P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation.

The genes coding for the tumor suppressors p53 and retinoblastoma (Rb) are inactivated in the vast majority of small cell lung cancer (SCLC) tumors. Data support the notion that these two deleterious genetic events represent the initial steps in the development of SCLC, making them essential for a lung epithelial cell to progress toward the acquisition of a malignant phenotype. With the loss of TP53 and RB1, their broad tumor suppressive functions are eliminated and a normal cell is able to proliferate indefinitely, escape entering into cellular senescence, and evade death, no matter the damage it has experienced. Within this setting, lung epithelial cells accumulate further oncogenic mutations and are well on their way to becoming SCLC cells. Understanding the molecular mechanisms of these genetic lesions and their effects within lung epithelial cells is of paramount importance, in order to tackle this aggressive and deadly lung cancer. The present review summarizes the current knowledge on p53 and Rb aberrations, their biological significance, and their prospective therapeutic potential, highlighting completed and ongoing clinical trials with agents that target downstream pathways.

Small airways in asthma: From inflammation and pathophysiology to treatment response.

Small airways are characterized as those with an inner diameter less than 2 mm and constitute a major site of pathology and inflammation in asthma disease. It is estimated that small airways dysfunction may occur before the emergence of noticeable symptoms, spirometric abnormalities and imaging findings, thus characterizing them as "the quiet or silent zone" of the lungs. Despite their importance, measuring and quantifying small airways dysfunction presents a considerable challenge due to their inaccessibility in usual functional measurements, primarily due to their size and peripheral localization. Several pulmonary function tests have been proposed for the assessment of the small airways, including impulse oscillometry, nitrogen washout, body plethysmography, as well as imaging methods. Nevertheless, none of these methods has been established as the definitive "gold standard," thus, a combination of them should be used for an effective assessment of the small airways. Widely used asthma treatments seem to also affect several parameters of the small airways. Emerging biologic treatments show promising results in reducing small airways inflammation and remodelling, providing evidence for potential alterations in the disease's progression and outcomes. These novel therapies have implications not only in the clinical aspects of asthma but also in its inflammatory and functional aspects.

Evaluation of the Acid-Base Status in Patients Admitted to the ICU Due to Severe COVID-19: Physicochemical versus Traditional Approaches.

BACKGROUND: Stewart's approach is known to have better diagnostic accuracy for the identification of metabolic acid-base disturbances compared to traditional methods based either on plasma bicarbonate concentration ([HCO3-]) and anion gap (AG) or on base excess/deficit (BE). This study aimed to identify metabolic acid-base disorders using either Stewart's or traditional approaches in critically ill COVID-19 patients admitted to the ICU, to recognize potential hidden acid-base metabolic abnormalities and to assess the prognostic value of these abnormalities for patient outcome. METHODS: This was a single-center retrospective study, in which we collected data from patients with severe COVID-19 admitted to the ICU. Electronical files were used to retrieve data for arterial blood gases, serum electrolytes, and proteins and to derive [HCO3-], BE, anion gap (AG), AG adjusted for albumin (AGadj), strong ion difference, strong ion gap (SIG), and SIG corrected for water excess/deficit (SIGcorr). The acid-base status was evaluated in each patient using the BE, [HCO3-], and physicochemical approaches. RESULTS: We included 185 patients. The physicochemical approach detected more individuals with metabolic acid-base abnormalities than the BE and [HCO3-] approaches (p < 0.001), and at least one acid-base disorder was recognized in most patients. According to the physicochemical method, 170/185 patients (91.4%) had at least one disorder, as opposed to the number of patients identified using the BE 90/186 (48%) and HCO3 62/186 (33%) methods. Regarding the derived acid-base status variables, non-survivors had greater AGadj, (p = 0.013) and SIGcorr (p = 0.035) compared to survivors. CONCLUSIONS: The identification of hidden acid-base disturbances may provide a detailed understanding of the underlying conditions in patients and of the possible pathophysiological mechanisms implicated. The association of these acid-base abnormalities with mortality provides the opportunity to recognize patients at increased risk of death and support them accordingly.

Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis.

BACKGROUND: Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking. METHODS: Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated. RESULTS: We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics. CONCLUSIONS: Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.

Glucocorticoid Receptor Signaling in NSCLC: Mechanistic Aspects and Therapeutic Perspectives.

