Molecular Biology and Therapeutic Targets of Primitive Tracheal Tumors: Focus on Tumors Derived by Salivary Glands and Squamous Cell Carcinoma.

Primary tracheal tumors are rare, constituting approximately 0.1-0.4% of malignant diseases. Squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC) account for about two-thirds of these tumors. Despite most primary tracheal cancers being eligible for surgery and/or radiotherapy, unresectable, recurrent and metastatic tumors may require systemic treatments. Unfortunately, the poor response to available chemotherapy as well as the lack of other real therapeutic alternatives affects the quality of life and outcome of patients suffering from more advanced disease. In this condition, target therapy against driver mutations could constitute an alternative to chemotherapy, and may help in disease control. The past two decades have seen extraordinary progress in developing novel target treatment options, shifting the treatment paradigm for several cancers such as lung cancer. The improvement of knowledge regarding the genetic and biological alterations, of major primary tracheal tumors, has opened up new treatment perspectives, suggesting the possible role of biological targeted therapies for the treatment of these rare tumors. The purpose of this review is to outline the state of knowledge regarding the molecular biology, and the preliminary data on target treatments of the main primary tracheal tumors, focusing on salivary-gland-derived cancers and squamous cell carcinoma.

Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults.

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.

Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia.

BACKGROUND: The main clinical consequences of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection are pneumonia and respiratory failure even requiring mechanical ventilation. In this context, the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacious in treating air leaks with a high success rate. CASE PRESENTATION: We report, for the first time, two cases of patients affected by SARS-CoV-2-related pneumonia complicated with bacterial super-infection, experiencing pneumothorax and persistent air leaks after invasive mechanical ventilation. Despite the severity of respiratory failure both patients underwent rigid interventional bronchoscopy and were successfully treated through EBV positioning. CONCLUSIONS: Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective minimally invasive therapeutic option for treating this subset of patients.

Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung.

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of "squishy balls", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

Endoscopic Bronchopleural Fistula Repair Using Autologous Fat Graft.

Bronchopleural fistulas (BPFs) represent a rare catastrophic complication of pulmonary resection and carry a high mortality rate. Surgical treatments of BPF are often technically difficult and can be tolerated only by a limited number of patients, while less invasive endoscopic approaches show variable success rates, mainly related to the size of the fistula. In this report, we describe the successful treatment of a large BPF by means of endoscopic autologous fat implantation; we also discuss the technical details of this surgical procedure.

Stenting versus balloon dilatation in patients with tracheal benign stenosis: The STROBE trial.

Background: It is well known that benign tracheal stenosis represents an obstacle to open surgery, and that its treatment could be challenging. Two endoscopic techniques have so far been adopted to restore tracheal patency: balloon dilatation (BA) through laryngoscopy, and tracheal stenting (ST) with rigid bronchoscopy. The main objective of this study was to compare the efficacy of BA and ST to treat benign tracheal stenosis not eligible for surgery. We also compared the rate of adverse events in the two treatment groups. Methods: A retrospective, observational cohort study was carried out at the University Hospital of Modena (Italy) from November 2012 to November 2017 in two separate departments. Patients were considered to be "stabilized" (primary outcome) if they did not report significant respiratory symptoms, or restenosis in the long-term (2 years) following the endoscopic procedure. Results: Sixty-six patients were included in the study (33 in the BA and 33 in the ST group, respectively). Unadjusted Kaplan-Meier estimates showed a greater therapeutic effect of ST compared to BA at 2 years (hazard ratio = 3.9 95%CI [1.5-9.8], p = .01). After adjusting for confounders, stratified analyses showed that this effect was significant in patients with complex stenosis, idiopathic etiology, and degree of stenosis >70%. Compared with BA, ST showed a higher rate of adverse events (p = .01). Conclusions: Compared to BA, ST seems to be more effective in achieving stabilization of tracheal patency in complex benign tracheal stenosis, although burdened with a significantly higher number of adverse effects. These findings warrant future prospective study for confirmation. Level of evidence: 3.

Spontaneous Breathing and Evolving Phenotypes of Lung Damage in Patients with COVID-19: Review of Current Evidence and Forecast of a New Scenario.

The mechanisms of acute respiratory failure other than inflammation and complicating the SARS-CoV-2 infection are still far from being fully understood, thus challenging the management of COVID-19 patients in the critical care setting. In this unforeseen scenario, the role of an individual's excessive spontaneous breathing may acquire critical importance, being one potential and important driver of lung injury and disease progression. The consequences of this acute lung damage may impair lung structure, forecasting the model of a fragile respiratory system. This perspective article aims to analyze the progression of injured lung phenotypes across the SARS-CoV-2 induced respiratory failure, pointing out the role of spontaneous breathing and also tackling the specific respiratory/ventilatory strategy required by the fragile lung type.

Integrated intErventional bronchoscopy in the treatment of locally adVanced non-small lung cancER with central Malignant airway Obstructions: a multicentric REtrospective study (EVERMORE).

OBJECTIVES: Despite new therapeutic perspectives, the presence of central airways occlusion (CAO) in patients with locally advanced non-small cell lung cancer (NSCLC) is associated with poor survival. There is no clear evidence on the clinical impact of interventional bronchoscopy as a part of an integrated treatment to cure these patients. MATERIALS AND METHODS: This retrospective cohort study was conducted in two teaching hospitals over a 10 years period (January 2010-January 2020) comparing patients with NSCLC at stage IIIB and CAO at disease onset treated with chemotherapy/radiotherapy (standard therapy-ST) with those receiving interventional bronchoscopy plus ST (integrated treatment-IT). Primary outcome was 1-year survival. The onset of respiratory events, symptoms-free interval, hospitalization, need for palliation, and overall mortality served as secondary outcomes. RESULTS: A total of 100 patients were included, 60 in the IT and 40 in the ST group. Unadjusted Kaplan-Meier estimates showed greater effect of IT compared to ST on 1-year survival (HR = 2.1 95%CI[1.1-4.8], p = 0.003). IT showed a significantly higher survival gain over ST in those patients showing KRAS mutation (7.6 VS 0.8 months,<0.0001), a lumen occlusion >65% (6.6 VS 2.9 months,<0.001), and lacking the involvement of left bronchus (7 VS 2.3 months,<0.0001). Compared to ST, IT also showed a favorable difference in terms of new hospitalizations (p = 0.03), symptom-free interval (p = 0.02), and onset of atelectasis (p = 0.01). CONCLUSIONS: In patients with NSCLC stage IIIB and CAO, additional interventional bronchoscopy might impact on 1-year survival. Genetic and anatomic phenotyping might allow identifying those patients who may gain life expectancy from the endoscopic intervention.

Unexpected positron emission tomography-positive actinomyces-related mass of the bronchial stump.

Pulmonary actinomycosis is a rare disease frequently misdiagnosed, even by experienced clinicians, as primary or metastatic lung cancer or as other more conventional lung infections. It is often an unexpected disease that is basically detected only on cytological/histological examination. A case involving a patient who presented with a mass in the bronchial stump (of a previous pulmonary lobectomy) is described. Despite a strong suspicion of recurrent lung cancer, positron emission tomography confirmed a diagnosis of a suture-related bronchial actinomycosis.