Association of Fetal Lung Development Disorders with Adult Diseases: A Comprehensive Review.

Fetal lung development is a crucial and complex process that lays the groundwork for postnatal respiratory health. However, disruptions in this delicate developmental journey can lead to fetal lung development disorders, impacting neonatal outcomes and potentially influencing health outcomes well into adulthood. Recent research has shed light on the intriguing association between fetal lung development disorders and the development of adult diseases. Understanding these links can provide valuable insights into the developmental origins of health and disease, paving the way for targeted preventive measures and clinical interventions. This review article aims to comprehensively explore the association of fetal lung development disorders with adult diseases. We delve into the stages of fetal lung development, examining key factors influencing fetal lung maturation. Subsequently, we investigate specific fetal lung development disorders, such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), and other abnormalities. Furthermore, we explore the potential mechanisms underlying these associations, considering the role of epigenetic modifications, transgenerational effects, and intrauterine environmental factors. Additionally, we examine the epidemiological evidence and clinical findings linking fetal lung development disorders to adult respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and other respiratory ailments. This review provides valuable insights for healthcare professionals and researchers, guiding future investigations and shaping strategies for preventive interventions and long-term care.

Expression patterns and clinical implications of PDL1 and DLL3 biomarkers in small cell lung cancer retrospectively studied: Insights for therapeutic strategies and survival prediction.

Lung cancer is a leading cause of cancer-related deaths globally, includes small cell lung cancer (SCLC), characterized by its aggressive nature and advanced disease at diagnosis. However, the identification of reliable biomarkers for SCLC has proven challenging, as no consistent predictive biomarker has been established. Nonetheless, certain tumor-associated antigens, including programmed death-ligand 1 (PDL1) and Delta-Like Ligand 3 (DLL3), show promise for targeted antibody-based immunotherapy. To ensure optimal patient selection, it remains crucial to comprehend the relationship between PDL1 and DLL3 expression and clinicopathological characteristics in SCLC. In this study, we investigated the expression patterns of PDL1 and DLL3 biomarkers in endobronchial samples from 44 SCLC patients, examining their association with clinical characteristics and survival. High PDL1 expression (>1%) was observed in 14% of patients, while the majority the SCLC patients (73%) exhibited high DLL3 expression (>75%). Notably, we found a positive correlation between high PDL1 expression (>1%) and overall survival. However, we did not observe any significant differences in the biomarkers expression concerning age, sex, disease status, smoking status, or distant metastases. Further subgroup analysis revealed that a high co-expression of both PDL1 (>1%) and DLL3 (100%) antigens was associated with improved overall survival. This suggests that SCLC expressing PDL1 and DLL3 antigens may exhibit increased sensitivity to therapy, indicating their potential as therapeutic targets. Thus, our findings provide novel insights into the simultaneous evaluation of PDL1 and DLL3 biomarkers in SCLC patients. These insights have significant clinical implications for therapeutic strategies, survival prediction, and development of combination immunotherapies.

Nebulisation of Paclitaxel, Sotatercept and Iloprost for pulmonary hypertension for lung cancer. From In vitro to In vivo.

Background: Pulmonary hypertension is common symptom among several diseases. The consequences are severe for several organs. Pulmonary hypertension is usually under-diagnosed and the main symptom observed is dyspnea with or without exercise. Currently we have several treatment modalities administered orally, via inhalation, intravenously and subcutaneously. In advanced disease then heart or lung transplantation is considered. The objective of the study was to investigate the optimum method of aerosol production for the drugs: iloprost, paclitaxel and the novel sotatercept. Materials and Methods: In our experiment we used the drugs iloprost, paclitaxel and the novel sotatercept, in an experimental concept of nebulization. We performed nebulization experiments with 3 jet nebulizers and 3 ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5µm in mass median aerodynamic diameter. Results: We concluded that paclitaxel cannot produce small droplets and is also still very greasy and possible dangerous for alveoli. However; iloprost vs sotatercept had smaller droplet size formation at both inhaled technologies (1.37<2.23 and 1.92<3.11, jet and ultrasound respectively). Moreover; residual cup designs C and G create the smallest droplet size in both iloprost and sotatercept. There was no difference for the droplet formation between the facemask and cone mouthpieces. Discussion: Iloprost and sotatercept can be administered as aerosol in any type of nebulisation system and they are both efficient with the residual cups loaded with small doses of the drug (2.08 and 2.12 accordingly).

Open and Closed Triple Inhaler Therapy in Patients with Uncontrolled Asthma.

Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting ß2-agonists (ICS + LABA) (closed triple inhaler therapy) or in a separate one (open triple inhaler therapy). This review summarizes the existing evidence on the addition of LAMAs in patients with persistently uncontrolled asthma despite ICS + LABA treatment based on clinical efficacy in the reduction of asthma symptoms and exacerbations, the improvement in lung function, and its safety profile.

Defining response to therapy with biologics in severe asthma: from global evaluation to super response and remission.

INTRODUCTION: In recent years, monoclonal antibodies targeting Type-2 inflammatory pathways have been developed for severe asthma treatment. However, even when patients are carefully selected, the response to treatment varies. AREAS COVERED: Different studies have evaluated response to therapy with biologics such as exacerbation reduction, symptom improvement, pulmonary function increase, improvement in QoL, or decrease of oral corticosteroids, showing that all patients do not respond to all disease aspects and leading to an extensive debate regarding the definition of response. EXPERT OPINION: Assessing response to therapy is of great importance, but since there is no uniform definition of treatment response, the recognition of patients who really benefit from these therapies remains an unmet need. In the same context, identifying non-responding patients in which biologic therapy should be switched or substituted by alternative treatment options is of paramount importance. In this review, we present the road trip of the definition of therapeutic response to biologics in severe asthmatics by presenting the current relevant medical literature. We also present the suggested predictors of response, with an emphasis on the so-called super-responders. Finally, we discuss the recent insights regarding asthma remission as a feasible treatment goal and provide a simple algorithm for the evaluation of response.

Endobronchial Radiofrequency Ablation for pulmonary nodules with Radial-Ebus and Navigation: Pros and Cons.

Introduction: Pulmonary nodules are common in the everyday clinical practice. There is always a diagnostic issue with this imaging finding. Based on the size we can use a variety of imaging and diagnostic techniques. Moreover; in the case of primary lung cancer or metastasis we can use radiofrequency ablation endobronchially. Patients and Methods: We used the radial-endobronchial ultrasound with C-arm and Archemedes, Bronchus electromagnetic navigation in order to acquire biopsy sample and we also used rapid on-site evaluation as a rapid diagnosis for pulmonary nodules. After rapid diagnosis we used the radiofrequency ablation catheter in order to ablate central pulmonary nodules. Results: Both techniques provide efficient navigation, however, with the Bronchus system less time is needed. The new radiofrequency ablation catheter provides efficient results in central lesions with low watts ≤40. Conclusion: We provided in our research a protocol to diagnose and treat such lesions. Future larger studies will provide more data on this subject.

Positron Emission-Computed Tomography, Cryobiopsy versus Bronchoalveolar Lavage and Computed Tomography Findings for Interstitial Lung Disease: A Long-Term Follow-Up.

Background and Objectives: Interstitial lung diseases have always been an issue for pulmonary and rheumatology physicians. Computed tomography scans with a high-resolution protocol and bronchoalveolar lavage have been used along with biochemical blood tests to reach a diagnosis. Materials and Methods: We included 80 patients in total. First, all patients had their diagnosis with computed tomography of the thorax, serological/ immunological blood tests and bronchoalveolar lavage. However; after 3 months, all were divided into 2 groups: those who had bronchoalveolar lavage again and those who had cryobiopsy instead of bronchoalveolar lavage (40/40). Positron emission-computed tomography was also performed upon the first and second diagnosis. The patients' follow-up was 4 years from diagnosis. Results: Patients suffered most from chronic obstructive pulmonary disease (56, 70%), while lung cancer was rarely encountered in the sample (7, 9.75%). Age distribution ranged between 53 and 68 years with a mean value of 60 years. The computed tomography findings revealed 25 patients with typical diagnosis (35.2%), 17 with interstitial pulmonary fibrosis (23.9%) and 11 with probable diagnosis (11%). The cryobiopsy technique led to a new diagnosis in 28 patients (35% of the total sample). Patients who had a new diagnosis with cryobiopsy had a mean survival time of 710 days (<1460). Positron emission-computed tomography SUV uptake was positively associated with the cryobiopsy technique/new disease diagnosis and improved all respiratory functions. Discussion: Positron emission-computed tomography is a tool that can be used along with respiratory functions for disease evaluation. Conclusions: Cryobiopsy is a safe tool for patients with interstitial lung disease and can assist in the diagnosis of interstitial lung diseases. The survival of patients was increased in the cryobiopsy group versus only bronchoalveolar lavage for disease diagnosis.

