World Association for Bronchology and Interventional Pulmonology (WABIP) guidelines on airway stenting for malignant central airway obstruction.

Malignant Central Airway Obstruction (MCAO) encompasses significant and symptomatic narrowing of the central airways that can occur due to primary lung cancer or metastatic disease. Therapeutic bronchoscopy is associated with high technical success and symptomatic relief and includes a wide range of airway interventions including airway stents. Published literature suggests that stenting practices vary significantly across the world primarily due to lack of guidance. This document aims to address this knowledge gap by addressing relevant questions related to airway stenting in MCAO. An international group of 17 experts from 17 institutions across 11 countries with experience in using airway stenting for MCAO was convened as part of this guideline statement through the World Association for Bronchology and Interventional Pulmonology (WABIP). We performed a literature and internet search for reports addressing six clinically relevant questions. This guideline statement, consisting of recommendations addressing these six PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with expert experience when necessary. Panel members participated in the development of the final recommendations using the modified Delphi technique.

Treg-dependent immunosuppression triggers effector T cell dysfunction via the STING/ILC2 axis.

Lung cancer remains the leading cause of cancer-related deaths and despite extensive research, the survival rate of lung cancer patients remains significantly low. Recent data reveal that aberrant Kras signaling drives regulatory T cells (Tregs) present in lung tumor microenvironment to establish immune deregulation and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras in Treg-related immunosuppression and its involvement in tumor-associated metabolic reprogramming. Findings reveal Tregs to prompt GATA3/NOS2-related immunosuppression via STING inhibition which triggers a decline in CD4+ T infiltration, and a subsequent increase in lung metastatic burden. Enhanced Treg expression was also associated with low T/MDSC ratio through restriction of CD8+CD44+CD62L- T effector cells, contributing to a tumor-promoting status. Specifically, TIM3+/LAG3+ Tregs prompted Kras-related immunosuppressive chemoresistance and were associated with T cell dysfunction. This Treg-dependent immunosuppression correlated with CD8 T cell exhaustion phenotype and ILC2 augmentation in mice. Moreover, enhanced Treg expression promoted activation-induced cell death (AICD) of T lymphocytes and guided lymph node metastasis in vivo. Overall, these findings demonstrate the multifaceted roles of Tregs in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

Localized Bronchial Hyperemia in Cases of Iatrogenic Hemoptysis: Clinical Presentations and Pathophysiological Mechanisms.

Hemoptysis is a frequently encountered symptom in many clinical settings, and etiologic diagnosis can sometimes prove challenging. Bronchoscopy may not promptly reveal the source or the cause of bleeding and few reports have focused so far on the abnormalities of bronchial mucosa vasculature that may unveil the underlying pathophysiology. In this special feature article, we present a series of cases presenting with hemoptysis after angiographic interventions in the thoracic vessels. Localized hyperemia and vascular dilatations in the bronchial mucosa observed during bronchoscopy as unique findings became clues enabling the correct diagnosis and management. We suggest the relevant pathophysiological mechanisms and discuss the available published experience on similar clinical entities.

Evaluation of Nickel Release from Endobronchial Valves as a Possible Cause of Hypersensitivity Pneumonitis in a Patient Treated with Bronchoscopic Lung Volume Reduction.

BACKGROUND: Endobronchial valve (EBV) placement is an established lung volume reduction procedure aiming to improve lung function and exercise capacity in patients with severe emphysema. As EBVs consist of silicone and nitinol (a metal alloy of nickel and titanium), there are concerns that nickel ions might be released and could have a clinical impact in patients with a contact allergy to nickel. Based on a case with hypersensitivity pneumonitis (HP) after treatment with EBVs, we aimed to evaluate the in vitro nickel release from EBVs using inductively coupled plasma mass spectrometry (ICP-MS) and scanning electron microscopy (SEM). METHODS: Six EBVs were immersed in artificial saliva for a period of 7 days. At 24-h intervals, the nickel ion concentration was measured using ICP-MS. RESULTS: There was evidence of a significant nickel release from EBV during the first 48 h, which is possibly due to an incomplete silicone layer detected by SEM. The concentration of released nickel was below the toxic limit. CONCLUSIONS: To the best of our knowledge, we report the first case of HP after EBV treatment. Our finding of in vitro release of nickel ions from EBVs may contribute to the current understanding on hypersensitivity reactions after nitinol implants in patients with nickel contact allergy. However, it did not confirm a causative relationship.

