Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry.

Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ cells in MPEs. We show that these states may be relevant to disease stage and therapy response. Furthermore, we found that the fraction of CD33+ myeloid cells in PEs was positively correlated to the fraction of CK+ cells. Longitudinal analysis of MPEs drawn 2 months apart from a patient undergoing therapy, revealed that CK+ cells acquired heterogeneous EMT features during treatment. We present this work as a feasibility study that justifies deeper characterization of EMT and MET states in malignant cells found in PEs as a promising clinical platform to better evaluate disease progression and treatment response at a personalized level.

Unilateral Diaphragmatic Paralysis After Stereotactic Ablative Radiation Therapy to a Lung Tumor Abutting the Course of the Phrenic Nerve.

We present the case of a woman with metastatic adenoid cystic carcinoma who received stereotactic ablative radiation therapy with a total dose of 50 Gy in 4 fractions to 2 lung metastases and developed symptomatic left phrenic nerve injury 2 years after radiation. The maximum dose to the approximate location of the phrenic nerve was 57.7 Gy, which corresponds to a biologically effective dose for late effects (using α/ß ratio = 3) of 335.14 Gy. Here, we discuss the case, planning considerations by radiation oncologists and medical physicists, and the multidisciplinary medical management of this patient.

Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer.

Genomic profiling of bronchoalveolar lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non-small cell lung cancer (NSCLC) to those detected in matched plasma samples. Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma, and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared with those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (P < 0.001) and in stage I to II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA [mean variant allele frequency (VAF) = 0.5%], suggesting the presence of somatic mutations in nonmalignant airway cells. Finally, using a Random Forest model with leave-one-out cross-validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility. SIGNIFICANCE: Hybrid-capture, targeted deep sequencing of lung cancer mutational burden in cell-free BAL fluid identifies more tumor-derived mutations with increased allele frequencies compared with plasma cell-free DNA. See related commentary by Rolfo et al., p. 2826.

Use of home pulse oximetry with daily short message service messages for monitoring outpatients with COVID-19: The patient's experience.

Studies have shown COVID-19 patients may have a low oxygen saturation (SpO2) independent of visible respiratory distress, a phenomenon termed "silent hypoxia." Silent hypoxia creates uncertainty in the outpatient setting for clinicians and patients alike. In this study, we examined the potential for pulse oximeters in identifying early signs of clinical deterioration. We report descriptive results on COVID-positive patients' experiences with a comprehensive home monitoring tool comprised of home SpO2 measurements with a novel symptom-tracking short message service/text messaging application. Of patients who required hospitalization, 83% sought care as a result of low pulse oximeter readings. Nearly all patients who did not require hospitalization reported that having a pulse oximeter provided them with the confidence to stay at home. Essentially all patients found a home pulse oximeter useful. Keeping COVID-19-positive patients at home reduces the potential for disease spread and prevents unnecessary costs and strain on the healthcare system.

Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines.

Lung neuroendocrine tumors (LNETs) are uncommon cancers, and there is a paucity of randomized evidence to guide practice. As a result, current guidelines from different neuroendocrine tumor societies vary considerably. There is a need to update and harmonize global consensus guidelines. This article reports the best practice guidelines produced by a collaboration between the Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society. We performed a formal endorsement and updating process of the 2015 European Neuroendocrine Tumor Society expert consensus article on LNET. A systematic review from January 2013 to October 2017 was conducted to procure the most recent evidence. The stepwise endorsement process involved experts from all major subspecialties, patients, and advocates. Guided by discussion of the most recent evidence, each statement from the European Neuroendocrine Tumor Society was either endorsed, modified, or removed. New consensus statements were added if appropriate. The search yielded 1109 new publications, of which 230 met the inclusion criteria. A total of 12 statements were endorsed, 22 statements were modified or updated, one was removed, and two were added. Critical answered questions for each topic in LNET were identified. Through the consensus process, guidelines for the management of patients with local and metastatic neuroendocrine tumors have been updated to include both recent evidence and practice changes relating to technological and definitional advances. The guidelines provide clear, evidence-based statements aimed at harmonizing the global approach to patients with LNETs, on the basis of the principles of person-centered and LNET-specific care. The importance of LNET-directed research and person-centered care throughout the diagnosis, treatment, and follow-up journey is emphasized along with directions for future collaborative research.

