Expression of Pluripotency Factors OCT4 and LIN28 Correlates with Survival Outcome in Lung Adenocarcinoma.

Background and Objectives: Lung adenocarcinoma is a leading cause of cancer-related mortality despite recent therapeutic advances. Cancer stem cells have gained increasing attention due to their ability to induce cancer cell proliferation through self-renewal and differentiation into multiple cell lineages. OCT4 and LIN28 (and their homologs A and B) have been identified as key regulators of pluripotency in mammalian embryonic (ES) and induced stem (IS) cells, and they are the crucial regulators of cancer progression. However, their exact role in lung adenocarcinoma has not yet been clarified. Materials and Methods: The aim of this study was to explore the role of the pluripotency factors OCT4 and LIN28 in a cohort of surgically resected human lung adenocarcinomas to reveal possible biomarkers for lung adenocarcinoma prognosis and potential therapeutic targets. The expressions of OCT4, LIN28A and LIN28B were analyzed in formalin-fixed, paraffin-embedded tissue samples from 96 patients with lung adenocarcinoma by immunohistochemistry. The results were analyzed with clinicopathologic parameters and were related to the prognosis of patients. Results: Higher OCT4 expression was related to an improved 5-year overall survival (OS) rate (p < 0.001). Nuclear LIN28B expression was lower in stage I and II tumors (p < 0.05) compared to advanced stage tumors. LIN28B cytoplasmic expression was associated with 5-year OS rates not only in univariate (p < 0.005), but also in multivariate analysis (where age, gender, histopathological subtype and stage were used as cofactors, p < 0.01 HR = 2.592). Patients with lower LIN28B expression showed improved 5-year OS rates compared to patients with increased LIN28B expression. Conclusions: Our findings indicate that OCT4 and LIN28B are implicated in lung adenocarcinoma progression and prognosis outcome; thus, they serve as promising prognostic biomarkers and putative therapeutic targets in lung adenocarcinomas.

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.

Management of patients with idiopathic pulmonary fibrosis and lung cancer: challenges in clinical practice.

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is the nonmalignant, chronic lung disease with the worst prognosis. Prevalent comorbidities including lung cancer exert a negative impact on patients' survival. However, there is considerable lack of knowledge on the diagnostic and therapeutic management of patients diagnosed with both clinical entities. This review article presents the main challenges in the management of patients with IPF and lung cancer and highlights future perspectives. RECENT FINDINGS: Recent registries for patients with IPF demonstrated that approximately 10% of patients developed lung cancer. Importantly, incidence of lung cancer was increasing remarkably over time in patients with IPF. Patients with IPF and otherwise technically operable lung cancer who underwent surgical resection had improved survival compared with those who did not undergo surgery. However, specific precautions perioperatively are crucial. Finally, the first randomized-controlled, phase 3 trial (J-SONIC trial) showed no significant difference in exacerbation-free survival for chemotherapy-naive patients with IPF and advanced nonsmall cell lung cancer that were allocated to receive carboplatin and nab-paclitaxel every 3 weeks with or without nintedanib. SUMMARY: Lung cancer is prevalent in IPF. Management of patients with IPF and lung cancer is challenging. A consensus statement aiming to attenuate confusion is greatly anticipated.

A comprehensive analysis of GATA3 expression in carcinomas of various origins with emphasis on lung carcinomas.