Recent advances in non-small cell lung cancer (NSCLC) biology and the discovery of novel therapeutic targets have led to the development of new pharmacological agents that may improve the clinical outcome of patients with NSCLC. The glucocorticoid receptor (GR) is an evolutionarily conserved protein belonging to the nuclear receptor superfamily of transcription factors and mediates the diverse actions of glucocorticoids in cells. Data suggest that the GR may play a relevant role in the molecular mechanisms of NSCLC tumorigenesis and malignant progression. Additionally, evidence indicates that glucocorticoids may affect the efficacy of standard treatment, including chemotherapy, immune checkpoint inhibitors, and targeted therapy. Furthermore, several findings show that GR expression may probably be associated with NSCLC patient survival. Finally, glucocorticoids may be used as therapeutic agents for the clinical management of NSCLC patients. Here, we briefly review the latest advances on the biological role of GR signaling in NSCLC and discuss the potential use of the GR as a prognostic and predictive biomarker. Importantly, we explore the therapeutic potential of glucocorticoids and the effect of adding such drugs to standard therapies for NSCLC.

Lung Cancer through Transcription Factors.

The body of knowledge on the molecular mechanisms that drive lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), is continuously growing [...].

COVID-19 Patients Presenting with Post-Intubation Upper Airway Complications: A Parallel Epidemic?

During the current pandemic, we witnessed a rise of post-intubation tracheal stenosis (PITS) in patients intubated due to COVID-19. We prospectively analyzed data from patients referred to our institution during the last 18 months for severe symptomatic post-intubation upper airway complications. Interdisciplinary bronchoscopic and/or surgical management was offered. Twenty-three patients with PITS and/or tracheoesophageal fistulae were included. They had undergone 31.85 (±22.7) days of ICU hospitalization and 17.35 (±7.4) days of intubation. Tracheal stenoses were mostly complex, located in the subglottic or mid-tracheal area. A total of 83% of patients had fracture and distortion of the tracheal wall. Fifteen patients were initially treated with rigid bronchoscopic modalities and/or stent placement and eight patients with tracheal resection-anastomosis. Post-treatment relapse in two of the bronchoscopically treated patients required surgery, while two of the surgically treated patients required rigid bronchoscopy and stent placement. Transient, non-life-threatening post-treatment complications developed in 60% of patients and were all managed successfully. The histopathology of the resected tracheal specimens didn't reveal specific alterations in comparison to pre-COVID-era PITS cases. Prolonged intubation, pronation maneuvers, oversized tubes or cuffs, and patient- or disease-specific factors may be pathogenically implicated. An increase of post-COVID PITS is anticipated. Careful prevention, early detection and effective management of these iatrogenic complications are warranted.

The Value of Dyspnea and Spirometry in Detecting Relapse of Benign Tracheal Stenosis.

BACKGROUND: Benign tracheal stenosis may relapse after management. OBJECTIVES: This study aimed to assess the value of dyspnea and spirometry in detecting relapse of benign tracheal stenosis. METHODS: Patients with benign tracheal stenosis were evaluated post-management, at regular follow-up and emergency visits, with the Medical Research Council (MRC) dyspnea scale, spirometry, and flexible bronchoscopy. Patient visits were categorized and compared, in terms of change in clinical and functional parameters, in 2 groups: visits with relapse (case group) and visits with no relapse (control group). The ability of the MRC dyspnea scale and spirometry to predict relapse was evaluated. RESULTS: Thirty-five patients with benign tracheal stenosis were included. Mean follow-up duration was 3.2 years (standard deviation = 3.3). Spirometry data were analyzed from 43 relapse visits (23 patients) versus 90 nonrelapse visits. The MRC dyspnea score and most spirometric indices were associated with relapse. In the receiver operating characteristic analysis, forced expiratory volume in 1 s, forced expiratory flow when 25% of forced vital capacity has been expired, peak expiratory flow (PEF), and total peak flow were superior to the MRC dyspnea score in predicting relapse. Among spirometric indices, >10.8% of PEF reduction has been very sensitive and specific. CONCLUSIONS: This study supports the role of dyspnea and spirometry in monitoring benign tracheal stenosis, with spirometry predicting relapse even in clinically stable patients. PEF being a very sensitive index has the additional advantage of being assessed by peak flow meter and could potentially be used for remote monitoring.

A 68-year-old man with haemoptysis and extensive ipsilateral lung infiltrates.

Can you diagnose this 68-year-old male with 24-h history of haemoptysis, 5-year history of productive cough and ipsilateral lung infiltrates? https://bit.ly/3tyhANB.

Bronchoscopic management as an alternative treatment in non-operable benign tracheal stenosis.

