The Performance of an Extended Next Generation Sequencing Panel Using Endobronchial Ultrasound-Guided Fine Needle Aspiration Samples in Non-Squamous Non-Small Cell Lung Cancer: A Pragmatic Study.

INTRODUCTION/BACKGROUND: Samples from endobronchial ultrasound-guided fine needle aspiration (EBUS-TBNA) are frequently used for next generation sequencing (NGS) in patients with non-small cell lung cancer (NSCLC) to look for genetic driver mutations. The objective of the current study was to evaluate the performance of extended NGS panels using EBUS-TBNA samples in a real-world setting and identify factors associated with the success of NGS. MATERIALS AND METHODS: This study included all patients who underwent EBUS and were diagnosed with non-squamous NSCLC with mediastinal metastasis from 2016 to 2019 at the University of Pennsylvania. We reviewed demographic information, imaging studies, procedure reports, pathology and NGS reports. Logistic regression was used to analyze factors associated with the success of NGS panels. RESULTS: The success rates of NGS using EBUS-TBNA samples were 92.5%, and 91.5% for DNA and RNA NGS panels respectively. Samples from higher N stage (N2 and N3 lymph nodes) and with higher tumor cellularity (>25%) resulted in higher success rate for DNA NGS. The effect of tumor cellularity remained borderline significant after entering multivariable logistic regression. The short-axis diameter of the sampled lymph node on CT scan, FDG-avidity on PET CT and >3 EBUS passes per lymph node during the procedure were not associated with NGS success. CONCLUSION: Both DNA and RNA extended-panel NGS had high performance using EBUS-TBNA samples. Sampling more advanced nodal stations and obtaining samples with higher tumor cellularity were associated with higher success rate of DNA NGS. Other imaging or procedural factors did not affect NGS performance.

Diagnostic Yield of Cone-beam-Derived Augmented Fluoroscopy and Ultrathin Bronchoscopy Versus Conventional Navigational Bronchoscopy Techniques.

BACKGROUND: Pulmonary nodules suspicious for lung cancer are frequently diagnosed. Evaluating and optimizing the diagnostic yield of lung nodule biopsy is critical as innovation in bronchoscopy continues to progress. METHODS: This is a retrospective cohort study. Consecutive patients undergoing guided bronchoscopy for suspicious pulmonary nodule(s) between February 2020 and July 2021 were included. The cone-beam computed tomography (CBCT)+ radial endobronchial ultrasound (r-EBUS) group had their procedure using CBCT-derived augmented fluoroscopy along with r-EBUS. The CBCT+ ultrathin bronchoscope (UTB)+r-EBUS group had the same procedure but with the use of an ultrathin bronchoscope. The r-EBUS group underwent r-EBUS guidance without CBCT or augmented fluoroscopy. We used multivariable logistic regression to compare diagnostic yield, adjusting for confounding variables. RESULTS: A total of 116 patients were included. The median pulmonary lesion diameter was 19.5 mm (interquartile range, 15.0 to 27.5 mm), and 91 (78.4%) were in the peripheral half of the lung. Thirty patients (25.9%) underwent CBCT+UTB, 27 (23.3%) CBCT, and 59 (50.9%) r-EBUS alone with unadjusted diagnostic yields of 86.7%, 70.4%, and 42.4%, respectively ( P <0.001). The adjusted diagnostic yields were 85.0% (95% CI, 68.6% to 100%), 68.3% (95% CI, 50.1% to 86.6%), and 44.5% (95% CI, 31.0% to 58.0%), respectively. There was significantly more virtual navigational bronchoscopy use in the r-EBUS group (45.8%) compared with the CBCT+UTB (13.3%) and CBCT (18.5%) groups, respectively. CBCT procedures required dose area product radiation doses of 7602.5 µGym 2 . CONCLUSION: Compared with the r-EBUS group, CBCT + UTB + r-EBUS was associated with higher navigational success, fewer nondiagnostic biopsy results, and a higher diagnostic yield. CBCT procedures are associated with a considerable radiation dose.

Plasma Genotyping at the Time of Diagnostic Tissue Biopsy Decreases Time-to-Treatment in Patients With Advanced NSCLC-Results From a Prospective Pilot Study.