GATA3 is a transcription factor involved in embryogenesis of multiple human tissues and in maintaining cell differentiation and tissue homeostasis in the adult organism. GATA3 is also involved in carcinogenesis and regarded as a sensitive marker for urothelial and breast carcinomas, albeit expression in carcinomas of non-breast/urothelial origin has been frequently reported. We sought to examine the extent and intensity of GATA3 expression in various carcinomas, mainly lung, urothelial, and breast and various other primary sites. Patients with breast carcinoma (N=40), carcinoma of the urinary bladder/renal pelvis (N=40), lung carcinoma (N=110) and various other origins (N=45) were included in the study. One hundred and sixty-five patients had a primary tumor diagnosis, and 70 cases had a metastatic tumor diagnosis. Our results showed that GATA3 expression was significantly more common in carcinomas of the breast, urinary bladder and renal pelvis compared to all other origins. All primary and 93% of metastatic urinary bladder carcinomas and 94% of the primary and 80% of metastatic breast carcinomas expressed GATA3. Expression was lower in non-urothelial histology of urinary primaries and in triple negative breast carcinomas. Focal staining, mostly faint, was seen in 5.6% of the primary lung adenocarcinomas and 35% of the primary lung squamous cell carcinomas. More extensive and intense staining was seen in 3.7% of the primary lung adenocarcinomas and 12% of the primary lung squamous cell carcinomas. Expression, mostly focal was also seen in 30% of the metastatic lung carcinomas. Finally, high expression was seen in 12.5% of the other tumors (one metastatic pancreatic carcinoma, one metastatic salivary gland adenocarcinoma NOS, one metastatic squamous cell carcinoma of the skin, one primary uterine cervix serous carcinoma, and one squamous cell carcinoma of the head and neck) and focal expression was present in another 22% of them. No ideal cut-off for positivity for GATA3 staining could be identified. In conclusion our study shows that GATA3 staining has two caveats in its use: the first is that non classical histologies of urothelial carcinomas and TNBC may be negative for the marker and secondly carcinomas of various origins may show (although rarely) intense positivity.

Pulmonary adverse events following immune checkpoint inhibitors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause inflammation in any organ system, with pneumonitis being one of the most severe immune-related adverse events (irAEs). Here, we review the most recent literature on pulmonary adverse events following ICIs. RECENT FINDINGS: Several systematic reviews and meta-analyses of data from trials of antiprogrammed death-1 (PD-1; nivolumab, pembrolizumab), anti-PD-ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab) and anticytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab or tremelimumab) in patients with advanced cancer have explored the relative risk and incidence of lung toxicity among different tumor types and therapeutic regimens. They have showed that the incidence of all-grade (1-4) and high-grade (3-4) pneumonitis is significantly higher in nonsmall cell lung cancer (NSCLC) compared with other tumor types. In addition, they have demonstrated that immunotherapy, especially monoimmunotherapy, has a significantly lower risk of irAEs compared to immune-chemotherapy. Treatment for lung cancer, preexisting interstitial lung disease, smoking history and male sex appear to increase the risk for ICI-related pneumonitis. SUMMARY: Lung toxicity is an uncommon but potentially severe and even fatal complication of ICIs. Timely recognition is critically important but challenging, particularly in patients with lung cancer wherein drug toxicity can mimic disease progression or recurrence.

Safety and Effectiveness of Mycophenolate Mofetil in Interstitial Lung Diseases: Insights from a Machine Learning Radiographic Model.

INTRODUCTION: Treatment of interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) often includes systemic corticosteroids. Use of steroid-sparing agents is amenable to avoid potential side effects. METHODS: Functional indices and high-resolution computed tomography (HRCT) patterns of patients with non-IPF ILDs receiving mycophenolate mofetil (MMF) with a minimum follow-up of 1 year were analyzed. Two independent radiologists and a machine learning software system (Imbio 1.4.2.) evaluated HRCT patterns. RESULTS: Fifty-five (n = 55) patients were included in the analysis (male: 30 [55%], median age: 65.0 [95% CI: 59.7-70.0], mean forced vital capacity %predicted [FVC %pred.] ± standard deviation [SD]: 69.4 ± 18.3, mean diffusing capacity of lung for carbon monoxide %pred. ± SD: 40.8 ± 14.3, hypersensitivity pneumonitis: 26, connective tissue disease-ILDs [CTD-ILDs]: 22, other ILDs: 7). There was no significant difference in mean FVC %pred. post-6 months (1.59 ± 2.04) and 1 year (-0.39 ± 2.49) of treatment compared to baseline. Radiographic evaluation showed no significant difference between baseline and post-1 year %ground glass opacities (20.0 [95% CI: 14.4-30.0] vs. 20.0 [95% CI: 14.4-25.6]) and %reticulation (5.0 [95% CI: 2.0-15.6] vs. 7.5 [95% CI: 2.0-17.5]). A similar performance between expert radiologists and Imbio software analysis was observed in assessing ground glass opacities (intraclass correlation coefficient [ICC] = 0.73) and reticulation (ICC = 0.88). Fourteen patients (25.5%) reported at least one side effect and 8 patients (14.5%) switched to antifibrotics due to disease progression. CONCLUSION: Our data suggest that MMF is a safe and effective steroid-sparing agent leading to disease stabilization in a proportion of patients with non-IPF ILDs. Machine learning software systems may exhibit similar performance to specialist radiologists and represent fruitful diagnostic and prognostic tools.