BACKGROUND: Endoluminal therapy either by dilatation, scar tissue resection or stent insertion is an established treatment for non-malignant airway stenosis although the surgical approach is still considered the "gold standard." No clear consensus exists on the structured role of each modality. AIMS: We aimed to investigate the role of bronchoscopic management in non-operable tracheal stenosis cases, evaluating the effectiveness and safety of each procedure based on a structured algorithmic approach. PATIENTS AND METHODS: This prospective study was carried out on (40) consecutive patients diagnosed between March 2017 and March 2020 with tracheal stenosis not amenable to surgery. All strictures were first evaluated by flexible bronchoscopy and classified as simple or complex. Patients were treated following a standardised therapeutic algorithm approach based on published evidence and our own expertise. RESULTS: The mean age of the study population was 45.25 ± 18.79; lesions were classified as simple (14) and complex (24), while two patients had mixed type stenosis. Long term success rate was 100% in simple stenosis and 87.5% in the complex ones. Stents were deployed in 24 cases, most of which were of the complex type and only two of the simple type. Post-procedural mild to moderate complications were detected overall in 70% of the patients. All complications were non-life threatening, mostly stent-related and were effectively managed. CONCLUSION: We conclude that after accurate classification and a structured algorithmic approach, interventional bronchoscopic management may play a crucial role in the effective treatment of benign tracheal stenosis.

Ashtrays and signage as determinants of a smoke-free legislation's success.

INTRODUCTION: Successful smoke-free legislation is dependent on political will, enforcement and societal support. We report the success and pitfalls of a non-enforced nationwide smoke-free legislation in Greece, as well as ways in which compliance and enforcement-related factors, including ashtrays and signage, may impact indoor secondhand smoke (SHS) concentrations. METHODS: A follow-up study of venues (n=150, at baseline, n=75 at 2-year follow-up) in Greece assessed indoor particulate matter with a diameter less than 2.5 micrometers (PM 2.5 ) concentrations attributable to SHS smoke every six months for two years (n=455 venue/measurements). RESULTS: Following the implementation of the 2010 smoke-free legislation, mean PM2.5 concentrations attributable to SHS fell from 175.3 µg/m(3) pre-ban to 84.52 µg/m(3) immediately post-ban, increasing over subsequent waves (103.8 µg/m(3) and 158.2 µg/m(3) respectively). Controlling for potential influential factors such as ventilation, time of day, day of week, city and venue type, all post-ban measurements were still lower than during the pre-ban period (Wave 2 beta: -118.7, Wave 3 beta: -87.6, and Wave 4 beta: -69.9). Outdoor or indoor signage banning smoking was not found to affect SHS concentrations (beta: -10.9, p=0.667 and beta: -18.1, p=0.464 respectively). However, ashtray or ashtray equivalents were strong determinants of the existence of indoor SHS (beta: +67 µg/m(3), p=0.017). CONCLUSIONS: While the public may be supportive of smoke-free legislation, adherence may decline rapidly if enforcement is limited or nonexistent. Moreover, enforcement agencies should also focus on the comprehensive removal of ashtray equivalents that could act as cues for smoking within a venue.

The acute effect of cigarette smoking on the respiratory function and FENO production among young smokers.

INTRODUCTION: Smoking is known to have a long-term impact on lung function; however, the acute physiological response of smoking a single cigarette and the influential role of pack years and cigarettes per day on pulmonary indices remains an area of interest, especially among young smokers. METHODS: 50 naive smokers (ages: 18-26, 24 males: mean pack years 3.8) participated in this experimental study. Respiratory resistance (R), reactance (X), and impedance (Z) were assessed through impulse oscillometry. The participants' fraction of exhaled nitric oxide (FENO) was measured. All tests were performed immediately before and after smoking one single cigarette. RESULTS: Smoking a single cigarette was found to immediately increase airway impedance (Z 5 Hz) by 0.024 kPa/(L/s) (P = .002), airway resistance at R 5 Hz, R 10 Hz, and R 20 Hz by 0.024 kPa/(L/s)(P < .001), 0.016 kPa/(L/s)(P = .019), and 0.023 kPa/(L/s) (P = .007), respectively, after adjusting for BMI, age, gender, and pack years. FENO concentrations also decreased from 11.70 ppb to 9.85 ppb, P < .001. Sensitivity analyses indicated that the participants' number of pack years and cigarettes per day influenced pulmonary reactance at 10 Hz and 20 Hz, however only at baseline with these differences found to disappear immediately after smoking. CONCLUSIONS: The present study indicates that the consumption of a single cigarette may alter lung mechanics and FENO production among young smokers. Further research is needed to assess the mechanisms and washout period after which these parameters return to normal.

Acute pulmonary effects of sidestream secondhand smoke at simulated car concentrations.