Towards Individualized Tracheobronchial Stents: Technical, Practical and Legal Considerations.

Stent placement has been established as a standard procedure for treating airway obstructions. Other indications are localized malacias and fistulas. Though many different stents with various diameters and lengths are available, the shapes are hardly ever ideal because of the distorted anatomy in patients with diseased airways. There are technical and legal limitations for customizing purchased airway stents. Individually tailored stents would be preferable. New techniques of additive manufacturing such as 3D printing make it possible to produce optimized stents for a particular patient. Using CT data and bronchoscopic images, stents can be constructed that match a particular anatomical situation and apply the optimized expansion force. We give an overview of the currently available manufacturing techniques for polymeric stents and report about our own experience. Direct on-site printing of polyurethane stents in a hospital and printing individual extrusion molds for silicone stents in a certified cleanroom are both feasible. Furthermore, there are promising attempts of combining mechanically customized stents with surface modifications, drug-eluting features, biodegradability, and time-dependent adaptation (4D printing). Truly optimized airway stents with the potential of solving the well-known stent problems such as granulation tissue formation, remodeling, mucostasis, and infections are in reach. The technical hurdles are probably easier to overcome than the legal constraints. The legal situations are discussed from a physician's and a manufacturer's perspective.

Target-controlled versus fractionated propofol sedation in flexible bronchoscopy: A randomized noninferiority trial.

BACKGROUND AND OBJECTIVE: Fractionated propofol administration (FPA) in flexible bronchoscopy (FB) may lead to oversedation and an increased risk of adverse events, because a stable plasma concentration of propofol is not maintainable. The purpose of this randomized noninferiority trial was to evaluate whether target-controlled infusion (TCI) of propofol is noninferior to FPA in terms of safety in FB. METHODS: Coprimary outcomes were the mean lowest arterial oxygen saturation (SpO2 ) during FB and the number of propofol dose adjustments in relation to procedure duration. Secondary outcomes were the number of occasions with SpO2 < 90% and/or oxygen desaturations of >4% from baseline, number of occasions with systolic blood pressure < 90 mm Hg, cough frequency, cumulative propofol dose, recovery time, maximum transcutaneous CO2 , mean SpO2 and O2 delivery during FB. RESULTS: Seventy-seven patients were included. TCI was noninferior to FPA in terms of mean (standard deviation) lowest SpO2 during the procedure (88.3% (5.4%) vs 86.9% (7.3%)) and required fewer dose adjustments (0.04/min vs 0.28/min, P < 0.001) but a higher cumulative propofol dose (264 vs 194 mg, P = 0.003). All other secondary outcomes were comparable between the groups. CONCLUSION: We suggest that TCI of propofol is a favourable sedation technique for FB with equal safety issues and fewer dose adjustments compared with FPA.

Bronchoscopic Lung Volume Reduction with Endobronchial Valves in Low-FEV1 Patients.

BACKGROUND: Bronchoscopic lung volume reduction (BLVR) with valves has been shown to improve lung function, exercise capacity, and quality of life in patients with emphysema, but only few patients with forced expiratory volume in 1 s (FEV1) ≤20% predicted have been included in former studies. Although the procedure can be performed safely, pneumothorax is a frequent complication, which can be critical for these very severely diseased patients. OBJECTIVES: The aim of the study was to assess the safety of BLVR in patients with a very advanced stage of emphysema, as indicated by FEV1 ≤20% predicted. PATIENTS AND METHODS: Patients in whom BLVR was performed between January 2013 and August 2015 were included in this analysis if their baseline predicted FEV1 was ≤20%. BLVR, performed only if collateral ventilation was absent, achieved complete occlusion of the target lobe. All patients were closely monitored and were not discharged before the fourth day after BLVR. RESULTS: Twenty patients with FEV1 ≤20% predicted were included in the analysis. Lung volume reduction was achieved in 65% of the cases. Pneumothorax occurred in 4 cases (20%). No patient died. Lung function and exercise tolerance improved after 1 and 3 months, respectively. CONCLUSIONS: BLVR with valves can be safely performed in patients with FEV1 ≤20% predicted when close postprocedural monitoring is provided. Improvement in lung function and exercise capacity can be achieved.

