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Introduction: In the current era of personalized medicine, liquid biopsy has acquired a relevant importance in patient management of advanced stage non-small cell lung cancer (NSCLC). As a matter of fact, liquid biopsy may supplant the problem of inadequate tissue for molecular testing. The term 'liquid biopsy' refers to a number of different biological fluids, but is most clearly associated with plasma-related platforms. It must be taken into account that pre-analytical processing and the selection of the appropriate technology according to the clinical context may condition the results obtained. In addition, novel clinical applications beyond the evaluation of the molecular status of predictive biomarkers are currently under investigation., Areas Covered: This review summarizes the available evidence on pre-analytical issues and different clinical applications of liquid biopsies in NSCLC patients., Expert Opinion: Liquid biopsy should be considered not only as a valid alternative but as complementary to tissue-based molecular approaches. Careful attention should be paid to the optimization and standardization of all phases of liquid biopsy samples management in order to determine a significant improvement in either sensitivity or specificity, while significant reducing the number of 'false negative' or 'false positive' molecular results.

Life-threatening hemoptysis is commonly encountered in the ICU and its management can be challenging even for experienced clinicians. Depending on the etiology and severity, one can tailor the treatment modality and therapeutic intervention(s). The grading of severity of hemoptysis varies greatly in the literature; however, unlike hemorrhage in other scenarios, small amounts of blood can significantly impair oxygenation and ventilation leading to cardiovascular collapse. Importantly, the initial evaluation and management should focus on airway and hemodynamic stabilization along with maintenance of oxygenation and ventilation. In this review, we discuss commonly encountered etiologies, vascular anatomy, diagnostic evaluation, and therapeutic interventions. We examine the evolving trends in etiologies of life-threating hemoptysis over the years. The role of flexible and rigid bronchoscopy as both a diagnostic and therapeutic modality is explored, as well as the use and indications of several bronchoscopic techniques, such as topical hemostatic agents, endobronchial tamponade, and tranexamic acid (TXA). In addition, we assess the use of multi-row detector computed tomography as the initial rapid diagnostic method of choice and its use in planning for definitive treatment. The efficacy and long-term results of bronchial artery embolization (BAE) are evaluated, as well as indications for surgical intervention. Furthermore, the importance of a multidisciplinary approach is emphasized. The necessary interplay between intensivists, consultative services, and radiologists is described in detail and an algorithmic management strategy incorporating the above is outlined. Given the complexity in management of life-threatening hemoptysis, this paper aims to summarize the available diagnostic and therapeutic methods and provide a standardized approach for the management of patients with this often difficult to treat condition., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/jtd-19-3991). The series “Interventional Pulmonology in the Intensive Care Unit Environment” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Percutaneous tracheostomy is a commonly performed procedure for patients in the intensive care unit (ICU) and offers many benefits, including decreasing ICU length of stay and need for sedation while improving patient comfort, effective communication, and airway clearance. However, there is no consensus on the optimal timing of tracheostomy in ICU patients. Ultrasound (US) and bronchoscopy are useful adjunct tools to optimize procedural performance. US can be used pre-procedurally to identify vascular structures and to select the optimal puncture site, intra-procedurally to assist with accurate placement of the introducer needle, and post-procedurally to evaluate for a pneumothorax. Bronchoscopy provides real-time visual guidance from within the tracheal lumen and can reduce complications, such as paratracheal puncture and injury to the posterior tracheal wall. A step-by-step detailed procedural guide, including preparation and procedural technique, is provided with a team-based approach. Technical aspects, such as recommended equipment and selection of appropriate tracheostomy tube type and size, are discussed. Certain procedural considerations to minimize the risk of complications should be given in circumstances of patient obesity, coagulopathy, or neurologic illness. Herein, we provide a practical state of the art review of percutaneous tracheostomy in ICU patients. Specifically, we will address pre-procedural preparation, procedural technique, and post-tracheostomy management., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/jtd-19-4121). The series “Interventional Pulmonology in the Intensive Care Unit Environment” was commissioned by the editorial office without any funding sponsorship. The authors have no other conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

A 55-year old woman with a history of relapsed T-cell ALL presented with right pleuritic chest pain and decreased breath sounds over the right hemithorax. Imaging of the chest showed loculated effusions. Tube thoracostomy was performed with intrapleural application of alteplase and dornase alpha over a 3-day period. Repeat imaging demonstrated a marked decrease in the volume of the effusion. In most prior published cases of pleural cryptococcosis, surgical drainage was required in addition to prolonged antifungal agents. More than 50% of patients with cryptococcal infection have severe underlying disease or immunodeficiency state making them high risk for surgery. This is the first case to our knowledge of cryptococcal empyema successfully treated with tube thoracostomy and intrapleural fibrinolysis.

