Update on Biomarkers for the Stratification of Indeterminate Pulmonary Nodules.

Lung cancer is the leading cause of cancer-related deaths. Early detection and diagnosis are critical, as survival decreases with advanced stages. Approximately 1.6 million nodules are incidentally detected every year on chest CT scan images in the United States. This number of nodules identified is likely much larger after accounting for screening-detected nodules. Most of these nodules, whether incidentally or screening detected, are benign. Despite this, many patients undergo unnecessary invasive procedures to rule out cancer because our current stratification approaches are suboptimal, particularly for intermediate probability nodules. Thus, noninvasive strategies are urgently needed. Biomarkers have been developed to assist through the continuum of lung cancer care and include blood protein-based biomarkers, liquid biopsies, quantitative imaging analysis (radiomics), exhaled volatile organic compounds, and bronchial or nasal epithelium genomic classifiers, among others. Although many biomarkers have been developed, few have been integrated into clinical practice as they lack clinical utility studies showing improved patient-centered outcomes. Rapid technologic advances and large network collaborative efforts will continue to drive the discovery and validation of many novel biomarkers. Ultimately, however, randomized clinical utility studies showing improved patient outcomes will be required to bring biomarkers into clinical practice.

Absolute and Relative Vaccine Effectiveness of Primary and Booster Series of COVID-19 Vaccines (mRNA and Adenovirus Vector) Against COVID-19 Hospitalizations in the United States, December 2021-April 2022.

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) studies are increasingly reporting relative VE (rVE) comparing a primary series plus booster doses with a primary series only. Interpretation of rVE differs from traditional studies measuring absolute VE (aVE) of a vaccine regimen against an unvaccinated referent group. We estimated aVE and rVE against COVID-19 hospitalization in primary-series plus first-booster recipients of COVID-19 vaccines. Methods: Booster-eligible immunocompetent adults hospitalized at 21 medical centers in the United States during December 25, 2021-April 4, 2022 were included. In a test-negative design, logistic regression with case status as the outcome and completion of primary vaccine series or primary series plus 1 booster dose as the predictors, adjusted for potential confounders, were used to estimate aVE and rVE. Results: A total of 2060 patients were analyzed, including 1104 COVID-19 cases and 956 controls. Relative VE against COVID-19 hospitalization in boosted mRNA vaccine recipients versus primary series only was 66% (95% confidence interval [CI], 55%-74%); aVE was 81% (95% CI, 75%-86%) for boosted versus 46% (95% CI, 30%-58%) for primary. For boosted Janssen vaccine recipients versus primary series, rVE was 49% (95% CI, -9% to 76%); aVE was 62% (95% CI, 33%-79%) for boosted versus 36% (95% CI, -4% to 60%) for primary. Conclusions: Vaccine booster doses increased protection against COVID-19 hospitalization compared with a primary series. Comparing rVE measures across studies can lead to flawed interpretations of the added value of a new vaccination regimen, whereas difference in aVE, when available, may be a more useful metric.

Predictive performance of selected breath volatile organic carbon compounds in stage 1 lung cancer.

Background: Lung cancer remains the leading cause of cancer deaths accounting for almost 25% of all cancer deaths. Breath-based volatile organic compounds (VOCs) have been studied in lung cancer but previous studies have numerous limitations. We conducted a prospective matched case to control study of the ability of preidentified VOC performance in the diagnosis of stage 1 lung cancer (S1LC). Methods: Study participants were enrolled in a matched case to two controls study. A case was defined as a patient with biopsy-confirmed S1LC. Controls included a matched control, by risk factors, and a housemate control who resided in the same residence as the case. We included 88 cases, 88 risk-matched, and 49 housemate controls. Each participant exhaled into a Tedlar® bag which was analyzed using gas chromatography-mass spectrometry. For each study participant's breath sample, the concentration of thirteen previously identified VOCs were quantified and assessed using area under the curve in the detection of lung cancer. Results: Four VOCs were above the limit of detection in more than 10% of the samples. Acetoin was the only compound that was significantly associated with S1LC. Acetoin concentration below the 10th percentile (0.026 µg/L) in the training data had accuracy of 0.610 (sensitivity =0.649; specificity =0.583) in the test data. In multivariate logistic models, the best performing models included Acetoin alone (AUC =0.650). Conclusions: Concentration of Acetoin in exhaled breath has low discrimination performance for S1LC cases and controls, while there was not enough evidence for twelve additional published VOCs.