"Extrafine single inhaler triple therapy effect on health status, lung function and adherence in COPD patients: A Panhellenic prospective non-interventional study - The TRIBUNE study".

The extrafine single inhaler triple therapy (efSITT) containing beclometasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 µg has proved to be efficacious in patients with Chronic Obstructive Pulmonary Disease (COPD) in randomized control trials. TRIBUNE study aimed to assess the efSITT effectiveness on health status, lung function, adherence and rescue medication use in COPD patients in Greece in a real-world setting. This was a 24-week prospective, multicenter, observational study in 1,195 patients with moderate/severe COPD and history of at least one exacerbation during the previous year despite dual therapy. Health status (COPD Assessment Test/CAT), lung function parameters and rescue medication use were recorded at baseline, 3 (Visit 2/V2) and 6 months (Visit 3/V3) after treatment. Adherence (Test of Adherence to Inhalers/TAI) and self-reported overall impression of health condition change (Visual Analogue Scale/VAS) were recorded at V2 and V3. Mean CAT score decreased from 20.9 points at V1, to 15.1 at V2 and 13 at V3 (p < 0.001, all pair comparisons). 85.9% of patients achieved a CAT decrease of minimal clinically important difference (MCID) or more (≥2) at V3, compared to V1. Mean FEV1 increased from 1.4 ± 0.5 L on V1, to 1.6 ± 0.5 L on V3 (p < 0.001, N = 275). The percentage of patients with "good adherence" increased from 58.4% (V2) to 64.0% (V3). Rescue medication use and VAS also significantly improved. The efSITT achieves improved outcomes on health status, lung function and rescue medication use as well as satisfactory adherence and patient-reported improvement of health condition, in moderate/severe COPD patients previously treated with a dual combination in a Greek real-world setting.

Case Report: Endoscopic radiofrequency ablation with radial-EBUS and ROSE.

Background: Single pulmonary nodules are a common issue in everyday clinical practice. Currently, there are navigation systems with radial-endobronchial ultrasound and electromagnetic navigation for obtaining biopsies. Moreover, rapid on-site evaluation can be used for a quick assessment. These small lesions, even when they do not have any clinically significant information with positron emission tomography, are important to investigate. Case description: Radiofrequency and microwave ablation have been evaluated as local treatment techniques. These techniques can be used as therapy for a patient population that cannot be operated on. Currently, one verified operating system is used for endoscopic radiofrequency ablation through the working channel of a bronchoscope. Conclusion: In our case, a new system was used to perform radiofrequency ablation with long-term follow-up.

Immunotherapy and Chemotherapy Versus Sleep Disturbances for NSCLC Patients.

INTRODUCTION: Cancer patients are known to experience sleep disturbances that differ between disease stages and treatments. Regarding lung cancer patients and immunotherapy, information on their sleep disturbances has been recently acquired, but no comparison has been made between different treatment modalities. PATIENTS AND METHODS: We recruited 98 non-small cell lung cancer patients; 49 had programmed death-ligand 1 expression of ≥50% and received immunotherapy as first-line treatment and 49 had programmed death-ligand 1 expression in the range from 0-49 and received chemotherapy as first-line treatment. All patients were stage IV, but with no bone metastasis. Sleep disturbances were recorded through polysomnography and sleep questionnaires. RESULTS: For immunotherapy patients with PD-L1 expression ≥ 50%, the disease response was rapid and the sleep disturbances decreased rapidly. On the other hand, for chemotherapy patients, the sleep disturbances remained for all those patients that had partial response and stable disease. It was noticed that chemotherapy drugs induce severe adverse effects. DISCUSSION: In our study, it was observed that patients with complete response had reduced sleep disturbances in the case of immunotherapy patients. However, sleep disturbances continued for several patients in the chemotherapy group due to the adverse effects of chemotherapy drugs. IN CONCLUSION: Immunotherapy drugs on their own do not induce sleep disturbances and, through treatment response, alleviate sleep disturbances in lung cancer patients.

Non-Small-Cell Lung Cancer Immunotherapy and Sleep Characteristics: The Crossroad for Optimal Survival.