1. Exposure to secondhand smoke (SHS) can occur in many places; however, regulations banning smoking may reduce the sources of exposure to SHS to personal areas such as the family car, a source of brief but potently intense exposure. 2. Fifteen non-smoking volunteers were exposed to sidestream SHS concentrations of 5000 µg/m(3), within a simulated car setting. The Fraction of Exhaled Nitric Oxide (FeNO) was calculated, dynamic flow volumes were assessed through spirometry; while airway impedance (Z), resistance (R), and reactance (X) was assessed through impulse oscillometry before and after exposure. 3. Exposure to sidestream SHS within this experimental condition did not affect dynamic flow volumes, however FENO decreased from 15.34 ppb to 11.15 ppb, (p < 0.001). Increases in airway resistance at R5Hz by 0.114 kPa/(L/s) (p = 0.002), at R10Hz by 0.093[kPa/(L/s)] (p = 0.006) and at R20Hz by 0.093[kPa/(L/s)] (p = 0.008) were noted. Correspondingly overall peripheral and central airway resistance was also found to increase by 40% (by 0.083 kPa/(L/s), p = 0.038) and 25% (by 0.045 kPa/(L/s), p = 0.047) respectively. 4. Brief but elevated exposure to sidestream SHS can alter airway resistance, and impedance indicating a potential additional mechanistic pathway between exposure to SHS and the development of respiratory disease. Further research is needed to verify these pilot results.

Five-year trends of second-hand smoke exposure in Greece: a comparison between complete, partial, and prelegislation levels.

BACKGROUND: Our aim was to assess second-hand smoke (SHS) exposure in hospitality venues after the smoke-free legislation implemented in September 2010 in Greece and to compare with when a partial ban was in place and in 2006 when no ban was in place. METHODS: Hospitality venues were prospectively assessed for their indoor concentrations of particulate matter (PM(2.5)) during the partial ban phase (n=149) and the complete ban phase (n=120, 80% followed up), while overall and matched by venue comparisons were also performed (no ban vs. partial ban vs. complete ban). Comparisons with previously collected data in 2006 when no ban was in place also was performed. RESULTS: Indoor air levels of PM(2.5) attributable to SHS dropped following the transition from a partial to a complete ban by 34% (137 µg/m(3) vs. 90 µg/m(3), p=0.003). This drop was larger in bars (from 195 µg/m(3) to 121 µg/m(3)), than in cafes (124 µg/m(3) vs. 87 µg/m(3)) or restaurants (42 µg/m(3) vs. 39 µg/m(3)). PM(2.5) concentrations between 2006 (no ban) and the partial ban of 2010 were also found to decrease by 94 µg/m(3); however, among matched venues, the levels of indoor air pollution were not found to change significantly (218 µg/m(3) vs. 178 µg/m(3), p=0.58). Comparing the 2010 complete ban results (n=120) with previously collected data from 2006 when no ban was in place (n=43), overall PM(2.5) concentrations were found to fall from 268 µg/m(3) to 89 µg/m(3), while a matched analysis found a significant reduction in PM(2.5) concentrations (249 µg/m(3) vs. 46 µg/m(3), p=0.011). CONCLUSION: The complete ban of smoking in hospitality venues in Greece led to a reduction in SHS exposure, in comparison to when the partial ban or no ban was in place; however, exposure to SHS was not eliminated indicating the need for stronger enforcement.

Short-term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide.

BACKGROUND: Debate exists over the scientific evidence for claims that electronic cigarettes (e-cigarettes) have no health-related ramifications. This study aimed to assess whether using an e-cigarette for 5 min has an impact on the pulmonary function tests and fraction of exhaled nitric oxide (Feno) of healthy adult smokers. METHODS: Thirty healthy smokers (aged 19-56 years, 14 men) participated in this laboratory-based experimental vs control group study. Ab lib use of an e-cigarette for 5 min with the cartridge included (experimental group, n = 30) or removed from the device (control group, n = 10) was assessed. RESULTS: Using an e-cigarette for 5 min led to an immediate decrease in Feno within the experimental group by 2.14 ppb (P = .005) but not in the control group (P = .859). Total respiratory impedance at 5 Hz in the experimental group was found to also increase by 0.033 kPa/(L/s) (P < .001), and flow respiratory resistance at 5 Hz, 10 Hz, and 20 Hz also statistically increased. Regression analyses controlling for baseline measurements indicated a statistically significant decrease in Feno and an increase in impedance by 0.04 kPa/(L/s) (P = .003), respiratory resistance at 5 Hz by 0.04 kPa/(L/s) (P = .003), at 10 Hz by 0.034 kPa/(L/s) (P = .008), at 20 Hz by 0.043 kPa/(L/s) (P = .007), and overall peripheral airway resistance (ß, 0.042 kPa/[L/s]; P = .024), after using an e-cigarette. CONCLUSIONS: e-Cigarettes assessed in the context of this study were found to have immediate adverse physiologic effects after short-term use that are similar to some of the effects seen with tobacco smoking; however, the long-term health effects of e-cigarette use are unknown but potentially adverse and worthy of further investigation.