Effectiveness of the Ad26.COV2.S (Johnson & Johnson) Coronavirus Disease 2019 (COVID-19) Vaccine for Preventing COVID-19 Hospitalizations and Progression to High Disease Severity in the United States.

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, we estimated VE against disease progression (VEp) to death or invasive mechanical ventilation (IMV), comparing odds of prior vaccination between patients with and without progression. Results . After excluding patients receiving mRNA vaccines, among 3979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2229 controls (13% vaccinated with Ad26.COV2.S), VEs of Ad26.COV2.S against COVID-19 hospitalization was 70% (95% confidence interval [CI]: 63-75%) overall, including 55% (29-72%) among immunocompromised patients, and 72% (64-77%) among immunocompetent patients, for whom VEs was similar at 14-90 days (73% [59-82%]), 91-180 days (71% [60-80%]), and 181-274 days (70% [54-81%]) postvaccination. Among hospitalized COVID-19 case-patients, VEp was 46% (18-65%) among immunocompetent patients. Conclusions . The Ad26.COV2.S COVID-19 vaccine reduced the risk of COVID-19 hospitalization by 72% among immunocompetent adults without waning through 6 months postvaccination. After hospitalization for COVID-19, vaccinated immunocompetent patients were less likely to require IMV or die compared to unvaccinated immunocompetent patients.

Assessment of Ergonomic Strain and Positioning During Bronchoscopic Procedures: A Feasibility Study.

BACKGROUND: Poor ergonomics place health care workers at risk for work-related overuse injuries. Repetitive and prolonged hand maneuvers, such as those performed during endoscopic procedures, may lead to musculoskeletal complaints and work-related injuries. However, the prevalence of health care-related work injuries among physicians is thought to be underreported and there is a paucity of literature investigating the impact of ergonomic strain on bronchoscopy. We designed a feasibility study to explore the differences in ergonomic strain and muscle activity of bronchoscopists. MATERIALS AND METHODS: A prospective study of bronchoscopic procedures was performed in a simulated environment. Preselected target areas were identified and airway sampling was performed with real-time ergonomic assessment utilizing electromyogram (EMG), grip strength, and musculoskeletal use and motion analysis. RESULTS: Procedural data was obtained for all procedures (78 bronchoscopies by 13 subjects) for both ergonomic and EMG scores. Experienced bronchoscopists demonstrated less EMG burden (P=0.007) and improved ergonomic positioning (P=0.007) during bronchoscopy when compared with less experienced bronchoscopists. Procedures performed with rotational-head bronchoscopes trended toward improved ergonomics (P=0.15) and lower EMG scores (P=0.88). A significant improvement in ergonomic scores was seen with the rotational-head bronchoscope when targeting the left upper lobe (P=0.036). CONCLUSION: Poor ergonomic positioning and excessive muscle strain appear present within bronchoscopy procedures but may be improved in those with more bronchoscopy experience. Technological advances in bronchoscope design may also have the potential to improve procedural ergonomics. Additional prospective studies are warranted to define the long-term impact on bronchoscopic ergonomics.

First-in-Human Use of a Hybrid Real-Time Ultrasound-Guided Fine-Needle Acquisition System for Peripheral Pulmonary Lesions: A Multicenter Pilot Study.