INTRODUCTION: Non-small-cell lung cancer is still diagnosed at an inoperable stage and systematic treatment is the only option. Immunotherapy is currently considered to be the tip of the arrow as the first-line treatment for patients with a programmed death-ligand 1 ≥ 50. Sleep is known to be an essential part of our everyday life. PATIENTS AND METHODS: We investigated, upon diagnosis and after nine months, 49 non-small-cell lung cancer patients undergoing immunotherapy treatment with nivolumab and pemprolisumab. A polysomnographic examination was conducted. Moreover, the patients completed the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), the Fatigue Severity Scale (FSS) and the Medical Research Council (MRC) dyspnea scale. RESULTS: Tukey mean-difference plots, summary statistics, and the results of paired t-test of five questionnaire responses in accordance with the PD-L1 test across groups were examined. The results indicated that, upon diagnosis, patients had sleep disturbances which were not associated with brain metastases or their PD-L1 expression status. However, the PD-L1 status and disease control were strongly associated, since a PD-L1 ≥80 improved the disease status within the first 4 months. All data from the sleep questionnaires and polysomnography reports indicated that the majority of patients with a partial response and complete response had their initial sleep disturbances improved. There was no connection between nivolumab or pembrolisumab and sleep disturbances. CONCLUSION: Upon diagnosis, lung cancer patients have sleep disorders such as anxiety, early morning wakening, late sleep onset, prolonged nocturnal waking periods, daytime sleepiness, and unrefreshing sleep. However, these symptoms tend to improve very quickly for patients with a PD-L1 expression ≥80, because disease status improves also very quickly within the first 4 months of treatment.

COVID-19 and liver injury: An ongoing challenge.

The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019, in Wuhan, China. The virus was rapidly spread worldwide, causing coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is presented, usually, with typical respiratory symptoms (i.e., dyspnea, cough) and fever, extrapulmonary manifestations are also encountered. Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and, even, acute liver failure. The pathogenesis of liver damage is not clearly defined; multiple mechanisms contribute to liver disorder, including direct cytopathic viral effect, cytokine storm and immune-mediated hepatitis, hypoxic injury, and drug-induced liver toxicity. Patients with underlying chronic liver disease (i.e., cirrhosis, non-alcoholic fatty liver disease, alcohol-related liver disease, hepatocellular carcinoma, etc.) may have greater risk to develop both severe COVID-19 and further liver deterioration, and, as a consequence, certain issues should be considered during disease management. The aim of this review is to present the prevalence, clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection. Moreover, we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.

Smoking-Induced Disturbed Sleep. A Distinct Sleep-Related Disorder Pattern?

The relationship between smoking and sleep disorders has not been investigated sufficiently yet. Many aspects, especially regarding non-obstructive sleep apnea−hypopnea (OSA)-related disorders, are still to be addressed. All adult patients who visited a tertiary sleep clinic and provided information about their smoking history were included in this cross-sectional study. In total, 4347 patients were divided into current, former and never smokers, while current and former smokers were also grouped, forming a group of ever smokers. Sleep-related characteristics, derived from questionnaires and sleep studies, were compared between those groups. Ever smokers presented with significantly greater body mass index (BMI), neck and waist circumference and with increased frequency of metabolic and cardiovascular co-morbidities compared to never smokers. They also presented significantly higher apnea−hypopnea index (AHI) compared to never smokers (34.4 ± 24.6 events/h vs. 31.7 ± 23.6 events/h, p < 0.001) and were diagnosed more frequently with severe and moderate OSA (50.3% vs. 46.9% and 26.2% vs. 24.8% respectively). Epworth sleepiness scale (ESS) (p = 0.13) did not differ between groups. Ever smokers, compared to never smokers, presented more frequent episodes of sleep talking (30.8% vs. 26.6%, p = 0.004), abnormal movements (31.1% vs. 27.7%, p = 0.021), restless sleep (59.1% vs. 51.6%, p < 0.001) and leg movements (p = 0.002) during sleep. Those were more evident in current smokers and correlated significantly with increasing AHI. These significant findings suggest the existence of a smoking-induced disturbed sleep pattern.

Association of sleep duration and quality with immunological response after vaccination against severe acute respiratory syndrome coronavirus-2 infection.

