Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.

Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that continues to have low cure rates despite the recent advances in therapies. Cisplatin is the most used chemotherapy agent, and treatment failure is largely driven by resistance to this drug. Amplification of chromosomal band 11q13 occurs in ∼30% of SCCHN tumors. This region harbors the ANO1 gene that encodes the TMEM16A ion channel, which is responsible for calcium-activated chloride transport in epithelial tissues. TMEM16A overexpression is associated with cisplatin resistance, and high TMEM16A levels correlate with decreased survival. However, the mechanistic underpinning of this effect remains unknown. Lysosomal biogenesis and exocytosis have been implicated in cancer because of their roles in the clearance of damaged organelles and exocytosis of chemotherapeutic drugs and toxins. Here, we show that TMEM16A overexpression promotes lysosomal biogenesis and exocytosis, which is consistent with the expulsion of intracellular cisplatin. Using a combination of genetic and pharmacologic approaches, we find that TMEM16A promotes lysosomal flux in a manner that requires reactive oxygen species, TRPML1, and the activation of the ß-catenin­melanocyte-inducing transcription factor pathway. The lysosomal inhibitor hydroxychloroquine (HCQ) synergizes with cisplatin in killing SCCHN cells in vitro. Using a murine model of SCCHN, we show that HCQ and cisplatin retard the growth of cisplatin-resistant patient-derived xenografts in vivo. We propose that TMEM16A enables cell survival by the up-regulation of lysosomal sequestration and exocytosis of the cytotoxic drugs. These results uncover a model of treatment for resistance in cancer, its reversal, and a role for TMEM16A.

Predicting malignant pleural effusion during diagnostic pleuroscopy with biopsy: A prospective multicentre study.

BACKGROUND AND OBJECTIVE: Pleuroscopy with pleural biopsy has a high sensitivity for malignant pleural effusion (MPE). Because MPEs tend to recur, concurrent diagnosis and treatment of MPE during pleuroscopy is desired. However, proceeding directly to treatment at the time of pleuroscopy requires confidence in the on-site diagnosis. The study's primary objective was to create a predictive model to estimate the probability of MPE during pleuroscopy. METHODS: A prospective observational multicentre cohort study of consecutive patients undergoing pleuroscopy was conducted. We used a logistic regression model to evaluate the probability of MPE with relation to visual assessment, rapid on-site evaluation (ROSE) of touch preparation and presence of pleural nodules/masses on computed tomography (CT). To assess the model's prediction accuracy, a bootstrapped training/testing approach was utilized to estimate the cross-validated area under the receiver operating characteristic curve. RESULTS: Of the 201 patients included in the study, 103 had MPE. Logistic regression showed that higher level of malignancy on visual assessment is associated with higher odds of MPE (OR = 34.68, 95% CI = 9.17-131.14, p < 0.001). The logistic regression also showed that higher level of malignancy on ROSE of touch preparation is associated with higher odds of MPE (OR = 11.63, 95% CI = 3.85-35.16, p < 0.001). Presence of pleural nodules/masses on CT is associated with higher odds of MPE (OR = 6.61, 95% CI = 1.97-22.1, p = 0.002). A multivariable logistic regression model of final pathologic status with relation to visual assessment, ROSE of touch preparation and presence of pleural nodules/masses on CT had a cross-validated AUC of 0.94 (95% CI = 0.91-0.97). CONCLUSION: A prediction model using visual assessment, ROSE of touch preparation and CT scan findings demonstrated excellent predictive accuracy for MPE. Further validation studies are needed to confirm our findings.

A Prediction Model to Help with Oncologic Mediastinal Evaluation for Radiation: HOMER.