BACKGROUND: The ability to successfully perform a biopsy on pulmonary lesions by means of bronchoscopy varies widely due to anatomic and technological limitations. One major limitation is the lack of the ability to utilize real-time guidance during tissue sampling in the periphery. A novel system has been developed that enables real-time visualization and sampling of peripheral lesions by displaying an ultrasound image of the lesion and needle simultaneously. METHODS: We performed a multicenter, prospective pilot in patients with peripheral pulmonary lesions undergoing a clinically indicated bronchoscopy. The purpose of this study was to demonstrate the feasibility of visualizing, accessing, and obtaining specimens adequate for the cytology of lung lesions when using a novel hybrid real-time ultrasound-guided fine-needle aspiration system for peripheral pulmonary lesions. RESULTS: Twenty-three patients underwent bronchoscopic sampling of a peripheral pulmonary lesion with the study device. Mean lesion size was 3.6 (range 1.7-5.7) cm. Targeted lesions were located in all lobes of the lung. All lesions were successfully visualized and sampled under real-time visualization with specimens adequate for cytological evaluation. The needle was visualized in all lesions throughout targeting and sampling. There were no incidents of pneumothorax or moderate-to-severe bleeding. CONCLUSION: In this feasibility study, we report the first-in-human use of a continuous real-time endobronchial ultrasound guidance system to sample peripheral pulmonary lesions. Future generations of this device may improve usability and further studies are needed to determine the true diagnostic capabilities of this novel technique.

Prospective Multicentered Safety and Feasibility Pilot for Endobronchial Intratumoral Chemotherapy.

BACKGROUND: Malignant airway obstruction (MAO) occurs in 30% of patients with advanced-stage lung cancer, leading to debilitating dyspnea, cough, and hemoptysis. Other than recanalization of the airways, these patients lack long-lasting palliative therapy. The goal of this study was to determine the safety and feasibility of local injection of paclitaxel into the airway wall with a novel microinjection catheter. METHODS: In this multicentered prospective trial, 23 patients with non-small cell lung cancer and MAO were enrolled from July 2014 through June 2016 to undergo rigid bronchoscopy with recanalization, followed by injection of 1.5 mg of paclitaxel with a novel injection catheter. Primary end points consisted of safety (adverse events, severe adverse events, and unanticipated adverse device effects) as well as feasibility (number of injections, injection success). Secondary end points consisted of airway patency improvement, quality of life metrics, and need for further interventions and/or stenting. RESULTS: Nineteen patients underwent rigid bronchoscopy with successful recanalization and paclitaxel injection. There were no adverse events, severe adverse events, or unanticipated adverse device effects. There was an average of 3.4 injections given for a total dose of 1.5 mg of paclitaxel in all patients. There was significantly less stenosis postprocedure vs preprocedure (25%-50% vs 75%-90%; P < .001), which was unchanged at 6 weeks (25%-50%). None of the participants required further interventions or airway stenting. CONCLUSIONS: The injection of paclitaxel after recanalization of MAO in patients with non-small cell lung cancer is safe and feasible, using a novel airway injection device. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02066103; URL: www.clinicaltrials.gov.

Safety and diagnostic performance of pulmonologists performing electromagnetic guided percutaneous lung biopsy (SPiNperc).

BACKGROUND AND OBJECTIVE: Percutaneous lung biopsy for diagnostic sampling of peripheral lung nodules has been widely performed by interventional radiologists under computed tomography (CT) guidance. New technology allows pulmonologists to perform percutaneous lung biopsies using electromagnetic (EM) guided technology. With the adoption of this new technique, the safety, feasibility and diagnostic yield need to be explored. The goal of this study was to determine the safety, feasibility and diagnostic yield of EM-guided percutaneous lung biopsy performed by pulmonologists. METHODS: We conducted a retrospective, multicentre study of 129 EM-guided percutaneous lung biopsies that occurred between November 2013 and March 2017. The study consisted of seven academic and three community medical centres. RESULTS: The average age of participants was 65.6 years, BMI was 26.3 and 50.4% were females. The majority of lesions were in the right upper lobe (37.2%) and left upper lobe (31.8%). The mean size of the lesions was 27.31 mm and the average distance from the pleura was 13.2 mm. Practitioners averaged two fine-needle aspirates and five core biopsies per procedure. There were 23 (17.8%) pneumothoraces, of which 16 (12.4%) received small-bore chest tube placement. The diagnostic yield of percutaneous lung biopsy was 73.7%. When EM-guided bronchoscopic sampling was also performed during the same procedural encounter, the overall diagnostic yield increased to 81.1%. CONCLUSION: In this large multicentred series, the use of EM guidance for percutaneous lung biopsies was safe and feasible, with acceptable diagnostic yield in the hands of pulmonologists. A prospective multicentre trial to validate these findings is currently underway (NCT03338049).

