Integrated endoscopic treatment of primitive unresectable tracheal tumor: the INTACT retrospective cohort study.

Background: Primitive tracheal tumors represent a rare entity whose management, when unresectable, remains challenging. Primary aim of this study was to explore the survival and the factors influencing prognosis of patients with unresectable primitive tracheal tumor undergoing multimodal treatment integrating interventional bronchoscopy and radiotherapy. Methods: This retrospective cohort study was conducted at the University Hospital of Modena (Italy) over a 12-year period (January 2010 to January 2022) analyzing patients with unresectable primary tracheal tumor receiving interventional bronchoscopy treatment followed by radiotherapy. Survival analysis was conducted for the whole population and according to histology, development of metastasis, stent placement and the onset of disease relapse. The raw and independent association between potential risk factor and 5-year mortality and the reported complications were investigated. Results: A total of 12 patients were included. Five-year survival rate was 42% with a median survival time of 26.7 (interquartile range, 4.1-82) months. Survivors showed a higher prevalence of cystic-adenoid histology (80% vs. 14%), while patients who were dead at 5 years were those with a more advanced T (prevalence of T2: 71% vs. 0%) and a lower response to first line treatment (57% vs. 0%). Treatment complications accounted for stent dislocation (33%) and the onset of granuloma (18%), while no major side effects were reported. The presence of cystic-adenoid histology resulted in significantly improved 5-year survival rate (80% vs. 14%). The onset of distal metastasis, the occurrence of disease relapse and the placement of tracheal stent did not result significantly associated with lower survival. Among analysed variables, only the presence of cystic-adenoid histology resulted independently associated with survival (odds ratio =0.1, P=0.04). Conclusions: Multimodal treatment including interventional bronchoscopy and associated radiotherapy for unresectable primary tracheal tumors seems not burdened by significant complications and may provide benefits in terms of survival for those patients with cystic-adenoid histology.

Stress-strain curve and elastic behavior of the fibrotic lung with usual interstitial pneumonia pattern during protective mechanical ventilation.

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH2O versus 11.4 [10.3-14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Physiological effects of lung-protective ventilation in patients with lung fibrosis and usual interstitial pneumonia pattern versus primary ARDS: a matched-control study.

BACKGROUND: Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung-protective ventilation in patients with AE-ILD-UIP compared with primary ARDS. METHODS: Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO2/FiO2 ratio). Three PEEP levels (zero = ZEEP, 4-8 cmH2O = PEEPLOW, and titrated to achieve positive end-expiratory transpulmonary pressure PL,EE = PEEPTITRATED) were used for measurements. RESULTS: Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was - 4.3 [- 7.6- - 2.3] cmH2O and lung elastance (EL) 44 [40-51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p = 0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3-1.5] cmH2O and EL to 49 [43-59] (p = 0.004 and p < 0.001 compared to ZEEP and PEEPLOW, respectively). ΔPL decreased at PEEPLOW (p = 0.018) and increased at PEEPTITRATED (p = 0.003). In matched ARDS control PEEP titration to obtain a positive PL,EE did not result in significant changes in EL and ΔPL. CONCLUSIONS: In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE significantly worsened lung mechanics.

Proteomic profiling of formalin-fixed paraffine-embedded tissue reveals key proteins related to lung dysfunction in idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) severely affects the lung leading to aberrant deposition of extracellular matrix and parenchymal stiffness with progressive functional derangement. The limited availability of fresh tissues represents one of the major limitations to study the molecular profiling of IPF lung tissue. The primary aim of this study was to explore the proteomic profiling yield of archived formalin-fixed paraffin-embedded (FFPE) specimens of IPF lung tissues. Methods: We further determined the protein expression according to respiratory functional decline at the time of biopsy. The total proteins isolated from 11 FFPE samples of IPF patients compared to 3 FFPE samples from a non-fibrotic lung defined as controls, were subjected to label-free quantitative proteomic analysis by liquid chromatography-mass spectrometry (LC-MS/MS) and resulted in the detection of about 400 proteins. Results: After the pairwise comparison between controls and IPF, functional enrichment analysis identified differentially expressed proteins that were involved in extracellular matrix signaling pathways, focal adhesion and transforming growth factor ß (TGF-ß) signaling pathways strongly associated with IPF onset and progression. Five proteins were significantly over- expressed in the lung of IPF patients with either advanced disease stage (Stage II) or impaired pulmonary function (FVC<75, DLCO<55) compared to controls; these were lymphocyte cytosolic protein 1 (LCP1), peroxiredoxin-2 (PRDX2), transgelin 2 (TAGLN2), lumican (LUM) and mimecan (OGN) that might play a key role in the fibrogenic processes. Discussion: Our work showed that the analysis of FFPE samples was able to identify key proteins that might be crucial for the IPF pathogenesis. These proteins are correlated with lung carcinogenesis or involved in the immune landscape of lung cancer, thus making possible common mechanisms between lung carcinogenesis and fibrosis progression, two pathological conditions at risk for each other in the real life.