Rationale: When stereotactic ablative radiotherapy is an option for patients with non-small cell lung cancer (NSCLC), distinguishing between N0, N1, and N2 or N3 (N2|3) disease is important.Objectives: To develop a prediction model for estimating the probability of N0, N1, and N2|3 disease.Methods: Consecutive patients with clinical-radiographic stage T1 to T3, N0 to N3, and M0 NSCLC who underwent endobronchial ultrasound-guided staging from a single center were included. Multivariate ordinal logistic regression analysis was used to predict the presence of N0, N1, or N2|3 disease. Temporal validation used consecutive patients from 3 years later at the same center. External validation used three other hospitals.Measurements and Main Results: In the model development cohort (n = 633), younger age, central location, adenocarcinoma, and higher positron emission tomography-computed tomography nodal stage were associated with a higher probability of having advanced nodal disease. Areas under the receiver operating characteristic curve (AUCs) were 0.84 and 0.86 for predicting N1 or higher (vs. N0) disease and N2|3 (vs. N0 or N1) disease, respectively. Model fit was acceptable (Hosmer-Lemeshow, P = 0.960; Brier score, 0.36). In the temporal validation cohort (n = 473), AUCs were 0.86 and 0.88. Model fit was acceptable (Hosmer-Lemeshow, P = 0.172; Brier score, 0.30). In the external validation cohort (n = 722), AUCs were 0.86 and 0.88 but required calibration (Hosmer-Lemeshow, P < 0.001; Brier score, 0.38). Calibration using the general calibration method resulted in acceptable model fit (Hosmer-Lemeshow, P = 0.094; Brier score, 0.34).Conclusions: This prediction model can estimate the probability of N0, N1, and N2|3 disease in patients with NSCLC. The model has the potential to facilitate decision-making in patients with NSCLC when stereotactic ablative radiotherapy is an option.

Shape-sensing robotic-assisted bronchoscopy for pulmonary nodules: initial multicenter experience using the Ion™ Endoluminal System.

BACKGROUND: Traditional bronchoscopy provides limited approach to peripheral nodules. Shape-sensing robotic-assisted bronchoscopy (SSRAB, Ion™ Endoluminal System) is a new tool for minimally invasive peripheral nodule biopsy. We sought to answer the research question: Does SSRAB facilitate sampling of pulmonary nodules during bronchoscopists' initial experience? METHODS: The lead-in stage of a multicenter, single-arm, prospective evaluation of the Ion Endoluminal System (PRECIsE) is described. Enrolled subjects ≥ 18 years old had recent computed tomography evidence of one or more solid or semi-solid pulmonary nodules ≥ 1.0 to ≤ 3.5 cm in greatest dimension and in any part of the lung. Subjects were followed at 10- and 30-days post-procedure. This stage provided investigators and staff their first human experience with the SSRAB system; safety and procedure outcomes were analyzed descriptively. Neither diagnostic yield nor sensitivity for malignancy were assessed in this stage. Categorical variables are summarized by percentage; continuous variables are summarized by median/interquartile range (IQR). RESULTS: Sixty subjects were enrolled across 6 hospitals; 67 nodules were targeted for biopsy. Median axial, coronal and sagittal diameters were < 18 mm with a largest cardinal diameter of 20.0 mm. Most nodules were extraluminal and distance from the outer edge of the nodule to the pleura or nearest fissure was 4.0 mm (IQR: 0.0, 15.0). Median bronchial generation count to the target location was 7.0 (IQR: 6.0, 8.0). Procedure duration (catheter-in to catheter-out) was 66.5 min (IQR: 50.0, 85.5). Distance from the catheter tip to the closest edge of the virtual nodule was 7.0 mm (IQR: 2.0, 12.0). Biopsy completion was 97.0%. No pneumothorax or airway bleeding of any grade was reported. CONCLUSIONS: Bronchoscopists leveraged the Ion SSRAB's functionality to drive the catheter safely in close proximity of the virtual target and to obtain biopsies. This initial, multicenter experience is encouraging, suggesting that SSRAB may play a role in the management of pulmonary nodules. Clinical Trial Registration identifier and date NCT03893539; 28/03/2019.

Complications following symptom-limited thoracentesis using suction.