Ultrathin bronchoscopy for solitary pulmonary lesions in a region endemic for tuberculosis: a randomised pilot trial.

BACKGROUND: The evaluation of solitary pulmonary lesions (SPL) requires a balance between procedure-related morbidity and diagnostic yield, particularly in areas where tuberculosis (TB) is endemic. Data on ultrathin bronchoscopy (UB) for this purpose is limited. To evaluate feasibility and safety of UB compared to SB for diagnosis of SPL in a TB endemic region. METHODS: In this prospective randomised trial we compared diagnostic yield and adverse events of UB with standard-size bronchoscopy (SB), both combined with fluoroscopy, in a cohort of patients with SPL located beyond the visible range of SB. RESULTS: We included 40 patients (mean age 55.2 years, 45 % male) with malignant SPL (n = 16; 40 %), tuberculous SPL (n = 11; 27.5 %) and other benign SPL (n = 13; 32.5 %). Mean procedure time in UB and SB was 30.6 and 26.0 min, respectively (p = 0.15). By trend, adverse events were recorded more often with UB than with SB (30.0 vs. 5.0 %, p = 0.091), including extensive coughing (n = 2), blocked working channel (n = 2), and arterial hypertension requiring therapeutic intervention (n = 1), all with UB. The overall diagnostic yield of UB compared to SB was 55.0 % vs. 80.0 %, respectively (p = 0.18). Sensitivity for the diagnosis of malignancy of UB and SB was 50.0 % and 62.5 %, respectively (p = 0.95). CONCLUSION: UB is not superior to SB for the evaluation of SPL in a region endemic with tuberculosis, when combined with fluoroscopic guidance only. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02490059 ).

Prognostic model for long-term survival of locally advanced non-small-cell lung cancer patients after neoadjuvant radiochemotherapy and resection integrating clinical and histopathologic factors.

BACKGROUND: Outcome of consecutive patients with locally advanced non-small cell lung cancer and histopathologically proven mediastional lymph node metastases treated with induction chemotherapy, neoadjuvant radiochemotherapy and thoracotomy at the West German Cancer Center between 08/2000 and 06/2012 was analysed. A clinico-pathological prognostic model for survival was built including partial or complete response according to computed tomography imaging (CT) as clinical parameters as well as pathologic complete remission (pCR) and mediastinal nodal clearance (MNC) as histopathologic factors. METHODS: Proportional hazard analysis (PHA) and recursive partitioning analysis (RPA) were used to identify prognostic factors for survival. Long-term survival was defined as survival ≥ 36 months. RESULTS: A total of 157 patients were treated, median follow-up was 97 months. Among these patients, pCR and MNC were observed in 41 and 85 patients, respectively. Overall survival was 56 ± 4% and 36 ± 4% at 24 and 60 months, respectively. Sensitivities of pCR and MNC to detect long-term survivors were 38% and 61%, specificities were 84% and 52%, respectively. Multivariable survival analysis revealed pCR, cN3 category, and gender, as prognostic factors at a level of α < 0.05. Considering only preoperative available parameters, CT response became significant. Classifying patients with a predicted hazard above the median as high risk group and the remaining as low risk patients yielded better separation of the survival curves by the inclusion of histopathologic factors than by preoperative factors alone (p < 0.0001, log rank test). Using RPA, pCR was identified as the top prognostic factor above clinical factors (p = 0.0006). No long term survivors were observed in patients with cT3-4 cN3 tumors without pCR. CONCLUSIONS: pCR is the dominant histopathologic response parameter and improves prognostic classifiers, based on clinical parameters. The validated prognostic model can be used to estimate individual prognosis and forms a basis for patient selection for treatment intensification.