Growing evidence suggests that sleep could affect the immunological response after vaccination. The aim of this prospective study was to investigate possible associations between regular sleep disruption and immunity response after vaccination against coronavirus disease 2019 (COVID-19). In total, 592 healthcare workers, with no previous history of COVID-19, from eight major Greek hospitals were enrolled in this study. All subjects underwent two Pfizer-BioNTech messenger ribonucleic acid (mRNA) COVID-19 vaccine BNT162b2 inoculations with an interval of 21 days between the doses. Furthermore, a questionnaire was completed 2 days after each vaccination and clinical characteristics, demographics, sleep duration, and habits were recorded. Blood samples were collected and anti-spike immunoglobulin G antibodies were measured at 20 ± 1 days after the first dose and 21 ± 2 days after the second dose. A total of 544 subjects (30% males), with median (interquartile range [IQR]) age of 46 (38-54) years and body mass index of 24·84 (22.6-28.51) kg/m2 were eligible for the study. The median (IQR) habitual duration of sleep was 6 (6-7) h/night. In all, 283 participants (52%) had a short daytime nap. In 214 (39.3%) participants the Pittsburgh Sleep Quality Index score was >5, with a higher percentage in women (74·3%, p < 0.05). Antibody levels were associated with age (r = -0.178, p < 0.001), poor sleep quality (r = -0.094, p < 0.05), insomnia (r = -0.098, p < 0.05), and nap frequency per week (r = -0.098, p < 0.05), but after adjusting for confounders, only insomnia, gender, and age were independent determinants of antibody levels. It is important to emphasise that insomnia is associated with lower antibody levels against COVID-19 after vaccination.

Engineered multifunctional nanocarriers for controlled drug delivery in tumor immunotherapy.

The appearance of chemoresistance in cancer is a major issue. The main barriers to conventional tumor chemotherapy are undesirable toxic effects and multidrug resistance. Cancer nanotherapeutics were developed to get around the drawbacks of conventional chemotherapy. Through clinical evaluation of thoughtfully developed nano delivery systems, cancer nanotherapeutics have recently offered unmatched potential to comprehend and combat drug resistance and toxicity. In different design approaches, including passive targeting, active targeting, nanomedicine, and multimodal nanomedicine combination therapy, were successful in treating cancer in this situation. Even though cancer nanotherapy has achieved considerable technological development, tumor biology complexity and heterogeneity and a lack of full knowledge of nano-bio interactions remain important hurdles to future clinical translation and commercialization. The recent developments and advancements in cancer nanotherapeutics utilizing a wide variety of nanomaterial-based platforms to overcome cancer treatment resistance are covered in this article. Additionally, an evaluation of different nanotherapeutics-based approaches to cancer treatment, such as tumor microenvironment targeted techniques, sophisticated delivery methods for the precise targeting of cancer stem cells, as well as an update on clinical studies are discussed. Lastly, the potential for cancer nanotherapeutics to overcome tumor relapse and the therapeutic effects and targeted efficacies of modern nanosystems are analyzed.

Recent insights in the role of biomarkers in severe asthma management.

Contemporary asthma management requires a proactive and individualized approach, combining precision diagnosis and personalized treatment. The introduction of biologic therapies for severe asthma to everyday clinical practice, increases the need for specific patient selection, prediction of outcomes and monitoring of these costly and long-lasting therapies. Several biomarkers have been used in asthma in disease identification, prediction of asthma severity and prognosis, and response to treatment. Novel advances in the area of personalized medicine regarding disease phenotyping and endotyping, encompass the development and application of reliable biomarkers, accurately quantified using robust and reproducible methods. The availability of powerful omics technologies, together with integrated and network-based genome data analysis, and microbiota changes quantified in serum, body fluids and exhaled air, will lead to a better classification of distinct phenotypes or endotypes. Herein, in this review we discuss on currently used and novel biomarkers for the diagnosis and treatment of asthma.

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance.

The tumor microenvironment plays a key role in progression of tumorigenesis, tumor progression, and metastasis. Accumulating data reveal that dendritic cells (DCs) appear to play a key role in the development and progression of metastatic neoplasia by driving immune system dysfunction and establishing immunosuppression, which is vital for tumor evasion of host immune response. Consequently, in this review, we will discuss the function of tumor-infiltrating DCs in immune cell signaling pathways that lead to treatment resistance, tumor recurrence, and immunosuppression. We will also review DC metabolism, differentiation, and plasticity, which are essential for metastasis and the development of lung tumors. Furthermore, we will take into account the interaction between myeloid cells and DCs in tumor-related immunosuppression. We will specifically look into the molecular immune-related mechanisms in the tumor microenvironment that result in reduced drug sensitivity and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. DCs play a crucial role in modulating the immune response. Especially, as cancer progresses, DCs may switch from playing an immunostimulatory to an inhibitory role. This article's main emphasis is on tumor-infiltrating DCs. We address how they affect tumor growth and expansion, and we highlight innovative approaches for therapeutic modulation of these immunosuppressive DCs which is necessary for future personalized therapeutic approaches.