The use of intrapleural alteplase and dornase in pregnant patients remains an uncertain practice because bleeding complications in these cases could be devastating. We present a case in which we successfully used a modified protocol safely., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Transbronchial lung biopsy (TBLB) is frequently performed in single-lung and double-lung transplant recipients for evaluation of clinical and radiological findings as well as routine surveillance for acute cellular rejection. While rates of clinically significant TBLB-related haemorrhage are <1% for all comers, the incidence in lung transplant recipients is reported to be higher, presumably due to persistent allograft inflammation and alterations in allograft blood flow. While routinely performed by some bronchoscopists, the efficacy and safety profile of prophylactic administration of topical intrabronchial diluted epinephrine for the prevention of TBLB-related haemorrhage has not been explored in a prospective manner., Methods and Analysis: In this randomised, double-blind, placebo-controlled multicentre trial (PROPHET Study), single-lung and double-lung transplant adult recipients from participating institutions who are scheduled for bronchoscopy with TBLB for clinical indications will be identified. Potential participants who meet inclusion and exclusion criteria and sign an informed consent will be randomised to receive either diluted epinephrine or placebo prior to performance of TBLB. The degree of TBLB-related haemorrhage will be graded by the performing bronchoscopist as well as independent observers. The primary analysis will compare the rates of severe and very severe bleeding in participants treated with epinephrine or placebo. The study will also evaluate the safety profile of prophylactic topical epinephrine including the occurrence of serious cardiovascular and haemodynamic adverse events. Additional secondary outcomes to be explored include rates of non-severe TBLB-related haemorrhage, overall yield of the bronchoscopic procedure and non-serious cardiovascular and haemodynamic adverse effects., Ethics and Dissemination: The study procedures were reviewed and approved by institutional review boards in participating institutions. This study is being externally monitored, and a data and safety monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences., Trial Registration Number: NCT03126968; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The spectrum of eosinophilic lung diseases comprises a diverse group of pulmonary disorders associated with tissue or peripheral eosinophilia. [Acute eosinophilic pneumonia (AEP)] is an uncommon eosinophilic lung disease that can be idiopathic, but identifiable causes include medications, inhalational exposures and infections. Most cases in the literature are associated with first-time cigarette smoking or resuming smoking. Herein, we present a case of AEP in an elderly man triggered by exposure to secondhand tobacco smoke, in whom a transbronchial biopsy was diagnostic. The patient recovered fully with glucocorticoid therapy without recurrence after avoiding further secondhand smoke.

Postsurgical empyema with bronchopleural fistula can be difficult to manage. We present a patient with postoperative empyema with bronchopleural fistula who was successfully treated nonoperatively by placing an intrabronchial valve to address the bronchopleural fistula, which allowed for safe administration of intrapleural fibrinolytics and antibiotics for definitive treatment of the empyema. Although the presence of a bronchopleural fistula is considered a contraindication to the administration of intrapleural tissue plasminogen activator and deoxyribonuclease, this case demonstrates a novel use of the intrabronchial valve that allowed these medications to be used., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Current approaches to building efficiency diagnoses include conventional energy audit techniques that can be expensive and time consuming. In contrast, virtual energy audits of readily available 15-minute-interval building electricity consumption are being explored to provide quick, inexpensive, and useful insights into building operation characteristics. A cross sectional analysis of six buildings in two different climate zones provides methods for data cleaning, population-based building comparisons, and relationships (correlations) of weather and electricity consumption. Data cleaning methods have been developed to categorize and appropriately filter or correct anomalous data including outliers, missing data, and erroneous values (resulting in < 0.5% anomalies). The utility of a cross-sectional analysis of a sample set of building's electricity consumption is found through comparisons of baseload, daily consumption variance, and energy use intensity. Correlations of weather and electricity consumption 15-minute interval datasets show important relationships for the heating and cooling seasons using computed correlations of a Time-Specific-Averaged-Ordered Variable (exterior temperature) and corresponding averaged variables (electricity consumption)(TSAOV method). The TSAOV method is unique as it introduces time of day as a third variable while also minimizing randomness in both correlated variables through averaging. This study found that many of the pair-wise linear correlation analyses lacked strong relationships, prompting the development of the new TSAOV method to uncover the causal relationship between electricity and weather. We conclude that a combination of varied HVAC system operations, building thermal mass, plug load use, and building set point temperatures are likely responsible for the poor correlations in the prior studies, while the correlation of time-specific-averaged-ordered temperature and corresponding averaged variables method developed herein adequately accounts for these issues and enables discovery of strong linear pair-wise correlation R values. TSAOV correlations lay the foundation for a new approach to building studies, that mitigates plug load interferences and identifies more accurate insights into weather-energy relationship for all building types. Over all six buildings analyzed the TSAOV method reported very significant average correlations per building of 0.94 to 0.82 in magnitude. Our rigorous statistics-based methods applied to 15-minute-interval electricity data further enables virtual energy audits of buildings to quickly and inexpensively inform energy savings measures.

Over the past decade, there has been significant advancement in the development/application of therapeutics in thoracic diseases. Ablation methods using heat or cold energy in the airway is safe and effective for treating complex airway disorders including malignant and non-malignant central airway obstruction (CAO) without limiting the impact of future definitive therapy. Timely and efficient use of endobronchial ablative therapies combined with mechanical debridement or stent placement results in immediate relief of dyspnea for CAO. Therapeutic modalities reviewed in this article including electrocautery, balloon dilation (BD), neodymium-doped:yttrium-aluminum-garnet (Nd:YAG) laser, argon plasma coagulation (APC), and cryotherapy are often combined to achieve the desired results. This review aims to provide a clinically oriented review of these technologies in the modern era of interventional pulmonology (IP).

