Expression of HOXB7 in the Lung of Patients with Idiopathic Pulmonary Fibrosis: A Proof-of-Concept Study.

BACKGROUND: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. METHODS: Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. RESULTS: The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50-75%)-measured with high-resolution computer tomography-compared to those with a lower extent (0-25%) (difference between means = 25.74 ± 6.72, p = 0.004). CONCLUSIONS: The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF.

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.

Lipoaspirate Injection in Relapsing Idiopathic Subglottic Stenosis: Preliminary Results.

OBJECTIVES: The management of idiopathic subglottic stenosis (iSGS) poses a clinical challenge due to high recurrence rates following both endoscopic and open approaches, often leading to tracheostomy. The activation of abnormal T-cells and cytokine pathways has been linked to iSGS pathogenesis. Autologous adipose tissue centrifugation yields lipoaspirate, offering optimal anti-inflammatory effects and biocompatibility widely utilized in various medical settings. This report presents the first 3 cases employing endoscopic dilation (ED) in combination with local lipoaspirate injection to address recurrent iSGS. METHODS: A prospective observational study was conducted, involving multidisciplinary evaluation by the Tracheal Team at the University of Modena. Patients meeting specific criteria were directed to undergo ED + lipoaspirate injection. RESULTS: Three patients fulfilled the inclusion criteria. The mean number of prior endoscopic procedures performed was 8. Endoscopic examination revealed 90% stenosis in patient A, 60% stenosis in patient B, and 60% stenosis in patient C. All patients presented inflammatory tissue or incipient granulations at the stenotic site, with an average time of 6 months between previous procedures. After 15 months, none of the patients required further procedures, and endoscopic examination revealed a significant reduction or disappearance of inflammatory tissue with a stable airway lumen. CONCLUSIONS: The observed results are encouraging in terms of reducing local inflammation and halting stenosis progression, especially in cases of short-term relapsing iSGS.

Predictors of respiratory failure in Guillain-Barré syndrome: a 22 year cohort study from a single Italian centre.

BACKGROUND AND PURPOSE: The study aimed to identify predictors of respiratory failure leading to mechanical ventilation (MV) and tracheostomy in Guillain-Barré syndrome (GBS). METHODS: Two hundred and thirty adult cases admitted to the Neurology Unit of Modena, Italy, between January 2000 and December 2021 were studied. A cut-off of MV starting within 8 weeks from onset of weakness was used. Univariable, multivariable logistic and Cox regression analyses were used to determine which pre-specified clinical and diagnostic characteristics were capable of predicting MV and tracheostomy, due to weaning failure. The model was internally validated within the full cohort. The Erasmus GBS Respiratory Insufficiency Score was retrospectively applied. RESULTS: One hundred and seventy-six cases (76.5%) were classified as classical sensorimotor GBS and 54 (23.4%) as variants. Thirty-two patients (13.9%) needed MV: 84.3% required respiratory support within 7 days. Independent predictors of respiratory failure and MV were older age, facial, bulbar, neck flexor weakness, dysautonomia, axonal electrophysiological subtype, cardiovascular comorbidities and higher disability score at entry. There was no association with abnormal spinal fluid parameters nor with positive serology for recent infections. Twenty-two patients (68.7%) were ventilated for more than 7 days; 4.7% died within 8 weeks. The patients who required MV were treated more often with plasma exchange. Independent predictors of tracheostomy due to weaning trial failure were facial, bulbar, neck flexor weakness, autonomic dysfunction, associated cardiovascular morbidities and axonal electrophysiological subtype on nerve conduction study. CONCLUSIONS: Our study indicates distinct predictors of MV and tracheostomy in GBS patients.

Effect of high flow nasal oxygen on inspiratory effort of patients with acute hypoxic respiratory failure and do not intubate orders.