Tocilizumab improves 28-day survival in hospitalized patients with severe COVID-19: an open label, prospective study.

BACKGROUND: Data on the safety and efficacy profile of tocilizumab in patients with severe COVID-19 needs to be enriched. METHODS: In this open label, prospective study, we evaluated clinical outcomes in consecutive patients with COVID-19 and PaO2/FiO2 < 200 receiving tocilizumab plus usual care versus usual care alone. Tocilizumab was administered at the time point that PaO2/FiO2 < 200 was observed. The primary outcome was 28-day mortality. Secondary outcomes included time to discharge, change in PaO2/FiO2 at day 5 and change in WHO progression scale at day 10. FINDINGS: Overall, 114 patients were included in the analysis (tocilizumab plus usual care: 56, usual care: 58). Allocation to usual care was associated with significant increase in 28-day mortality compared to tocilizumab plus usual care [Cox proportional-hazards model: HR: 3.34, (95% CI: 1.21-9.30), (p = 0.02)]. There was not a statistically significant difference with regards to hospital discharge over the 28 day period for patients receiving tocilizumab compared to usual care [11.0 days (95% CI: 9.0 to 16.0) vs 14.0 days (95% CI: 10.0-24.0), HR: 1.32 (95% CI: 0.84-2.08), p = 0.21]. ΔPaO2/FiO2 at day 5 was significantly higher in the tocilizumab group compared to the usual care group [42.0 (95% CI: 23.0-84.7) vs 15.8 (95% CI: - 19.4-50.3), p = 0.03]. ΔWHO scale at day 10 was significantly lower in the tocilizumab group compared to the usual care group (-0.5 ± 2.1 vs 0.6 ± 2.6, p = 0.005). CONCLUSION: Administration of tocilizumab, at the time point that PaO2/FiO2 < 200 was observed, improved survival and other clinical outcomes in hospitalized patients with severe COVID-19 irrespective of systemic inflammatory markers levels.

Increased monocyte count and red cell distribution width as prognostic biomarkers in patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) represents a chronic lung disease with unpredictable course. METHODS: We aimed to investigate prognostic performance of complete blood count parameters in IPF. Treatment-naïve patients with IPF were retrospectively enrolled from two independent cohorts (derivation and validation) and split into subgroups (high and low) based on median baseline monocyte count and red cell distribution width (RDW). RESULTS: Overall, 489 patients (derivation cohort: 300, validation cohort: 189) were analyzed. In the derivation cohort, patients with monocyte count ≥ 0.60 K/µL had significantly lower median FVC%pred [75.0, (95% CI 71.3-76.7) vs. 80.9, (95% CI 77.5-83.1), (P = 0.01)] and DLCO%pred [47.5, (95% CI 44.3-52.3) vs. 53.0, (95% CI 48.0-56.7), (P = 0.02)] than patients with monocyte count < 0.60 K/µL. Patients with RDW ≥ 14.1% had significantly lower median FVC%pred [75.5, (95% CI 71.2-79.2) vs. 78.3, (95% CI 76.0-81.0), (P = 0.04)] and DLCO%pred [45.4, (95% CI 43.3-50.5) vs. 53.0, (95% CI 50.8-56.8), (P = 0.008)] than patients with RDW < 14.1%. Cut-off thresholds from the derivation cohort were applied to the validation cohort with similar discriminatory value, as indicated by significant differences in median DLCO%pred between patients with high vs. low monocyte count [37.8, (95% CI 35.5-41.1) vs. 45.5, (95% CI 41.9-49.4), (P < 0.001)] and RDW [37.9, (95% CI 33.4-40.7) vs. 44.4, (95% CI 41.5-48.9), (P < 0.001)]. Patients with high monocyte count and RDW of the validation cohort exhibited a trend towards lower median FVC%pred (P = 0.09) and significantly lower median FVC%pred (P = 0.001), respectively. Kaplan-Meier analysis in the derivation cohort demonstrated higher all-cause mortality in patients with high (≥ 0.60 K/µL) vs. low monocyte count (< 0.60 K/µL) [HR 2.05, (95% CI 1.19-3.53), (P = 0.01)]. CONCLUSIONS: Increased monocyte count and RDW may represent negative prognostic biomarkers in patients with IPF.