Biodegradable Airway Stents - Bench to Bedside: A Comprehensive Review.

Airway stents are indicated to treat symptomatic narrowing or to close fistulas of the central airways. They are generally divided into two types: the silicone stents and the metallic stents. Unlike in malignancies, removability is a major objective of temporary stenting in benign conditions, which poses the challenge of a new rigid bronchoscopic procedure under general anesthesia and stent removal with all its attendant risks and costs. The concept of a biodegradable (BD) stent that could maintain the patency of an airway for a predetermined duration of time is very appealing. These BD stents would gradually degrade and eventually vanish from the airway once they are no longer needed. Such stents are currently an area of intense research. Another very promising concept of drug delivery with such stents is also a very exciting area of current research. The aim of this comprehensive review is to discuss all pertinent available literature on the use of BD materials in various clinical applications and to extensively review all animal and humans trials involving BD airway stents.

Functional bronchoscopy: development of a new bronchoscopic method for real-time gas exchange assessment of lobes and lung segments.

BACKGROUND: There are various imaging methods in use designed to provide information on lung functional status, particularly gas exchange within specific lung segments. These complex imaging methods provide indirect information about volume and local lung function. OBJECTIVES: The objective of this research was to develop a simpler and more direct method for the functional assessment of gas exchange in lung segments. METHOD: We have developed a new bronchoscopic method to sample gas concentrations of oxygen and carbon dioxide at the orifices of segmental bronchi in a breathing patient. Endocapnometry and oximetry curves are displayed in real time and superimposed on the endoscopic video images. RESULTS: The gas exchange mapping of a lung could be achieved in <5 min. We identified typical curve patterns of localized slow and fast clearance regions, and segments with higher or lower oxygen uptake. This method is simple and versatile and the data displayed can help to identify target zones for endoscopic emphysema treatments, e.g. for lowering the risk of resection surgery, or to improve ventilation strategies in ICU patients. CONCLUSION: This new method enables gas sampling at the lung segment level. The concomitant display of local endocapnometry and endooximetry curves allows for a better identification of target zones for endoscopic emphysema treatments or to improve ventilation strategies for patients on respiratory support.

Expert statement: pneumothorax associated with endoscopic valve therapy for emphysema--potential mechanisms, treatment algorithm, and case examples.

The use of endoscopically placed unidirectional valves for the treatment of emphysema is increasing. With better patient selection, there is also an increased likelihood of complications associated with the procedure, such as postprocedural pneumothorax. There is, however, little evidence of pneumothorax management in patients with severe COPD and emphysema. This report describes an expert recommendation that has been developed to outline pneumothorax management after valve placement to inform physicians and patients of the risk-benefit profile and to assist them in decision making. Skilled and aggressive pneumothorax management is necessary in this patient population, and by following these recommendations traumatic scenarios, prolonged drainage, extended hospitalizations, and/or surgery might be avoided in many cases.

Inhaled gene therapy in lung cancer: proof-of-concept for nano-oncology and nanobiotechnology in the management of lung cancer.

Lung cancer still remains one of the leading causes of death among cancer patients. Although novel targeted therapies have been established in everyday treatment practice, and conventional platinum-based doublets have demonstrated effective results regarding overall and progression-free survival, we have still failed to achieve long-term survival. Therefore, several strategies of applying locoregional therapy are under investigation. Aerosol chemotherapy is already under investigation and, taking this a step further, aerosol gene therapies with multiple delivery systems are being developed. Several efforts have demonstrated its efficiency and effectiveness, but there are still multiple factors that have to be considered and combined to achieve an overall more effective multifunctional treatment. In the current review, we present data regarding aerosol delivery systems, transporters, carriers, vectors, genes, toxicity, efficiency, specificity, lung microenvironment and delivery gene therapy systems. Finally, we present current studies and future perspectives.