High flow nasal oxygen (HFNO) is recommended as a first-line respiratory support during acute hypoxic respiratory failure (AHRF) and represents a proportionate treatment option for patients with do not intubate (DNI) orders. The aim of the study is to assess the effect of HFNO on inspiratory effort as assessed by esophageal manometry in a population of DNI patients suffering from AHRF. Patients with AHRF and DNI orders admitted to Respiratory intermediate Care Unit between January 1st, 2018 and May 31st, 2023 to receive HFNO and subjected to esophageal manometry were enrolled. Esophageal pressure swing (ΔPes), clinical variables before and after 2 h of HFNO and clinical outcome (including HFNO failure) were collected and compared as appropriate. The change in physiological and clinical parameters according to the intensity of baseline breathing effort was assessed and the correlation between baseline ΔPes values and the relative change in breathing effort and clinical variables after 2 h of HFNO was explored. Eighty-two consecutive patients were enrolled according to sample size calculation. Two hours after HFNO start, patients presented significant improvement in ΔPes (12 VS 16 cmH2O, p < 0.0001), respiratory rate (RR) (22 VS 28 bpm, p < 0.0001), PaO2/FiO2 (133 VS 126 mmHg, p < 0.0001), Heart rate, Acidosis, Consciousness, Oxygenation and respiratory rate (HACOR) score, (4 VS 6, p < 0.0001), Respiratory rate Oxygenation (ROX) index (8.5 VS 6.1, p < 0.0001) and BORG (1 VS 4, p < 000.1). Patients with baseline ΔPes below 20 cmH2O where those who improved all the explored variables, while patients with baseline ΔPes above 30 cmH2O did not report significant changes in physiological or clinical features. A significant correlation was found between baseline ΔPes values and after 2 h of HFNO (R2 = 0.9, p < 0.0001). ΔPes change 2 h after HFNO significantly correlated with change in BORG (p < 0.0001), ROX index (p < 0.0001), HACOR score (p < 0.001) and RR (p < 0.001). In DNI patients with AHRF, HFNO was effective in reducing breathing effort and improving respiratory and clinical variables only for those patients with not excessive inspiratory effort.

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.

Updates on Larynx Cancer: Risk Factors and Oncogenesis.

Laryngeal cancer is a very common tumor in the upper aero-digestive tract. Understanding its biological mechanisms has garnered significant interest in recent years. The development of laryngeal squamous cell carcinoma (LSCC) follows a multistep process starting from precursor lesions in the epithelium. Various risk factors have been associated with laryngeal tumors, including smoking, alcohol consumption, opium use, as well as infections with HPV and EBV viruses, among others. Cancer development involves multiple steps, and genetic alterations play a crucial role. Tumor suppressor genes can be inactivated, and proto-oncogenes may become activated through mechanisms like deletions, point mutations, promoter methylation, and gene amplification. Epigenetic modifications, driven by miRNAs, have been proven to contribute to LSCC development. Despite advances in molecular medicine, there are still aspects of laryngeal cancer that remain poorly understood, and the underlying biological mechanisms have not been fully elucidated. In this narrative review, we examined the literature to analyze and summarize the main steps of carcinogenesis and the risk factors associated with laryngeal cancer.

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.

Case report: Endoscopic closure with double stenting and autologous fascia lata graft of large tracheo-esophageal fistula.

Introduction: Radiotherapy and esophageal stenting are usually employed to manage esophageal localization of distant cancer. However, they are also related to the occurrence of an increased risk of tracheoesophageal fistula. Tracheoesophageal fistula management in these patients involves dealing with poor general conditions and short-term prognosis. This paper presents the first case in literature of bronchoscopic fistula closure through an autologous fascia lata graft placement between two stents. Case report and aim: A 67-years-old male patient was diagnosed with pulmonary squamous cell carcinoma in the inferior lobe of the left lung with mediastinal lymph node metastasis. After a multidisciplinary discussion, bronchoscopic repair of tracheoesophageal fistula with autologous fascia lata was decided without the removal of the esophageal stent due to the high risk on the esophagus possibly related to such a procedure. Oral feeding was progressively introduced without the development of aspiration symptoms. Videofluoroscopy and esophagogastroduodenoscopy were performed at 7 months showing no signs of tracheoesophageal fistula patency. Conclusion: This technique might represent a low risks viable option for patients unsuitable for open surgical approaches.

Tumors of the Nose and Paranasal Sinuses: Promoting Factors and Molecular Mechanisms-A Systematic Review.