Single-Lumen Endotracheal Tube and Bronchial Blocker for Airway Management During Tracheobronchoplasty for Tracheobronchomalacia: A Case Report.

We present a case of a 69-year-old man who underwent tracheobronchoplasty for tracheobronchomalacia using a single-lumen endotracheal tube and a Y-shaped bronchial blocker for airway management. Tracheobronchoplasty is performed by sewing mesh to plicate the posterior, membranous wall of the distal trachea and main bronchi through a right posterolateral thoracotomy. The goals of airway management include continuous left-lung ventilation and lung protection from aspiration. Ideally, only conventional airway management tools are used. This case demonstrates that a single-lumen endotracheal tube with a bronchial blocker can be a straightforward strategy for airway management during tracheobronchoplasty.

Predictors of Respiratory Decline Following Stereotactic Ablative Radiotherapy to Multiple Lung Tumors.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) is highly effective at controlling early stage primary lung cancer and lung metastases. Although previous studies have suggested that treating multiple lung tumors with SABR is safe, post-treatment changes in respiratory function have not been analyzed in detail. PATIENTS AND METHODS: We retrospectively identified patients with 2 or more primary lung cancers or lung metastases treated with SABR and analyzed clinical outcomes and predictors of toxicity. We defined a composite respiratory decline endpoint to include increased oxygen requirement, increased dyspnea scale, or death from respiratory failure not owing to disease progression. RESULTS: A total of 86 patients treated with SABR to 203 lung tumors were analyzed. A total of 21.8% and 41.8% of patients developed composite respiratory decline at 2 and 4 years, respectively. When accounting for intrathoracic disease progression, 12.7% of patients developed composite respiratory decline at 2 years. Of the patients, 7.9% experienced grade 2 or greater radiation pneumonitis. No patient- or treatment-related factor predicted development of respiratory decline. The median overall survival was 46.9 months, and the median progression-free survival was 14.8 months. The cumulative incidence of local failure was 9.7% at 2 years. CONCLUSION: Although our results confirm that SABR is an effective treatment modality for patients with multiple lung tumors, we observed a high rate of respiratory decline after treatment, which may be owing to a combination of treatment and disease effects. Future studies may help to determine ways to avoid pulmonary toxicity from SABR.

First Human Use of a New Robotic-Assisted Fiber Optic Sensing Navigation System for Small Peripheral Pulmonary Nodules.

BACKGROUND: We tested a new, investigational robotic-assisted bronchoscope system with a remotely controlled catheter to access small peripheral bronchi with real-time driving under live visualization and distal tip articulation of the catheter. The unique catheter remains stationary once located at the biopsy position. OBJECTIVES: The primary objectives of this study were to evaluate the safety and feasibility of a new shape-sensing robotic bronchoscope system to bronchoscopically approach and facilitate the sampling of small peripheral pulmonary nodules of 1-3 cm. Secondary objectives included evaluating procedural characteristics and early performance trends associated with the use of the new robotic bronchoscope system. METHODS: Subjects were enrolled according to study eligibility criteria at a single center. Navigation pathways were semi-automatically created using pre-procedure CT scans. Simultaneous (real-time) viewing of actual and virtual bronchi was used real time during navigation to the displayed target. An endobronchial ultrasound mini-probe was used to confirm lesion location. Flexible 19- to 23-G needles specifically designed to accommodate tight bend radii in transbronchial needle aspiration were used along with conventional biopsy tools. Enrolled subjects completed follow-up visits up to 6 months after the procedure. RESULTS: The study included 29 subjects with a mean lesion size of 12.2 ± 4.2, 12.3 ± 3.3, and 11.7 ± 4.1 mm in the axial, coronal, and sagittal planes, respectively. The CT bronchus sign was absent in 41.4% of cases. In 96.6% of cases, the target was reached, and samples were obtained. No device-related adverse events and no instances of pneumothorax or excessive bleeding were observed during the procedure. Early performance trends demonstrated an overall diagnostic yield of 79.3% and a diagnostic yield for malignancy of 88%. CONCLUSION: This new robotic-assisted bronchoscope system safely navigated to very small peripheral airways under continuous visualization, and through maintenance of a static position, it provides a unique sampling capability for the biopsy of small solitary pulmonary nodules.