Introduction: The availability of targeted therapies has transformed the management of advanced NSCLC; however, most patients do not undergo guideline-recommended tumor genotyping. The impact of plasma-based next-generation sequencing (NGS) performed simultaneously with diagnostic biopsy in suspected advanced NSCLC has largely been unexplored. Methods: We performed a prospective cohort study of patients with suspected advanced lung cancer on the basis of cross-sectional imaging results. Blood from the time of biopsy was sequenced using a commercially available 74-gene panel. The primary outcome measure was time to first-line systemic treatment compared with a retrospective cohort of consecutive patients with advanced NSCLC with reflex tissue NGS. Results: We analyzed the NGS results from 110 patients with newly diagnosed advanced NSCLC: cohorts 1 and 2 included 55 patients each and were well balanced regarding baseline demographics. In cohort 1, plasma NGS identified therapeutically informative driver mutations in 32 patients (58%) (13 KRAS [five KRAS G12C], 13 EGFR, two ERRB2, two MET, one BRAF, one RET). The NGS results were available before the first oncology visit in 85% of cohort 1 versus 9% in cohort 2 (p < 0.0001), with more cohort 1 patients receiving a guideline-concordant treatment recommendation at this visit (74% versus 46%, p = 0.005). Time-to-treatment was significantly shorter in cohort 1 compared with cohort 2 (12 versus 20 d, p = 0.003), with a shorter time-to-treatment in patients with specific driver mutations (10 versus 19 d, p = 0.001). Conclusions: Plasma-based NGS performed at the time of diagnostic biopsy in patients with suspected advanced NSCLC is associated with decreased time-to-treatment compared with usual care.

Sedation and Analgesia in Patients Undergoing Tracheostomy in COVID-19, a Multi-Center Registry.

INTRODUCTION: Patients with COVID-19 ARDS require significant amounts of sedation and analgesic medications which can lead to longer hospital/ICU length of stay, delirium, and has been associated with increased mortality. Tracheostomy has been shown to decrease the amount of sedative, anxiolytic and analgesic medications given to patients. The goal of this study was to assess whether tracheostomy decreased sedation and analgesic medication usage, improved markers of activity level and cognitive function, and clinical outcomes in patients with COVID-19 ARDS. STUDY DESIGN AND METHODS: A retrospective registry of patients with COVID-19 ARDS who underwent tracheostomy creation at the University of Pennsylvania Health System or the Johns Hopkins Hospital from 3/2020 to 12/2020. Patients were grouped into the early (≤14 days, n = 31) or late (15 + days, n = 97) tracheostomy groups and outcome data collected. RESULTS: 128 patients had tracheostomies performed at a mean of 19.4 days, with 66% performed percutaneously at bedside. Mean hourly dose of fentanyl, midazolam, and propofol were all significantly reduced 48-h after tracheostomy: fentanyl (48-h pre-tracheostomy: 94.0 mcg/h, 48-h post-tracheostomy: 64.9 mcg/h, P = .000), midazolam (1.9 mg/h pre vs. 1.2 mg/h post, P = .0012), and propofol (23.3 mcg/kg/h pre vs. 8.4 mcg/kg/h post, P = .0121). There was a significant improvement in mobility score and Glasgow Coma Scale in the 48-h pre- and post-tracheostomy. Comparing the early and late groups, the mean fentanyl dose in the 48-h pre-tracheostomy was significantly higher in the late group than the early group (116.1 mcg/h vs. 35.6 mcg/h, P = .03). ICU length of stay was also shorter in the early group (37.0 vs. 46.2 days, P = .012). INTERPRETATION: This data supports a reduction in sedative and analgesic medications administered and improvement in cognitive and physical activity in the 48-h period post-tracheostomy in COVID-19 ARDS. Further, early tracheostomy may lead to significant reductions in intravenous opiate medication administration, and ICU LOS.

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.

Outcomes After Tracheostomy in COVID-19 Patients.

OBJECTIVE: To determine the outcomes of patients undergoing tracheostomy for COVID-19 and of healthcare workers performing these procedures. BACKGROUND: Tracheostomy is often performed for prolonged endotracheal intubation in critically ill patients. However, in the context of COVID-19, tracheostomy placement pathways have been altered due to the poor prognosis of intubated patients and the risk of transmission to providers through this highly aerosolizing procedure. METHODS: A prospective single-system multi-center observational cohort study was performed on patients who underwent tracheostomy after acute respiratory failure secondary to COVID-19. RESULTS: Of the 53 patients who underwent tracheostomy, the average time from endotracheal intubation to tracheostomy was 19.7 days ±â€Š6.9 days. The most common indication for tracheostomy was acute respiratory distress syndrome, followed by failure to wean ventilation and post-extracorporeal membrane oxygenation decannulation. Thirty patients (56.6%) were liberated from the ventilator, 16 (30.2%) have been discharged alive, 7 (13.2%) have been decannulated, and 6 (11.3%) died. The average time from tracheostomy to ventilator liberation was 11.8 days ±â€Š6.9 days (range 2-32 days). Both open surgical and percutaneous dilational tracheostomy techniques were performed utilizing methods to mitigate aerosols. No healthcare worker transmissions resulted from performing the procedure. CONCLUSIONS: Alterations to tracheostomy practices and processes were successfully instituted. Following these steps, tracheostomy in COVID-19 intubated patients seems safe for both patients and healthcare workers performing the procedure.

Predicting the need for nonstandard tracheostomy tubes in critically ill patients.