Sinonasal neoplasms are uncommon diseases, characterized by heterogeneous biological behavior, which frequently results in challenges in differential diagnosis and treatment choice. The aim of this review was to examine the pathogenesis and molecular mechanisms underlying the regulation of tumor initiation and growth, in order to better define diagnostic and therapeutic strategies as well as the prognostic impact of these rare neoplasms. A systematic review according to Preferred Reporting Items for Systematic Review and Meta-Analysis criteria was conducted between September and November 2022. The authors considered the three main histological patterns of sinonasal tumors, namely Squamous Cell Carcinoma, Intestinal-Type Adenocarcinoma, and Olfactory Neuroblastoma. In total, 246 articles were eventually included in the analysis. The genetic and epigenetic changes underlying the oncogenic process were discussed, through a qualitative synthesis of the included studies. The identification of a comprehensive model of carcinogenesis for each sinonasal cancer subtype is needed, in order to pave the way toward tailored treatment approaches and improve survival for this rare and challenging group of cancers.

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.

Acute neuromuscular syndromes with respiratory failure during COVID-19 pandemic: Where we stand and challenges ahead.

Coronavirus disease 2019 (COVID-19), a disease caused by the novel betacoronavirus SARS-COV-2, has become a global pandemic threat. SARS- COV-2 is structurally similar to SARS-COV, and both bind to the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. While patients typically present with fever, shortness of breath, sore throat, and cough, in some cases neurologic manifestations occur due to both direct and indirect involvement of the nervous system. Case reports include anosmia, ageusia, central respiratory failure, stroke, acute necrotizing hemorrhagic encephalopathy, toxic-metabolic encephalopathy, headache, myalgia, myelitis, ataxia, and various neuropsychiatric manifestations. Some patients with COVID-19 may present with concurrent acute neuromuscular syndromes such as myasthenic crisis (MC), Guillain-Barré syndrome (GBS) and idiopathic inflammatory myopathies (IIM); these conditions coupled with respiratory failure could trigger a life-threatening condition. Here, we review the current state of knowledge on acute neuromuscular syndromes with respiratory failure related to COVID-19 infection in an attempt to clarify and to manage the muscle dysfunction overlapping SARS-COV-2 infection.

Delirium incidence and risk factors in patients undergoing non-invasive ventilation for acute respiratory failure: a multicenter observational trial.

BACKGROUND: Noninvasive ventilation (NIV) still has high failure rate when used for de novo acute respiratory failure (ARF). Delirium may impact the outcome, however data regarding its incidence, timing of occurrence and clinical predictors in this subset of patients are scarce. METHODS: Consecutive patients with de novo ARF subjected to NIV were recruited in 10 Italian Respiratory Intensive Care Units (RICUs) and Intensive Care Units (ICUs). Demographics and clinical features, including tolerance to interface and NIV setting were recorded on admission and during stay, whereas delirium onset and type was assessed by the Confusion Assessment Method for ICU (CAM-ICU)-7 scale and Richmond Agitation Sedation Scale (RASS) twice/per day up to a week. The association between clinical variables and the occurrence of delirium and its influence on NIV failure and other clinical outcomes were analyzed. RESULTS: Thirty-two out of 90 enrolled patients (36%) developed delirium over seven days upon admission; median time to onset was 48 hours (24-60). Older age (OR=2.7 [1.9-9], P=0.01), the presence of cancer OR=3.7 [2-5.4], P=0.002), sepsis (OR=1.7 [1.1-3.4], P=0.01), SOFA Score (OR=1.8 [1.1-3.1], P=0.01), low tolerance to interface (OR=3.2 [2.1-5], P=0.002), use of helmet (OR=1.9 [1.2-4.3] P=0.04), and higher PRE-DELIRIC (OR=3.5 [1.3-15], P=0.03) and BORG (OR=1.7 [1.1-4.6], P=0.02] scores were significantly associated with delirium. Delirium had high risk for NIV failure (HR=3.5 95% CI: [1.4-8.6], P=0.0002) and it significantly associated with longer RICU/ICU stay and higher mortality. CONCLUSIONS: Delirium onset in acute hypoxic patients undergoing NIV is frequent and negatively affects the outcome. Multiple related clinical factors should be addressed early on admission to prevent the delirium-related risk of NIV failure in these patients.

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.