A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (LIBERATE).

RATIONALE: This is the first multicenter randomized controlled trial to evaluate the effectiveness and safety of Zephyr Endobronchial Valve (EBV) in patients with little to no collateral ventilation out to 12 months. OBJECTIVES: To evaluate the effectiveness and safety of Zephyr EBV in heterogeneous emphysema with little to no collateral ventilation in the treated lobe. METHODS: Subjects were enrolled with a 2:1 randomization (EBV/standard of care [SoC]) at 24 sites. Primary outcome at 12 months was the ΔEBV-SoC of subjects with a post-bronchodilator FEV1 improvement from baseline of greater than or equal to 15%. Secondary endpoints included absolute changes in post-bronchodilator FEV1, 6-minute-walk distance, and St. George's Respiratory Questionnaire scores. MEASUREMENTS AND MAIN RESULTS: A total of 190 subjects (128 EBV and 62 SoC) were randomized. At 12 months, 47.7% EBV and 16.8% SoC subjects had a ΔFEV1 greater than or equal to 15% (P < 0.001). ΔEBV-SoC at 12 months was statistically and clinically significant: for FEV1, 0.106 L (P < 0.001); 6-minute-walk distance, +39.31 m (P = 0.002); and St. George's Respiratory Questionnaire, -7.05 points (P = 0.004). Significant ΔEBV-SoC were also observed in hyperinflation (residual volume, -522 ml; P < 0.001), modified Medical Research Council Dyspnea Scale (-0.8 points; P < 0.001), and the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index (-1.2 points). Pneumothorax was the most common serious adverse event in the treatment period (procedure to 45 d), in 34/128 (26.6%) of EBV subjects. Four deaths occurred in the EBV group during this phase, and one each in the EBV and SoC groups between 46 days and 12 months. CONCLUSIONS: Zephyr EBV provides clinically meaningful benefits in lung function, exercise tolerance, dyspnea, and quality of life out to at least 12 months, with an acceptable safety profile in patients with little or no collateral ventilation in the target lobe. Clinical trial registered with www.clinicaltrials.gov (NCT 01796392).

Improving Quality of Dynamic Airway Computed Tomography Using an Expiratory Airflow Indicator Device.

PURPOSE: Dynamic computed tomography (CT) of the airways is increasingly used to evaluate patients with suspected expiratory central airway collapse, but current protocols are susceptible to inadequate exhalation caused by variable patient compliance with breathing instructions during the expiratory phase. We developed and tested a low-cost single-use expiratory airflow indicator device that was designed to improve study quality by providing a visual indicator to both patient and operator when adequate expiratory flow was attained. MATERIALS AND METHODS: A total of 56 patients undergoing dynamic airway CT were evaluated, 35 of whom were scanned before introduction of the indicator device (control group), with the rest comprising the intervention group. Lung volumes and tracheal cross-sectional areas on inspiratory/expiratory phases were computed using automated lung segmentation and quantitative software analysis. Inadequate exhalation was defined as absolute volume change of <500 mL during the expiratory phase. RESULTS: Fewer patients in the intervention group demonstrated inadequate exhalation. The average change in volume was higher in the intervention group (P=0.004), whereas the average minimum tracheal cross-sectional area was lower (P=0.01). CONCLUSIONS: The described expiratory airflow indicator device can be used to ensure adequate exhalation during the expiratory phase of dynamic airway CT. A higher frequency of adequate exhalation may improve reliability and sensitivity of dynamic airway CT for diagnosis of expiratory central airway collapse.