Learning Electromagnetic Navigational Bronchoscopy and Percutaneous Transthoracic Needle Biopsy (LEAP): A Pilot Study.

BACKGROUND: Prior studies in pulmonology have examined the validity of procedural training tools, however, translation of simulation skill acquisition into real world competency remains understudied. We examine an assessment process with a simulation training course for electromagnetic navigational (EMN) bronchoscopy and percutaneous transthoracic needle aspiration (PTTNA). METHODS: A cohort study was conducted by subjects using EMN bronchoscopy and PTTNA. A procedural assessment tool was developed to measure basic competency for EMN bronchoscopy and PTTNA at 3 different time points: first simulation case, final simulation case upon reaching a competent score, and at their first live case. The assessment tool was divided into 4 domains (total score, 4 to 16; competency ≥12) with each domain requiring a passing score (1 to 4; competency ≥3.0). Complication and procedural time were collected during their first live case. RESULTS: Twenty-two serial procedures (12 EMN bronchoscopies, 10 EMN PTTNA) were observed by 14 subjects. The mean first simulation score for EMN bronchoscopy (4.66±0.89) improved after cadaver simulation (12.67±0.89, median 3 simulations attempts). The subjects' mean score for their first live case was 13.0±0.85 (self-reported score 12.5±1.07). For EMN PTTNA, the mean first simulation score (4.3±2.40) improved after cadaver simulation (12.6±1.51, median 3 simulation attempts). The subjects' mean score for their first live PTTNA case was 12.5±2.87 (self-reported score 12.1±1.05). There was only 1 minor complication. CONCLUSION: Learning EMN bronchoscopy/PTTNA is feasible using a structured simulation course with an assessment tool.

Minimally invasive palliative interventions in advanced lung cancer.

INTRODUCTION: Lung cancer is the leading cause of cancer-related deaths in the United States. Nearly 85% of all lung cancers are diagnosed at a late stage, with an associated five-year survival rate of 4%. Malignant central airway obstruction and malignant pleural effusions occur in upwards of 30% of these patients. Many of these patients are in need of palliative interventions for symptom control and to help improve their quality of life. Areas covered: This review covers the treatment modalities of malignant central airway obstruction and malignant pleural effusion. PubMed was used to search for the most up to date and clinically relevant articles that guide current treatment strategies. This review focuses on rigid bronchoscopy and the tools used for the relief of central airway obstruction, as well as intra-pleural catheter use and pleurodesis for the management of malignant pleural effusions. Expert commentary: There are multiple treatment modalities that may be used to help alleviate the symptoms of malignant central airway obstruction and pleural effusion. The modality used depends on the urgency of the situation, and specific patient's goals. An open dialog to understand the patient's end of life goals is an important factor when choosing the appropriate treatment strategy.

Study Design and Rationale: A Multicenter, Prospective Trial of Electromagnetic Bronchoscopic and Electromagnetic Transthoracic Navigational Approaches for the Biopsy of Peripheral Pulmonary Nodules (ALL IN ONE Trial).