BACKGROUND: Thoracentesis using suction is perceived to have increased risk of complications, including pneumothorax and re-expansion pulmonary oedema (REPO). Current guidelines recommend limiting drainage to 1.5 L to avoid REPO. Our purpose was to examine the incidence of complications with symptom-limited drainage of pleural fluid using suction and identify risk factors for REPO. METHODS: A retrospective cohort study of all adult patients who underwent symptom-limited thoracentesis using suction at our institution between January 1, 2004 and August 31, 2018 was performed, and a total of 10 344 thoracenteses were included. RESULTS: Pleural fluid ≥1.5 L was removed in 19% of the procedures. Thoracentesis was stopped due to chest discomfort (39%), complete drainage of fluid (37%) and persistent cough (13%). Pneumothorax based on chest radiography was detected in 3.98%, but only 0.28% required intervention. The incidence of REPO was 0.08%. The incidence of REPO increased with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥3 compounded with ≥1.5 L (0.04-0.54%; 95% CI 0.13-2.06 L). Thoracentesis in those with ipsilateral mediastinal shift did not increase complications, but less fluid was removed (p<0.01). CONCLUSIONS: Symptom-limited thoracentesis using suction is safe even with large volumes. Pneumothorax requiring intervention and REPO are both rare. There were no increased procedural complications in those with ipsilateral mediastinal shift. REPO increased with poor ECOG PS and drainage ≥1.5 L. Symptom-limited drainage using suction without pleural manometry is safe.

Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Long-term quality-adjusted survival following therapeutic bronchoscopy for malignant central airway obstruction.

BACKGROUND: While therapeutic bronchoscopy has been used to treat malignant central (CAO) airway obstruction for >25 years, there are no studies quantifying the impact of therapeutic bronchoscopy on long-term quality-adjusted survival. METHODS: We conducted a prospective observational study of consecutive patients undergoing therapeutic bronchoscopy for CAO. Patients had follow-up at 1 week and monthly thereafter until death. Outcomes included technical success (ie, relief of anatomic obstruction), dyspnoea, health-related quality of life (HRQOL) and quality-adjusted survival. RESULTS: Therapeutic bronchoscopy was performed on 102 patients with malignant CAO. Partial or complete technical success was achieved in 90% of patients. At 7 days postbronchoscopy, dyspnoea improved (mean ∆Borg-day-7=-1.8, 95% CI -2.2 to -1.3, p<0.0001) and HRQOL improved (median prebronchoscopy 0.618 utiles, 25%-75% IQR 0.569 to 0.699, mean ∆utility-day-7+0.047 utiles, 95% CI +0.023 to 0.071, p=0.0002). Improvements in dyspnoea and HRQOL were maintained long-term. Compared with the prebronchoscopy baseline, HRQOL per day of life postbronchoscopy improved (mean ∆utility-long-term+0.036 utiles, 95% CI +0.014 to 0.057, p=0.002). Median quality-adjusted survival was 109 quality-adjusted life-days (QALDs) (95% CI 74 to 201 QALDs). Factors associated with longer quality-adjusted survival included better functional status, treatment-naïve tumour, endobronchial disease, less dyspnoea, shorter time from diagnosis to bronchoscopy, absence of cardiac disease, bronchoscopic dilation and receiving chemotherapy. CONCLUSIONS: Therapeutic bronchoscopy improves HRQOL as compared with baseline, resulting in approximately a 5.8% improvement in HRQOL per day of life. The risk-benefit profile in these carefully selected patients was very favourable. TRIAL REGISTRATION NUMBER: Results; NCT03326570.

Centrally located lung cancer and risk of occult nodal disease: an objective evaluation of multiple definitions of tumour centrality with dedicated imaging software.