Tracheal Diverticulum Following Paratracheal Hypofractionated Radiotherapy in the Setting of Prior and Subsequent Bevacizumab.

We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions (70 Gy equivalent dose in 2 Gy fractions). The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy.

Interventional pulmonologist perspective: treatment of malignant pleural effusion.

OPINION STATEMENT: The management of known malignant pleural effusions focuses around the initial thoracentesis and subsequent objective and subjective findings. A completely reexpanded lung after fluid removal and with symptomatic improvement predicts successful pleurodesis. Pleurodesis method depends on center expertise as well as patient preference. Medical thoracoscopy does not require the operating room setting and is performed on the spontaneously breathing patient with similar success rate to surgical thoracoscopy in the appropriately selected patients. However, it is not widely available. Talc insufflation is preferred for even distribution of sprayed particles to pleural surfaces. Most often, patients can be discharged home within 24 to 48 hours after continuous chest tube suction. Indwelling pleural catheter has become popular given the ease of insertion and patient centered home drainage. Coordinated care with good patient and family education and support is paramount to maximizing the beneficial potential of the catheter. Complications are minimal, and catheters are easily removed if patients can no longer benefit from drainage, or if pleurodesis has occurred. In the setting of trapped lung as a result of visceral pleura encasement from tumor, indwelling catheter can still be useful if the patient improves with thoracentesis. However, if no subjective improvement is seen after thoracentesis for trapped lung, then no procedure is recommended and other modes of palliation should be sought.

Interventional pulmonology approaches in the diagnosis and treatment of early stage non small cell lung cancer.

Lung cancer management is complex and requires a multi-disciplinary approach to provide comprehensive care. Interventional pulmonology (IP) is an evolving field that utilizes minimally invasive modalities for the initial diagnosis and staging of suspected lung cancers. Endobronchial ultrasound guided sampling of mediastinal lymph nodes for staging and detection of driver mutations is instrumental for prognosis and treatment of early and later stage lung cancers. Advances in navigational bronchoscopy allow for histological sampling of suspicious peripheral lesions with minimal complication rates, as well as assisting with fiducial marker placements for stereotactic radiation therapy. Furthermore, IP can also offer palliation for inoperable cancers and those with late stage diseases. As the trend towards early lung cancer detection with low dose computed tomography is developing, it is paramount for the pulmonary physician with expertise in lung nodule management, minimally invasive sampling and staging to integrate into the paradigm of multi-specialty care.

Interpretation of plain chest roentgenogram.

Plain chest roentgenogram remains the most commonly ordered screening test for pulmonary disorders. Its lower sensitivity demands greater accuracy in interpretation. This greater accuracy can be achieved by adhering to an optimal and organized approach to interpretation. It is important for clinicians not to misread an abnormal chest radiograph (CXR) as normal. Clinicians can only acquire the confidence in making this determination if they read hundreds of normal CXRs. An individual should follow the same systematic approach to reading CXRs each time. All clinicians must make a concerted effort to read plain CXRs themselves first without reading the radiologist report and then discuss the findings with their radiology colleagues. Looking at the lateral CXR may shed light on 15% of the lung that is hidden from view on the posteroanterior film. Comparing prior films with the recent films is mandatory, when available, to confirm and/or extend differential diagnosis. This article outlines one of the many systematic approaches to interpreting CXRs and highlights the lesions that are commonly missed. A brief description of the limitations of CXR is also included.

Bronchiolar disorders: a clinical-radiological diagnostic algorithm.