PURPOSE: Few guidelines exist regarding the selection of a particular type or size of tracheostomy tube. Although nonstandard tubes can be placed over the percutaneous kit dilator, clinicians often place standard tracheostomy tubes and change to nonstandard tubes only after problems arise. This practice risks early tracheostomy tube change, possible bleeding, or loss of the airway. We sought to identify predictors of nonstandard tracheostomy tubes. MATERIALS AND METHODS: In this matched case-control study at an urban, academic, tertiary care medical center, we reviewed 1220 records of patients who received a tracheostomy. Seventy-seven patients received nonstandard tracheostomy tubes (cases), and 154 received standard tracheostomy tubes (controls). RESULTS: Sex, endotracheal tube size, severity of illness, and computed tomography scan measurement of the distance from the trachea to the skin at the level of the superior aspect of the anterior clavicle were significant predictors of nonstandard tracheostomy tubes. Specifically, trachea-to-skin distance >4.4 cm and endotracheal tube sizes ≥8.0 were associated with nonstandard tracheostomy. CONCLUSIONS: The findings suggest that clinicians should consider using nonstandard tracheostomy tubes as the first choice if the patient is male with an endotracheal tube size ≥8.0 and has a trachea-to-skin distance >4.4 cm on the computed tomography scan.

Infectious mimicry complicates diagnosis in hemophagocytic syndrome caused by anaplastic large-cell lymphoma.

Hemophagocytic syndrome (HPS) arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL). This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS-first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified.

Accessing the vocal folds by transcutaneous injection.

This study tested three techniques and two approaches to access the vocal fold (VF) by transcutaneous injection using a cadaver model. The three techniques include an anatomically informed geometric technique, flexible laryngoscope (FL) guidance, and planned injection with use of computed tomography (CT). The two approaches for injection include the thyrohyoid membrane (THM) and the cricothyroid membrane (CTM). The hypothesis was that the VF is more reliably reached with techniques using technological visualization and the THM and CTM provides equal access to the VF. A geometric approach to the VF was developed and tested on seven formalin-fixed human cadavers with three injections of 0.5 ml pigmented acrylic polymer through the CTM and one through the THM. The FL-guided technique through the THM and the CTM was tested on eight formalin-fixed human cadavers and the CT informed technique on two subjects. All tests were inspected by dissection and results recorded. Pertinent measurements and characteristics of each technique were recorded. Data were analyzed for statistical significance for each approach and technique. A chi-square analysis revealed that a technology guided technique was more successful than anatomical knowledge alone (X(2) = 6.55, P = 0.01). The null hypothesis that the VF was equally accessed through the THM and the CTM was rejected (X(2) = 5.33, P = 0.02). We found that technology guided visualization is better than anatomical knowledge alone in accessing the VF. We also found that the CTM approach provides more reliable access to the entire length of the VF.

Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms.

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 microM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 microM)-a selective inhibitor of c-Jun NH(2)-terminal kinase (JNK)-inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 microM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg*kg body wt(-1)*day(-1)) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)alpha ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases.

Analysis of recurrent angiotensin converting enzyme inhibitor-induced angioedema.

OBJECTIVE/HYPOTHESIS: A known risk for patients taking angiotensin converting enzyme-inhibitors (ACE-Is) is angioedema that can involve the face, lips, oral cavity, and larynx. Such upper airway obstruction may be severe enough to require an emergency department visit or even necessitate prompt airway intervention. Once a patient has had an episode of ACE-inhibitor induced angioedema (AIIA), certainly a thrust of continuing case management would be to avoid the occurrence of subsequent episodes of AIIA that potentially can be life-threatening. Nevertheless, recurrent episodes of AIIA do occur. This study aims to characterize a patient's risk for recurrent AIIA, determine the cause for repeat episodes of AIIA and recommend steps to be taken to minimize the recurrence of AIIA. STUDY DESIGN: Retrospective study. METHODS: A retrospective chart review of all patient encounters at our medical center between January 1, 1991 and December 30, 2005 with a diagnosis of angioedema was performed. The documented etiology of the angioedema, comorbidities, and documentation of an "allergy" to ACE-I were noted. Observations regarding risk factors for recurrent AIIA were made. RESULTS: Recurrent AIIA occurred in 23 patients with a recurrence rate of 6.2%. Risk factors for recurrence were categorized as patient factors, physician factors, or systems factors. Physician error with failure to document in the medical record, the suspicion of AIIA, and failure to consider risk in prescribing ACE-I after an episode of angioedema had occurred were the most common causes of recurrent AIIA. CONCLUSIONS: Angioedema can cause life-threatening airway compromise yet patients with a history of one episode of AIIA are at risk for a subsequent episode. Physicians can modify clinical practices to avert the potentially life-threatening side effects of ACE-inhibitors in patients with a prior episode of AIIA.