INTRODUCTION: Current guidelines recommend invasive mediastinal staging in patients with centrally located radiographic stage T1N0M0 nonsmall cell lung cancer (NSCLC). The lack of a specific definition of a central tumour has resulted in discrepancies among guidelines and heterogeneity in practice patterns. METHODS: Our objective was to study specific definitions of tumour centrality and their association with occult nodal disease. Pre-operative chest computed tomography scans from patients with clinical (c) T1N0M0 NSCLC were processed with a dedicated software system that divides the lungs in thirds following vertical and concentric lines. This software accurately assigns tumours to a specific third based both on the location of the centre of the tumour and its most medial aspect, creating eight possible definitions of central tumours. RESULTS: 607 patients were included in our study. Surgery was performed for 596 tumours (98%). The overall pathological (p) N disease was: 504 (83%) N0, 56 (9%) N1, 47 (8%) N2 and no N3. The prevalence of N2 disease remained relatively low regardless of tumour location. Central tumours were associated with upstaging from cN0 to any N (pN1/pN2). Two definitions were associated with upstaging to any N: concentric lines, inner one-third, centre of the tumour (OR 3.91, 95% CI 1.85-8.26; p<0.001) and concentric lines, inner two-thirds, most medial aspect of the tumour (OR 1.91, 95% CI 1.23-2.97; p=0.004). CONCLUSIONS: We objectively identified two specific definitions of central tumours. While the rate of occult mediastinal disease was relatively low regardless of tumour location, central tumours were associated with upstaging from cN0 to any N.

Risk factors for pleural effusion recurrence in patients with malignancy.

BACKGROUND AND OBJECTIVE: The main purpose of treatment in patients with malignant pleural effusion (MPE) is symptom palliation. Currently, patients undergo repeat thoracenteses prior to receiving a definitive procedure as clinicians are not aware of the risk factors associated with fluid recurrence. The primary objective of this study was to identify risk factors associated with recurrent symptomatic MPE. METHODS: Retrospective multicentre cohort study of patients who underwent first thoracentesis was performed. The primary outcome was time to fluid recurrence requiring intervention in patients with evidence of metastatic disease. We used a cause-specific hazard model to identify risk factors associated with fluid recurrence. We also developed a predictive model, utilizing Fine-Gray subdistribution hazard model, and externally validated the model. RESULTS: A total of 988 patients with diagnosed metastatic disease were included. Cumulative incidence of recurrence was high with 30% of patients recurring by day 15. On multivariate analysis, size of the effusion on chest X-ray (up to the top of the cardiac silhouette (hazard ratio (HR): 1.84, 95% CI: 1.21-2.80, P = 0.004) and above the cardiac silhouette (HR: 2.22, 95% CI: 1.43-3.46, P = 0.0004)), larger amount of pleural fluid drained (HR: 1.06, 95% CI: 1.04-1.07, P < 0.0001) and higher pleural fluid LDH (HR: 1.008, 95% CI: 1.004-1.011, P < 0.0001) were associated with increased hazard of recurrence. Negative cytology (HR: 0.52, 95% CI: 0.43-0.64, P < 0.0001) was associated with decreased hazard of recurrence. The model had low prediction accuracy. CONCLUSION: Pleural effusion size, amount of pleural fluid drained, LDH and pleural fluid cytology were found to be risk factors for recurrence.

Intrabronchial Valves for Air Leaks After Lobectomy, Segmentectomy, and Lung Volume Reduction Surgery.

PURPOSE: Air leaks are common after lobectomy, segmentectomy, and lung volume reduction surgery (LVRS). This can increase post-operative morbidity, cost, and hospital length of stay. The management of post-pulmonary resection air leaks remains challenging. Minimally invasive effective interventions are necessary. The Spiration Valve System (SVS, Olympus/Spiration Inc., Redmond, WA, US) is approved by the FDA under humanitarian use exemption for management of prolonged air leaks. METHODS: This is a prospective multicenter registry of 39 patients with air leaks after lobectomy, segmentectomy, and LVRS managed with an intention to use bronchoscopic SVS to resolve air leaks. RESULTS: Bronchoscopic SVS placement was feasible in 82.1% of patients (32/39 patients) and 90 valves were placed with a median of 2 valves per patient (mean of 2.7 ± 1.5 valves, range of 1 to 7 valves). Positive response to SVS placement was documented in 76.9% of all patients (30/39 patients) and in 93.8% of patients when SVS placement was feasible (30/32 patients). Air leaks ultimately resolved when SVS placement was feasible in 87.5% of patients (28/32 patients), after a median of 2.5 days (mean ± SD of 8.9 ± 12.4 days). Considering all patients with an intention to treat analysis, bronchoscopic SVS procedure likely contributed to resolution of air leaks in 71.8% of patients (28/39 patients). The post-procedure median hospital stay was 4 days (mean 6.0 ± 6.1 days). CONCLUSIONS: This prospective registry adds to the growing body of literature supporting feasible and effective management of air leaks utilizing one-way valves.