IL-33 contributes to disease processes in association with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated, but the fate of synthesized IL-33 protein is unknown. To understand the interplay among IL-33, IFN-γ, and IL-4 proteins, recombinant replication-deficient adenoviruses were produced and used for dual expression of IL-33 and IFN-γ or IL-33 and IL-4. The effects of such dual gene delivery were compared with the effects of similar expression of each of these cytokines alone. In lung fibroblast culture, co-expression of IL-33 and IFN-γ resulted in suppression of the levels of both proteins, whereas co-expression of IL-33 and IL-4 led to mutual elevation. In vivo, co-expression of IL-33 and IFN-γ in the lungs led to attenuation of IL-33 protein levels. Purified IFN-γ also attenuated IL-33 protein in fibroblast culture, suggesting that IFN-γ controls IL-33 protein degradation. Specific inhibition of caspase-1, -3, and -8 had minimal effect on IFN-γ-driven IL-33 protein down-regulation. Pharmacological inhibition, siRNA-mediated silencing, or gene deficiency of STAT1 potently up-regulated IL-33 protein expression levels and attenuated the down-regulating effect of IFN-γ on IL-33. Stimulation with IFN-γ strongly elevated the levels of the LMP2 proteasome subunit, known for its role in IFN-γ-regulated antigen processing. siRNA-mediated silencing of LMP2 expression abrogated the effect of IFN-γ on IL-33. Thus, IFN-γ, IL-4, and IL-33 are engaged in a complex interplay. The down-regulation of IL-33 protein levels by IFN-γ in pulmonary fibroblasts and in the lungs in vivo occurs through STAT1 and non-canonical use of the LMP2 proteasome subunit in a caspase-independent fashion.

We have previously described an alternatively spliced isoform of IL-4 mRNA that omits exon 2 and is termed IL-4δ2. However, the natural production of IL-4δ2 protein and its association with disease have not been previously assessed due to unavailability of an antibody that interacts with IL-4δ2 without cross-reactivity with full length IL-4. We used a unique monoclonal antibody (mAb) that reacts with IL-4δ2, but not with IL-4, and observed that IL-4δ2 is naturally produced by T cells from patients with asthma, but not from healthy controls. The kinetics of IL-4δ2 and IL-4 production by phorbol myristate acetate (PMA)/ionomycin-activated cells differed, with IL-4δ2 increasing at 48-72h and IL-4 peaking at 24h. The steady-state levels of IL-4δ2 mRNA varied significantly among the donors and were discordant with the corresponding protein levels, suggesting post-transcriptional regulation of protein production. Polarized Th1 or Th2 lymphocytes were not a major source of IL-4δ2. Stimulation of cultured T lymphocytes with IL-4δ2 caused elevated production of IFN-γ, IL-10, IL-6, MCP-1, and TNF-α, with notable differences between patients and controls in the production of IFN-γ, IL-10, and IL-6. Thus, IL-4δ2 is natively produced not only as mRNA but also as a protein by cells other than Th1 or Th2. It is regulated post-transcriptionally, is associated with allergic asthma, and regulates production of other cytokines by primary T lymphocytes. Alternatively spliced interleukin-4 may be a new biomarker, a pathophysiological player, and possibly a molecular target for future therapies in asthma., (Published by Elsevier Ltd.)

Background: Discovery of tumor-selective antibodies or antibody fragments is a promising approach for delivering therapeutic agents to antigen over-expressing cancers. Therefore it is important to develop methods for the identification of target- and function specific antibodies for effective drug delivery. Here we describe a highly selective and sensitive method for characterizing the internalizing potential of multivalently displayed antibodies or ligands conjugated to liposomes into tumor cells. The assay requires minute amounts of histidine-tagged ligand and relies on the non-covalent coupling of these antibodies to fluorescent liposomes containing a metal ion-chelating lipid. Following incubation of cells with antibody-conjugated liposomes, surface bound liposomes are gently removed and the remaining internalized liposomes are quantitated based on fluorescence in a high throughput manner. We have termed this methodology "Chelated Ligand Internalization Assay", or CLIA., Results: The specificity of the assay was demonstrated with different antibodies to the ErbB-2 and EGF receptors. Antibody-uptake correlated with receptor expression levels in tumor cell lines with a range of receptor expression. Furthermore, Ni-NTA liposomes containing doxorubicin were used to screen for the ability of antibodies to confer target-specific cytotoxicity. Using an anti-ErbB2 single chain Fv (scFv) (F5) antibody, cytotoxicity could be conferred to ErbB2-overexpressing cells; however, a poly(ethylene glycol)-linked lipid (DSPE-PEG-NTA-Ni) was necessary to allow for efficient loading of the drug and to reduce nonspecific drug leakage during the course of the assay., Conclusion: The CLIA method we describe here represents a rapid, sensitive and robust assay for the identification and characterization of tumor-specific antibodies capable of high drug-delivery efficiency when conjugated to liposomal nanocarriers.