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.

Risk Factors for Pulmonary Air Leak and Clinical Prognosis in Patients With COVID-19 Related Acute Respiratory Failure: A Retrospective Matched Control Study.

Background: The role of excessive inspiratory effort in promoting alveolar and pleural rupture resulting in air leak (AL) in patients with SARS-CoV-2 induced acute respiratory failure (ARF) while on spontaneous breathing is undetermined. Methods: Among all patients with COVID-19 related ARF admitted to a respiratory intensive care unit (RICU) and receiving non-invasive respiratory support, those developing an AL were and matched 1:1 [by means of PaO2/FiO2 ratio, age, body mass index-BMI and subsequent organ failure assessment (SOFA)] with a comparable population who did not (NAL group). Esophageal pressure (ΔPes) and dynamic transpulmonary pressure (ΔPL) swings were compared between groups. Risk factors affecting AL onset were evaluated. The composite outcome of ventilator-free-days (VFD) at day 28 (including ETI, mortality, tracheostomy) was compared between groups. Results: Air leak and NAL groups (n = 28) showed similar ΔPes, whereas AL had higher ΔPL (20 [16-21] and 17 [11-20], p = 0.01, respectively). Higher ΔPL (OR = 1.5 95%CI[1-1.8], p = 0.01), positive end-expiratory pressure (OR = 2.4 95%CI[1.2-5.9], p = 0.04) and pressure support (OR = 1.8 95%CI[1.1-3.5], p = 0.03), D-dimer on admission (OR = 2.1 95%CI[1.3-9.8], p = 0.03), and features suggestive of consolidation on computed tomography scan (OR = 3.8 95%CI[1.1-15], p = 0.04) were all significantly associated with AL. A lower VFD score resulted in a higher risk (HR = 3.7 95%CI [1.2-11.3], p = 0.01) in the AL group compared with NAL. RICU stay and 90-day mortality were also higher in the AL group compared with NAL. Conclusion: In spontaneously breathing patients with COVID-19 related ARF, higher levels of ΔPL, blood D-dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset.

Nasal pressure swings as the measure of inspiratory effort in spontaneously breathing patients with de novo acute respiratory failure.

BACKGROUND: Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔPes) and nasal (ΔPnos) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF. METHODS: From January 1, 2021, to September 1, 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of non-invasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 h after starting NRS. Correlation between ΔPes and ΔPnos served as primary outcome. The effect of ΔPnos measurements on respiratory rate and ΔPes was also assessed. RESULTS: ΔPes and ΔPnos were strongly correlated at admission (R2 = 0.88, p < 0.001) and 24 h apart (R2 = 0.94, p < 0.001). The nasal plug insertion and the mouth closure required for ΔPnos measurement did not result in significant change of respiratory rate and ΔPes. The correlation between measures at 24 h remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R2 = 0.79, p < 0.001] or non-invasive ventilation [R2 = 0.95, p < 0.001]). CONCLUSIONS: In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔPnos might warrant further investigation as a measure of inspiratory effort in patients with ARF. TRIAL REGISTRATION: NCT03826797 . Registered October 2016.

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.

Early awake proning in critical and severe COVID-19 patients undergoing noninvasive respiratory support: A retrospective multicenter cohort study.

BACKGROUND/MATERIALS AND METHODS: This retrospective cohort study was conducted in two teaching hospitals over a 3-month period (March 2010-June 2020) comparing severe and critical COVID-19 patients admitted to Respiratory Intensive Care Unit for non-invasive respiratory support (NRS) and subjected to awake prone position (PP) with those receiving standard care (SC). Primary outcome was endotracheal intubation (ETI) rate. In-hospital mortality, time to ETI, tracheostomy, length of RICU and hospital stay served as secondary outcomes. Risk factors associated to ETI among PP patients were also investigated. RESULTS: A total of 114 patients were included, 76 in the SC and 38 in the PP group. Unadjusted Kaplan-Meier estimates showed greater effect of PP compared to SC on ETI rate (HR = 0.45 95% CI [0.2-0.9], p = 0.02) even after adjustment for baseline confounders (HR = 0.59 95% CI [0.3-0.94], p = 0.03). After stratification according to non-invasive respiratory support, PP showed greater significant benefit for those on High Flow Nasal Cannulae (HR = 0.34 95% CI [0.12-0.84], p = 0.04). Compared to SC, PP patients also showed a favorable difference in terms of days free from respiratory support, length of RICU and hospital stay while mortality and tracheostomy rate were not significantly different. CONCLUSIONS: Prone positioning in awake and spontaneously breathing Covid-19 patients is feasible and associated with a reduction of intubation rate, especially in those patients undergoing HFNC. Although our results are intriguing, further randomized controlled trials are needed to answer all the open questions remaining pending about the real efficacy of PP in this setting.

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2-4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.

Fibrotic Idiopathic Interstitial Lung Disease: The Molecular and Cellular Key Players.

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision.

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.

Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis: Cause or Solution.

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung's architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.

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.