Non-specific pleuritis in patients with active malignancy.

BACKGROUND AND OBJECTIVE: Pleuroscopy is the test of choice for patients with suspected malignant pleural effusion and negative cytology. Biopsies negative for malignancy are frequently attributed to non-specific pleuritis, which poses a dilemma in patients with a known active malignancy, raising concern for a false-negative result. Our primary objective was to determine the outcomes of patients with active malignancy who had a non-malignant diagnosis on pleuroscopy. METHODS: Retrospective review of all pleuroscopy cases from January 2005 to January 2015 at our institution was conducted. Biopsies were categorized by histopathology as malignant, eosinophilic or non-specific pleuritis. Malignant histopathology was considered a true positive. Eosinophilic or non-specific pleuritis was categorized as malignant, if malignancy was later identified during follow-up, or chemotherapy induced, possible radiation induced, other paramalignant, other benign or idiopathic. RESULTS: Of the 199 pleuroscopy cases reviewed, 172 (86%) had a history of active malignancy. On histopathology, 73 (42%) had malignancy, 9 (5%) had eosinophilic pleuritis and 90 (52%) had non-specific pleuritis. Three patients with non-specific pleuritis were diagnosed with malignancy at follow-up. Pleuritis in 24 patients was chemotherapy induced, 27 were possibly radiation induced, 11 were other paramalignant and 3 were other benign. Idiopathic pleuritis was diagnosed in 31 patients. Patients were monitored for a mean of 23 ± 11 months. CONCLUSION: The prevalence of malignant pleural disease was lower than expected for our patient population. Patients with no malignancy on histopathology were most likely to have non-specific pleuritis, a cause for which was identified in a majority of patients after clinical review.

Diagnostic performance of endobronchial ultrasound-guided mediastinal lymph node sampling in early stage non-small cell lung cancer: A prospective study.

BACKGROUND AND OBJECTIVE: Standard nodal staging of lung cancer consists of positron emission tomography/computed tomography (PET/CT), followed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) if PET/CT shows mediastinal lymphadenopathy. Sensitivity of EBUS-TBNA in patients with N0/N1 disease by PET/CT is unclear and largely based on retrospective studies. We assessed the sensitivity of EBUS-TBNA in this setting. METHODS: We enrolled patients with proven or suspected lung cancer staged as N0/N1 by PET/CT and without metastatic disease (M0), who underwent staging EBUS-TBNA. Primary outcome was sensitivity of EBUS-TBNA compared with a composite reference standard of surgical stage or EBUS-TBNA stage if EBUS demonstrated N2/N3 disease. RESULTS: Seventy-five patients were included in the analysis. Mean tumour size was 3.52 cm (±1.63). Fifteen of 75 patients (20%) had N2 disease. EBUS-TBNA identified six while nine were only identified at surgery. Sensitivity of EBUS-TBNA for N2 disease was 40% (95% CI: 16.3-67.7%). CONCLUSION: A significant proportion of patients with N0/N1 disease by PET/CT had N2 disease (20%) and EBUS-TBNA identified a substantial fraction of these patients, thus improving diagnostic accuracy compared with PET/CT alone. Sensitivity of EBUS-TBNA however appears lower compared with historical data from patients with larger volume mediastinal disease. Therefore, strategies to improve EBUS-TBNA accuracy in this population should be further explored.

Safety of Monitored Anesthesia Care Using Propofol-Based Sedation for Pleuroscopy.

