with a high probability for tuberculous pleurisy, closed pleural biopsy using Abrams needle is available, inexpensive and has a good diagnostic yield and low complication rate. We believe that there is great importance in preserving the ability to perform a closed pleural biopsy in all. medical centers in Israel.

[THE ASSOCIATION BETWEEN OBESITY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)].

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease, with major respiratory and systemic expressions. Obesity is defined as a BMI>30 kg/ m2 and its prevalence has doubled in recent decades. The possible relationship of obesity to COPD, and its influence on respiratory pathophysiology, is considered a mystery. Studies show obesity to be a survival advantage among COPD patients, unlike in the general population, in which obesity correlates to decreased life expectancy. This study aims to assess the differences between obese and non-obese COPD patients. The main clinical aspect assessed is the number of COPDexacerbation related hospital admissions. METHODS: We conducted a retrospective cohort study of 323 COPD patients (95 obese, 228 non-obese), who had been followed from 2003-2010 by the Pulmonology Institute at the Soroka Medical Center. We collected demographics, medical history, BMI, lung function tests, information about hospital admissions and mortality. RESULTS: Non-obese COPD patients are 1.6 times more likely to be hospitalized due to COPD exacerbation. Additionally, women are 1.8 times more likely to be hospitalized due to COPD exacerbation. The FEV1 and FEV1/FVC ratios, which were measured latest during the study period, were higher among obese COPD patients. There was no significant difference in mortality. CONCLUSIONS: Obesity and male gender act as protective factors against COPD exacerbations requiring hospitalization. Lung function test values are higher among obese patients. Despite this, obesity has no influence on COPD patient survival. Subsequent studies are required, in order to define nutrition recommendations and target weights for COPD patients.

[THE UTILITY OF BRONCHOSCOPY IN INTENSIVE CARE UNIT PATIENTS WITH VENTILATOR ASSOCIATED PNEUMONIA].

BACKGROUND: Ventilator associated pneumonia (VAPI is a common complication leading to lengthier hospitalizations and higher mortality. Prompt adequate initial antibiotic coverage is the crucial issue affecting survival. Currently, there is no gold standard diagnostic test. No conclusive data regarding the benefit of bronchoscopy exists in the literature reviewed. AIM: This study aims to evaluate the change of prognosis for patients who developed VAP, following a positive culture from bronchoalveolar lavage (BAL). DESIGN: This is a retrospective cohort study. SETTING: General intensive care unit in a tertiary university healthcare center. PARTICIPANTS: All patients who were admitted to Surgical ICU and developed VAP and who then underwent diagnostic bronchoscopy with BAL between the period 01/02/2007 - 31/02/2011. MEASUREMENTS AND RESULTS: A total of 66 patients who were admitted to the ICU, developed VAP and underwent bronchoscopy while ventilated; 30 patients were excluded. The positive BAL culture group was compared to the negative BAL culture group; there was no difference between demographic and clinical characteristics, mortality rates (for 30 days) or therapy change between the two groups. No complications were reported regarding the bronchoscopy procedure. CONCLUSIONS: Our findings demonstrate that performing y a diagnostic bronchoscopy with BAL does not improve the prognosis of patients with VAP. Furthermore, expanded prospective studies will be needed to conclude regarding its benefit in diagnosis and subsequent rectifying of therapy.

Efficacy and long-term durability of intradermal recombinant hepatitis B virus vaccine among intramuscular vaccine nonresponders: A prospective study in healthcare personnel.

BACKGROUND: Data on efficacy, safety, and durability of intradermal vaccine administration in persons who have not responded appropriately to intramuscular administration of hepatitis B virus (HBV) vaccine are relatively scarce. METHODS: We designed a prospective case series in an urban tertiary care hospital in Israel. The medical records of 4007 healthcare personnel who had worked in the hospital between 1996 and 2006 were examined and those with an unsatisfactory level (<10 mIU/ml) of hepatitis B surface antibody (HBsAb) following two courses of a three-dose intramuscular HBV vaccine ("nonresponders") were identified. Nonresponders were vaccinated with three doses of 5 µg of intradermal recombinant hepatitis B surface antigen-based vaccine at weeks 0, 2, and 4. Level of HBsAb was determined 4 weeks after the last dose, and an additional dose was administered as needed. HBsAb level was again determined 24 weeks after the final vaccine dose to assess late immune reactivity and long-term durability of the vaccine. Vaccine safety was assessed at each vaccination and testing session. RESULTS: Twenty-seven subjects were included in the study, and 21 completed the study. The proportion of subjects with satisfactory HBsAb level at 4 weeks after the last administered dose was 70.3% (19/27). The proportion of subjects with sustained immune response at 24 weeks was 62.9% (17/27) according to intention-to-treat analysis and 80.9% (17/21) according to per protocol analysis. There were no reports of adverse events in response to the administration of the vaccine. CONCLUSIONS: Intradermal administration of HBV vaccine offers an efficient, safe, and durable option for intramuscular vaccine nonresponders and represents a means to optimize utilization of the widespread HBs antigen-based vaccine formulation.

Characterizing a learning curve for robotic-assisted bronchoscopy: Analysis of skills acquisition in a high-volume academic center.

OBJECTIVE: Shape-sensing robotic-assisted bronchoscopy (ssRAB) is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the ssRAB learning curve at an academic center. METHODS: SsRAB 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 (IQR, 60-63) lesions. Lesion size was 1.90 cm (IQR, 1.33-2.80). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P<0.001). 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 ssRAB 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.

Spontaneous Bilateral Chylothorax Development During Alectinib Therapy for ALK-Rearranged NSCLC-A Case Report.

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.

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).

Feasibility of shape-sensing robotic-assisted bronchoscopy for biomarker identification in patients with thoracic malignancies.

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.

Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy.

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.

Shape-Sensing Robotic-Assisted Bronchoscopy in the Diagnosis of Pulmonary Parenchymal Lesions.

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.

Outcomes of Early Versus Late Tracheostomy in Patients With COVID-19: A Multinational Cohort Study.

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.