Inhaled cisplatin deposition and distribution in lymph nodes in stage II lung cancer patients.

Lung cancer therapies during the last decade have focused on targeting the genome of cancer cells, and novel routes for administering lung cancer therapies have been investigated for decades. Aerosol therapies for several systematic diseases and systemic infections were introduced into the market a decade ago. One of the main issues of aerosol therapies has been the ability to investigate the deposition of a drug compound throughout the systematic circulation and lymph node circulation. Until now, none of the published studies have efficiently shown the deposition of a chemotherapy pharmaceutical within the lymph node tissue. In our current work we present, for the first time, with the novel CytoViva(®) (AL, USA) technique, the deposition of cisplatin aerosol therapy in surgically resected stage II lymph nodes from lung cancer patients. Finally, we present the distribution of cisplatin in correlation with the cisplatin concentration in different lymph stations and comment on the possible mechanisms of distribution.

Evaluation of a novel endobronchial ultrasound-guided lymph node forceps in enlarged mediastinal lymph nodes.

BACKGROUND: Endobronchial ultrasound-transbronchial nee dle aspiration (EBUS-TBNA) is a useful technique for cytological assessment of enlarged mediastinal lymph nodes with a high diagnostic yield for lung cancer. However, the small sample volume can be problematic in diagnosing benign diseases and for molecular analysis of malignant tumours. OBJECTIVES: The aim of the study was to evaluate a novel lymph node forceps for EBUS-guided lymph node biopsy (EBUS-transbronchial forceps biopsy; EBUS-TBFB) in malignant and benign conditions concerning safety, feasibility, and diagnostic yield. METHODS: Patients with enlarged mediastinal or hilar lymph nodes were included. EBUS-TBNA was performed followed by EBUS-guided TBFB with the lymph node forceps. Three biopsy specimens were obtained. The diagnostic yields of EBUS-TBFB, EBUS-TBNA, and the combination of both sampling techniques were compared. Complications were systematically recorded. RESULTS: Fifty-five patients with enlarged mediastinal nodes were enrolled into this study. Specimens adequate for histological analysis were obtained in all but one case using EBUS-TBFB. EBUS-TBFB increased the diagnostic yield of EBUS-TBNA from 64 to 93% in benign conditions. The overall diagnostic yield was higher compared to EBUS-TBNA alone. EGFR mutation analysis could be achieved in the forceps biopsy samples as needed. No complications were observed. CONCLUSIONS: EBUS-TBFB with a novel lymph node forceps is safe and provides adequate histological specimens of enlarged mediastinal lymph nodes. EBUS-TBFB increases the diagnostic yield in benign conditions and may add value in molecular analysis of non-small cell lung cancer.

A health condition index for assessing disease progression.

INTRODUCTION: Currently immunotherapy is considered a cutting edge pharmaceutical treatment for non-small cell lung cancer. Tumor profile plays a crucial role in identifying the correct patient group. METHODS: Therefore, initial biopsies and re-biopsies are necessary in order to identify the expression of programmed death-ligand-1. RESULTS: This information is crucial and therefore all future immunotherapy studies have to be built upon a specific statistical model which associates the tumor profile and tumor profile expression along with treatment efficiency. DISCUSSION: We present a novel statistical methodology for future immunotherapy studies of non-small cell lung cancer.

Tentative study on radial endobronchial ultrasonography evaluating airway wall thickness before and after bronchial thermoplasty.