BACKGROUND: The optimal approach to sedation for pleuroscopy remains undefined. Propofol is the favored sedative-hypnotic for many proceduralists but has a narrow therapeutic window and the risk for oversedation is high. Propofol-based sedation administered by anesthesiologists and the routine use of end-tidal capnography and bispectral index (BIS) monitoring may attenuate risks of complications. OBJECTIVES: The purpose of our study was to evaluate the safety and efficacy of monitored anesthesia care for pleuroscopy. METHODS: We conducted a retrospective cohort study of patients who underwent pleuroscopy. The primary outcome of interest was the incidence of anesthesia complications in patients undergoing pleuroscopy. Hypoxia was defined as oxygen saturation of less than 90% for 2 min and hypotension was defined as the need for vasopressors. RESULTS: Of 199 enrolled patients, there were no significant complications attributed directly to anesthesia. Minor complications included hypoxia in 9 patients (4.5%), hypotension in 76 patients (38.2%), and insertion of a nasopharyngeal tube airway in 2 patients (1.0%). There was no significant difference in anesthesia-related complications between those with BIS monitoring and those without. Lower mean oxygen saturations (p = 0.028) and hypoxia (p = 0.021) were found in patients receiving the combination of propofol plus narcotics plus sedatives compared to those receiving propofol only, propofol plus narcotics or propofol plus sedatives. CONCLUSION: Our study demonstrates that pleuroscopy using propofol with end-tidal capnography monitoring, with or without BIS monitoring, is safe and effective. The combination of propofol with narcotics and sedatives is associated with more hypoxia and lower mean oxygen saturation compared with propofol alone, propofol plus narcotics or propofol plus sedatives.

A Prediction Model to Help with the Assessment of Adenopathy in Lung Cancer: HAL.

RATIONALE: Estimating the probability of finding N2 or N3 (prN2/3) malignant nodal disease on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with non-small cell lung cancer (NSCLC) can facilitate the selection of subsequent management strategies. OBJECTIVES: To develop a clinical prediction model for estimating the prN2/3. METHODS: We used the AQuIRE (American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education) registry to identify patients with NSCLC with clinical radiographic stage T1-3, N0-3, M0 disease that had EBUS-TBNA for staging. The dependent variable was the presence of N2 or N3 disease (vs. N0 or N1) as assessed by EBUS-TBNA. Univariate followed by multivariable logistic regression analysis was used to develop a parsimonious clinical prediction model to estimate prN2/3. External validation was performed using data from three other hospitals. MEASUREMENTS AND MAIN RESULTS: The model derivation cohort (n = 633) had a 25% prevalence of malignant N2 or N3 disease. Younger age, central location, adenocarcinoma histology, and higher positron emission tomography-computed tomography N stage were associated with a higher prN2/3. Area under the receiver operating characteristic curve was 0.85 (95% confidence interval, 0.82-0.89), model fit was acceptable (Hosmer-Lemeshow, P = 0.62; Brier score, 0.125). We externally validated the model in 722 patients. Area under the receiver operating characteristic curve was 0.88 (95% confidence interval, 0.85-0.90). Calibration using the general calibration model method resulted in acceptable goodness of fit (Hosmer-Lemeshow test, P = 0.54; Brier score, 0.132). CONCLUSIONS: Our prediction rule can be used to estimate prN2/3 in patients with NSCLC. The model has the potential to facilitate clinical decision making in the staging of NSCLC.

Randomized trial of endobronchial ultrasound-guided transbronchial needle aspiration under general anesthesia versus moderate sedation.