BACKGROUND: Pulmonary nodules are a common but difficult issue for physicians as most identified on imaging are benign but those identified early that are cancerous are potentially curable. Multiple diagnostic options are available, ranging from radiographic surveillance, minimally invasive biopsy (bronchoscopy or transthoracic biopsy) to more invasive surgical biopsy/resection. Each technique has differences in diagnostic yield and complication rates with no established gold standard. Currently, the safest approach is bronchoscopic but it is limited by variable diagnostic yields. Percutaneous approaches are limited by nodule location and complications. With the recent advent of electromagnetic navigation (EMN), a combined bronchoscopic and transthoracic approach is now feasible in a single, staged procedure. Here, we present the study design and rationale for a single-arm trial evaluating a staged approach for the diagnosis of pulmonary nodules. METHODS: Participants with 1-3 cm, intermediate to high-risk pulmonary nodules will undergo a staged approach with endobronchial ultrasound (EBUS) followed by EMN-bronchoscopy (ENB), then EMN-transthoracic biopsy (EMN-TTNA) with the procedure terminated at any stage after a diagnosis is made via rapid onsite cytopathology. We aim to recruit 150 EMN participants from eight academic and community settings to show significant improvements over other historic bronchoscopic guided techniques. The primary outcome is overall diagnostic yield of the staged approach. CONCLUSION: This is the first study designed to evaluate the diagnostic yield of a staged procedure using EBUS, ENB and EMN-TTNA for the diagnosis of pulmonary nodules. If effective, the staged procedure will increase minimally invasive procedural diagnostic yield for pulmonary nodules.

External beam radiation therapy combined with airway stenting leads to better survival in patients with malignant airway obstruction.

BACKGROUND AND OBJECTIVE: Malignant airway obstruction (MAO), a common complication of patients with advanced lung cancer, causes debilitating dyspnoea and poor quality of life. Two common interventions used in the treatment of MAO include bronchoscopy with airway stenting and external beam radiotherapy (EBRT). Data are limited regarding their clinical effectiveness and overall effect on survival. METHODS: A retrospective chart review of patients treated with airway stenting and/or EBRT at the Johns Hopkins Hospital for MAO between July 2010 and January 2017 was reviewed. Demographics, performance status, cancer histology, therapeutic intervention and date of death were recorded. Survival was calculated using cox regression analysis. RESULTS: Of the 606 patients who were treated for MAO, 237 were identified as having MAO and included in the study. Sixty-eight patients underwent rigid bronchoscopy and stenting, 102 EBRT and 67 a combined approach. Patients who underwent stenting hand an increased hazard ratio (HR) of death in comparison to those who received combination therapy (HR: 2.12, 95% CI: 1.02, 4.39), while there was a trend towards significance in the EBRT alone group in comparison to the combination therapy group (HR: 1.62, 95% CI: 0.93, 2.83). CONCLUSION: In this retrospective analysis, combination therapy with stenting and EBRT led to better survival in comparison to stenting or EBRT alone. Prospective cohort trials are needed to confirm these results.

The Relative Effects of Artemether-lumefantrine and Non-artemisinin Antimalarials on Gametocyte Carriage and Transmission of Plasmodium falciparum: A Systematic Review and Meta-analysis.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have been widely adopted as first-line agents to treat uncomplicated falciparum malaria due to their activity against multidrug resistant parasites. ACTs may also disrupt transmission through a direct antigametocyte effect, but the extent of this effect is uncertain. We assessed the evidence for and estimated the effects of the most widely-deployed ACT, artemether-lumefantrine (AL), relative to non-ACTs on gametocyte clearance and transmission interruption. METHODS: We searched electronic databases for randomized controlled trials comparing AL to non-ACTs that reported gametocyte counts or results of mosquito-feeding assays. Two authors working independently assessed eligibility, extracted data, and evaluated the risk of bias. We conducted meta-analyses using a random-effects model. RESULTS: We identified 22 eligible trials. The pooled odds of gametocytemia at 1 week were lower in AL- compared to non-ACT-treated participants (odds ratio [OR] 0.09; 95% confidence interval [CI], 0.06-0.15; I2 = 0.60, P < .01; 15 trials). The odds of transmission to mosquitoes were also lower in AL treatment groups (OR 0.06; 95% CI, 0.00-0.47, P < .01 at 7 days post-treatment; 1 trial; OR 0.56; 95% CI, 0.36-0.88, P = .01 at 14 days post-treatment; 1 trial). CONCLUSION: AL is superior to non-ACTs in reducing gametocytemia, and, based on limited evidence, abating transmission to mosquitoes. The transmission-limiting benefit of AL has relevance for policymakers planning optimal utilization of control strategies, including use of ACTs for malaria treatment and chemoprevention.