Bronchiolar disorders are generally difficult to diagnose because most patients present with nonspecific respiratory symptoms of variable duration and severity. A detailed clinical history may point toward a specific diagnosis. Pertinent clinical questions include history of smoking, collagen vascular disease, inhalational injury, medication usage, and organ transplant. It is important also to evaluate possible systemic and pulmonary signs of infection, evidence of air trapping, and high-pitched expiratory wheezing, which may suggest small airways involvement. In this context, pulmonary function tests and plain chest radiographs may demonstrate abnormalities; however, they rarely prove sufficiently specific to obviate bronchoscopic or surgical biopsy. Given these limitations, in our experience, high-resolution CT (HRCT) scanning of the chest often proves to be the most important diagnostic tool to guide diagnosis in these difficult cases, because different subtypes of bronchiolar disorders may present with characteristic image findings. Three distinct HRCT patterns in particular are of value in assisting differential diagnosis. A tree-in-bud pattern of well-defined nodules is seen primarily as a result of infectious processes. Ill-defined centrilobular ground-glass nodules point toward respiratory bronchiolitis when localized in upper lobes in smokers or subacute hypersensitivity pneumonitis when more diffuse. Finally, a pattern of mosaic attenuation, especially when seen on expiratory images, is consistent with air-trapping characteristic of bronchiolitis obliterans or constrictive bronchiolitis. Based on an appreciation of the critical role played by HRCT scanning, this article provides clinicians with a practical algorithmic approach to the diagnosis of bronchiolar disorders.

Relapsing polychondritis and airway involvement.

OBJECTIVE: To assess the prevalence and characteristics of airway involvement in relapsing polychondritis (RP). METHODS: Retrospective chart review and data analysis of RP patients seen in the Rheumatology Clinic and the Complex Airway Center at Beth Israel Deaconess Medical Center from January 2004 through February 2008. RESULTS: RP was diagnosed in 145 patients. Thirty-one patients had airway involvement, a prevalence of 21%. Twenty-two patients were women (70%), and they were between 11 and 61 years of age (median age, 42 years) at the time of first symptoms. Airway symptoms were the first manifestation of disease in 17 patients (54%). Dyspnea was the most common symptom in 20 patients (64%), followed by cough, stridor, and hoarseness. Airway problems included the following: subglottic stenosis (n = 8; 26%); focal and diffuse malacia (n = 15; 48%); and focal stenosis in different areas of the bronchial tree in the rest of the patients. Twelve patients (40%) required and underwent intervention including balloon dilatation, stent placement, tracheotomy, or a combination of the above with good success. The majority of patients experienced improvement in airway symptoms after intervention. One patient died during the follow-up period from the progression of airway disease. The rest of the patients continue to undergo periodic evaluation and intervention. CONCLUSION: In this largest cohort described in the English language literature, we found symptomatic airway involvement in RP to be common and at times severe. The nature of airway problems is diverse, with tracheomalacia being the most common. Airway intervention is frequently required and in experienced hands results in symptom improvement.

High-resolution chest tomography in idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia: utility and challenges.

PURPOSE OF REVIEW: High-resolution computed tomography (HRCT) scan is regarded as the imaging modality of choice to evaluate patients with known or suspected interstitial lung disease. With current technology, HRCT allows for detailed assessment of interstitial compartments. We examine recent data on its role in the diagnostic evaluation, clinical decision-making, and prognosis of patients with interstitial lung disease, and we highlight the challenges related to its application in this field. RECENT FINDINGS: HRCT findings are either diagnostic or strongly suggestive of underlying pathologic patterns. By identifying the presence of certain characteristics, radiologists have developed a clearer understanding of HRCT patterns that coincide with underlying pathology. Challenges and controversies still remain, however. For example, recent studies indicate that the diagnostic accuracy and performance characteristics of HRCT depend predominantly on the study setting; intra-observer and inter-observer variability are less between academic radiologists than between community radiologists. Despite this, clinicians tend to rely primarily on HRCT when a radiologic pattern characteristic for histologic usual interstitial pneumonia is identified. SUMMARY: Specific HRCT patterns help to differentiate and prognosticate different interstitial lung diseases. It is important for clinicians to understand the utility and limitations of HRCT in managing their patients. A multidisciplinary approach remains the gold standard.