RATIONALE: Data about the influence of the type of sedation on yield, complications, and tolerance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are based mostly on retrospective studies and are largely inconsistent. OBJECTIVES: To determine whether the type of sedation influences the diagnostic yield of EBUS-TBNA, its complication rates, and patient tolerance. METHODS: Patients referred for EBUS-TBNA were randomized (1:1) to undergo this procedure under general anesthesia (GA) or moderate sedation (MS). Pathologists were blinded to group allocation. MEASUREMENTS AND MAIN RESULTS: The main outcome was "diagnostic yield," defined as the percentage of patients for whom EBUS-TBNA rendered a specific diagnosis. One hundred and forty-nine patients underwent EBUS-TBNA, 75 under GA and 74 under MS. Demographic and baseline clinical characteristics were well balanced. Two hundred and thirty-six lymph nodes (LNs) and six masses were sampled in the GA group (average, 3.2 ± 1.9 sites/patient), and 200 LNs and six masses in the MS group (average, 2.8 ± 1.5 sites/patient) (P = 0.199). The diagnostic yield was 70.7% (53 of 75) and 68.9% (51 of 74) for the GA group and MS group, respectively (P = 0.816). The sensitivity was 98.2% in the GA group (confidence interval, 97-100%) and 98.1% in the MS group (confidence interval, 97-100%) (P = 0.979). EBUS was completed in all patients in the GA group, and in 69 patients (93.3%) in the MS group (P = 0.028). There were no major complications or escalation of care in either group. Minor complications were more common in the MS group (29.6 vs. 5.3%) (P < 0.001). Most patients stated they "definitely would" undergo this procedure again in both groups (P = 0.355). CONCLUSIONS: EBUS-TBNA performed under MS results in comparable diagnostic yield, rate of major complications, and patient tolerance as under GA. Future prospective multicenter studies are required to corroborate our findings. Clinical trial registered with www.clinicaltrials.gov (NCT 01430962).

The use of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of thyroid lesions.

BACKGROUND: Non-palpable thyroid nodules can be difficult to access by conventional ultrasound-guided fine needle aspiration, particularly when they are intrathoracic. Many of these patients are subject to multiple follow up scans or invasive diagnostic procedures such as mediastinoscopy or surgical resection. We aim to describe the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis of thyroid lesions. METHODS: All EBUS-TBNA performed at our institutions from February 2010 to February 2013 were screened, and those in which a thyroid biopsy was performed were reviewed. RESULTS: We identified 12 cases of EBUS-TBNA thyroid biopsy. Nine patients had an indication for EBUS in addition to their thyroid lesions. The median age was 64 years (range 44 to 84 years), and 10 patients were male. Median lesion size was 22.5 mm (range, 10 to 43 mm). Five lesions were strictly intrathoracic. All cases were sampled with a 22G needle and rapid on-site cytologic examination. Adequate samples were obtained in all 12 cases. Malignancy was identified in 3 of the 12 patients (metastatic breast adenocarcinoma, large B-cell lymphoma, and metastatic lung adenocarcinoma). The remaining 9 samples were deemed to be benign nodules. Seven of these were confirmed by clinical follow-up (n = 3), biopsies (n = 3), or surgery (n = 1).There were no EBUS-related complications. CONCLUSIONS: EBUS-TBNA might be a safe and effective alternative for sampling thyroid lesions, particularly useful for those located below the thoracic inlet. Further prospective studies are required to compare its diagnostic yield and safety profile with standard techniques.

Guideline for the acquisition and preparation of conventional and endobronchial ultrasound-guided transbronchial needle aspiration specimens for the diagnosis and molecular testing of patients with known or suspected lung cancer.

RATIONALE: Conventional transbronchial needle aspiration (TBNA) and endobronchial ultrasound (EBUS)-TBNA are widely accepted tools for the diagnosis and staging of lung cancer and the initial procedure of choice for staging. Obtaining adequate specimens is key to provide a specific histologic and molecular diagnosis of lung cancer. OBJECTIVES: To develop practice guidelines on the acquisition and preparation of conventional TBNA and EBUS-TBNA specimens for the diagnosis and molecular testing of (suspected) lung cancer. We hope to improve the global unification of procedure standards, maximize the yield and identify areas for research. METHODS: Systematic electronic database searches were conducted to identify relevant studies for inclusion in the guideline [PubMed and the Cochrane Library (including the Cochrane Database of Systematic Reviews)]. MAIN RESULTS: The number of needle aspirations with both conventional TBNA and EBUS-TBNA was found to impact the diagnostic yield, with at least 3 passes needed for optimal performance. Neither needle gauge nor the use of miniforceps, the use of suction or the type of sedation/anesthesia has been found to improve the diagnostic yield for lung cancer. The use of rapid on-site cytology examination does not increase the diagnostic yield. Molecular analysis (i.e. EGFR, KRAS and ALK) can be routinely performed on the majority of cytological samples obtained by EBUS-TBNA and conventional TBNA. There does not appear to be a superior method for specimen preparation (i.e. slide staining, cell blocks or core tissue). It is likely that optimal specimen preparation may vary between institutions depending on the expertise of pathology colleagues.