AIM: We aimed to observe the clinical practicing value of radial endobronchial ultrasonography evaluating airway wall thickness before and after bronchial thermoplasty. METHODS: We selected two patients who received bronchial thermoplasty in our hospital. We measured the thickness of each segmental airway wall of each patient by radial endobronchial ultrasonography, and observed the difference before and after the therapy. All the treatments and measurement were performed by a designated bronchoscopist and the locations and depths of the ultrasound probe were relatively fixed, to reduce the operational error. RESULTS: In both two patients, the mean thicknesses of all segmental airway walls was 4.9 ± 0.7 mm before the first session of BT; the mean thickness was 4.13 ± 0.92 mm before the second session; the mean thickness was 2.69 ± 0.68 mm before the third session; the mean thickness was 2.7 ± 0.5 mm in the follow-up measurement at six months after the BT treatment; all thicknesses of airway wall were significantly reduced comparing with those before treatment; all the thicknesses of the airway walls were stable without any tendency of thickening after six months. Although the airways in the right middle lobe of both two patients were not received BT, their thicknesses were also decreased comparing with those before the treatment; both upper lobes bronchus of both two patients were not activated in the first and second sessions, but their thicknesses were also decreased at the third measurement. CONCLUSION: Radial endobronchial ultrasonography is a simple and practical method to measure the thickness of patient's airway wall. Bronchial thermoplasty can effectively reduce the thickness of airway wall. It can reduce airway smooth muscle by direct activation and other possible more complicated mechanism, which need further research.

Corrigendum to "Tentative study on radial endobronchial ultrasonography evaluating airway wall thickness before and after bronchial thermoplasty" [Respir. Med. Case Rep. 36 (2022) 101571].

[This corrects the article DOI: 10.1016/j.rmcr.2021.101571.].

Radial-EBUS: CryoBiopsy Versus Conventional Biopsy: Time-Sample and C-Arm.

INTRODUCTION: Diagnosis of lung nodules is still under investigation. We use computed tomography scans and positron emission tomography in order to identify their origin. PATIENTS AND METHODS: In our retrospective study, we included 248 patients with a single lung nodule or multiple lung nodules of size ≥1 cm. We used a radial-endobronchial ultrasound and a C-Arm. We used a 1.1 mm cryoprobe versus a 22G needle vs. forceps/brush. We compared the sample size of each biopsy method with the number of cell-block slices. RESULTS: Central lesions indifferent to the method provided the same mean number of cell-block slices (0.04933-0.02410). Cryobiopsies provide less sample size for peripheral lesions due to the higher incidence of pneumothorax (0.04700-0.02296). CONCLUSION: The larger the lesion ≥2 cm, and central, more cell-blocks are produced indifferent to the biopsy method (0.13386-0.02939). The time of the procedure was observed to be less when the C-Arm was used as an additional navigation tool (0.14854-0.00089).

Engineered Hybrid Treg-Targeted Nanosomes Restrain Lung Immunosuppression by Inducing Intratumoral CD8+T Cell Immunity.

Introduction: Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse. Materials: To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment. This is achieved through the combination of Dasatinib and Epacadostat integrated into biodegradable nanosomes which can inhibit and reverse Treg-supporting immunosuppression. Flow cytometry and immunofluorescence analysis, PET/CT scan, PTT/PA imaging and the Balb/c tumor model were used to explore the anti-tumor effect of Treg-targeted NCs both in vitro and in vivo. Results: Findings reveal that NC treatment triggered substantial tumor cell apoptosis and drastically decreased tumor volume followed by downregulation of Ki-67 antigen expression, respectively. Drug circulation time was also increased as shown by biodistribution analysis accompanied by greater accumulation in lung and peripheral tissues. Intratumoral Th1 cytokines' expression was also increased, especially TNF-A, IL-12 by 42%, and IL-6 by 18% compared to PBS treatment. In addition, the presence of mature CD80+/CD86+dendritic cells (DCs) revealed T cell enrichment and a decline in MDSC infiltration and myeloid subsets. Interestingly, a significant decline of Gr/CD11b myeloid cell population in blood and tissue samples was also observed. This immune activation can be attributed to the enhanced PTT efficiency and tumor targeting ability of the nanospheres which under near infrared (NIR) exposure can prompt highly efficient tumor ablation. We also demonstrated their therapeutic efficacy against 4T1 metastatic breast cancer model. Additionally, the photothermal therapy in combination with PD-L1 checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Discussion: Overall, our findings present a novel nano-enabled platform for the inhibition of Treg-dependent immunosuppression in NSCLC and provide a novel nanotherapeutic strategy for the treatment of metastatic neoplasia.