Stylet Use Does Not Improve Diagnostic Outcomes in Endobronchial Ultrasonographic Transbronchial Needle Aspiration: A Randomized Clinical Trial.

BACKGROUND: Endobronchial ultrasonographically guided transbronchial needle aspiration (EBUS-TBNA) of thoracic structures is a commonly performed tissue sampling technique. The use of an inner-stylet in the EBUS needle has never been rigorously evaluated and may be unnecessary. METHODS: In a prospective randomized single-blind controlled clinical trial, patients with a clinical indication for EBUS-TBNA underwent lymph node sampling using both with-stylet and without-stylet techniques. Sample adequacy, diagnostic yield, and various cytologic quality measures were compared. RESULTS: One hundred twenty-one patients were enrolled, with 194 lymph nodes sampled, each using both with-stylet and without-stylet techniques. There was no significant difference in sample adequacy or diagnostic yield between techniques. The without-stylet technique resulted in adequate samples in 87% of the 194 study lymph nodes, which was no different from the with-stylet adequacy rate (82%; P = .371). The with-stylet technique resulted in a diagnosis in 50 of 194 samples (25.7%), which was similar to the without-stylet group (49 of 194 [25.2%]; P = .740). There was a high degree of concordance in the determination of adequacy (84.0%; 95% CI, 78.1-88.9) and diagnostic sample generation (95.4%; 95% CI, 91.2-97.9) between the two techniques. A similar qualitative number of lymphocytes, malignant cells, and bronchial respiratory epithelia were recovered using each technique. CONCLUSIONS: Omitting stylet use during EBUS-TBNA does not affect diagnostic outcomes and reduces procedural complexity. TRIAL REGISTRY: ClinicalTrials.Gov: No. NCT 02201654; URL:www.clinicaltrials.gov.

Same-Day Computed Tomographic Chest Imaging for Pulmonary Nodule Targeting with Electromagnetic Navigation Bronchoscopy May Decrease Unnecessary Procedures.

RATIONALE: Bronchoscopy is commonly used for the diagnosis of suspicious pulmonary nodules discovered on computed tomographic (CT) imaging of the chest. Procedural CT imaging for bronchoscopy planning is often completed weeks to months before the date of a scheduled bronchoscopy, which may not allow discovery of a decrease in nodule size or resolution before the bronchoscopic procedure. OBJECTIVES: To determine whether same-day CT imaging of the chest discovers partial or total resolution of some lung nodules and thereby reduces unnecessary bronchoscopic procedures. METHODS: We performed a prospective case series study of patients undergoing navigational bronchoscopy using a new technology requiring same-day preprocedural CT imaging at one university teaching hospital. Patients scheduled to undergo bronchoscopy who were found to have partial or complete resolution of their lesion on the same-day CT exam leading to the cancellation of their procedure were identified and further characterized. MEASUREMENTS AND MAIN RESULTS: From January 2015 to June 2016, 116 patients were scheduled for navigational bronchoscopy for the diagnosis of a pulmonary lesion. Of the 116 patients scheduled, 8 (6.9%) had a decrease in size or resolution of their lesion, leading to the cancellation of their procedure. The number needed to screen to prevent one unnecessary procedure was 15. For cancelled cases, the average time from initial CT prompting referral for bronchoscopy to the day of procedure scan was 53 days. CONCLUSIONS: Time from initial imaging to day of procedure is variable, occasionally allowing enough time for lesions to resolve, thereby obviating the need for biopsy. Same-day imaging may decrease unnecessary procedural risk.