Incremental Application of Positive End-Expiratory Pressure for the Evaluation of Atelectasis During RP-EBUS and Bronchoscopy (I-APPEAR).

BACKGROUND: CT-to-body divergence-described as the difference between preprocedural CT scans and intraprocedural lung architecture-is a significant barrier to improving diagnostic yield during navigational bronchoscopy. A major proposed contributor to CT-to-body divergence is the development of atelectasis, which can confound visualization of peripheral lung lesions via radial probe endobronchial ultrasound (RP-EBUS). High positive end-expiratory pressure (PEEP) ventilatory strategies have been used to decrease atelectasis, allowing the lesion to re-APPEAR on intraprocedure imaging. However, standardized PEEP levels may not be appropriate for all patients due to hemodynamic and ventilatory impacts. METHODS: We performed a multicenter, prospective observational study in which patients were imaged with RP-EBUS under general anesthesia to determine if subsegmental atelectasis would resolve as incremental increases in PEEP were applied. Resolution of atelectasis was based on the transition from a non-aerated pattern to an aerated appearance on RP-EBUS. RP-EBUS images were reviewed by 3 experienced operators to determine correlation. RESULTS: Forty-three patients underwent RP-EBUS examination following navigational bronchoscopy. Thirty-seven patients underwent incremental PEEP application and subsequent RP-EBUS imaging. Atelectasis was determined to have resolved in 33 patients (88.2%) following increased PEEP. The intraclass correlation coefficient between reviewers was 0.76. A recruitment maneuver was performed in 7 (16.3%) patients after atelectasis persisted at maximal PEEP. Atelectasis was not identified in the examined subsegments in 6 (10.8%) patients despite zero PEEP. CONCLUSION: RP-EBUS is an effective tool to monitor what pressure atelectasis within a lung segment has resolved with increasing levels of PEEP.

Severity of Atelectasis during Bronchoscopy: Descriptions of a New Grading System (AtelectasisSeverity Scoring System-"ASSESS") and At-Risk-Lung Zones.

Atelectasis during bronchoscopy under general anesthesia is very common and can have a detrimental effect on navigational and diagnostic outcomes. While the intraprocedural incidence and anatomic location have been previously described, the severity of atelectasis has not. We reviewed chest CT images of patients who developed atelectasis in the VESPA trial (Ventilatory Strategy to Prevent Atelectasis). By drawing boundaries at the posterior chest wall (A), the anterior aspect of the vertebral body (C), and mid-way between these two lines (B), we delineated at-risk lung zones 1, 2, and 3 (from posterior to anterior). An Atelectasis Severity Score System ("ASSESS") was created, classifying atelectasis as "mild" (zone 1), "moderate" (zones 1-2), and "severe" (zones 1-2-3). A total of 43 patients who developed atelectasis were included in this study. A total of 32 patients were in the control arm, and 11 were in the VESPA arm; 20 patients (47%) had mild atelectasis, 20 (47%) had moderate atelectasis, and 3 (6%) had severe atelectasis. A higher BMI was associated with increased odds (1.5 per 1 unit change; 95% CI, 1.10-2.04) (p = 0.0098), and VESPA was associated with decreased odds (0.05; 95% CI, 0.01-0.47) (p = 0.0080) of developing moderate to severe atelectasis. ASSESS is a simple method used to categorize intra-bronchoscopy atelectasis, which allows for a qualitative description of this phenomenon to be developed. In the VESPA trial, a higher BMI was not only associated with increased incidence but also increased severity of atelectasis, while VESPA had the opposite effect. Preventive strategies should be strongly considered in patients with risk factors for atelectasis who have lesions located in zones 1 and 2, but not in zone 3.