Response to COVID-19 in Cyprus: Policy changes and epidemic trends.

OBJECTIVES: In late July, Cyprus experienced the second epidemic wave of COVID-19. We present the steps taken by the government and evaluate their effect on epidemic trends. MATERIALS: Cyprus Press and Information Office data were analysed. Using an R-based forecasting program, two models were created to predict cases up to 01/09/2020: Model 1, which utilised data up to 09/06/2020, when airports reopened to foreign travelers with COVID-19 screening; and Model 2, which utilised data until 24/06/2020, when screening for passengers from low-transmission countries was discontinued. RESULTS: PIO data revealed no significant policy changes between 24/06/2020 and 31/07/2020. Prediction models were robust and accurate (Model 1, R2  = 0.999, P < .001; Model 2, R2  = 0.998, P < .001). By August 30th, recorded cases exceeded those predicted by Model 1 by 24.47% and by Model 2 by 20.95%, with P values <.001 for both cases. CONCLUSIONS: The significant difference between recorded cases and those projected by Models 1 and 2 suggests that changes in epidemic trends may have been associated with policy changes after their respective dates. Discontinuation of major restrictions such as airport reopening, can destabilise the control of the epidemic, and may concomitantly necessitate a reevaluation of the current epidemic status. In the face of an evolving situation such as the COVID-19 pandemic, states are forced to balance the imposing of restrictions against their impact on the economy.

Platypnea orthodeoxia syndrome in a patient with patent foramen ovale and normal atrial pressure. Case report and presentation of underlying pathophysiological mechanisms.

Platypnea-orthodeoxia Syndrome is characterized by clinically significant postural hypoxia. The full spectrum of the syndrome includes intracardial and extracardial abnormalities with R->L shunt. Various concurrent underlying physiological abnormalities are usually encountered that require thorough clinical and laboratory evaluation. A high clinical suspicion in patients with unexplained dyspnea is also required to reach a firm diagnosis. We herein present a rare case of an 82-years-old patient with episodic unexplained dyspnea, patent foramen ovale with normal pulmonary pressures and we review the underlying physiologic mechanisms.

Measles-associated pneumonia and hepatitis during the measles outbreak of 2018.

Background Between 2017 and 2018, Greece experienced a measles outbreak, affecting >3000 patients, most of which were unvaccinated. Measles-associated pneumonia (MAP) is the most common serious compilation of the disease, but very few recent reports regarding its presentation are available. Materials and Methods Between January and May 2018, 11 adult patients presented to our department with acute measles virus infection, hypoxia and findings on chest X-ray. Clinical, laboratory and radiological data were collected and assessed. Nine out of eleven patients had hypoxic respiratory failure. Other complications included hepatitis, cholestasis and myositis, which were observed in the majority of patients. All patients received supplementary oxygen administration, whereas five patients required continuous positive airway pressure ventilation. Scoring of the radiological examinations performed was most notable for the presence of reticular opacities and consolidations. Statistical analysis demonstrated a significant association between PaO2/FiO2 values and the presence of reticular opacities, with PaO2/FiO2 decreasing as the mean value of the reticular opacities score increased (P = .02). Conclusion To our knowledge, this is the first report demonstrating an association between PaO2/FiO2 values and the presence of reticular opacities in patients with MAP. MAP should be suspected in any patient presenting with acute onset hypoxaemia and a reticular pattern on radiological examination, especially in outbreak settings. What is known Measles infections are on the rise in Europe, with epidemics affecting several European countries, resulting from suboptimal immunisation. The most common serious complication of measles is pneumonia, which is more common in adult patients and can cause significant morbidity. It is the most common cause of death due to measles. What is new In this report, we present 11 adults with measles-associated pneumonia, who presented with the combination of acute measles virus infection, hypoxia and findings on chest X-ray. To our knowledge, this is the first report demonstrating an association between the severity of hypoxaemia and the presence of reticular opacities on chest imaging studies.

EBUS: Faster, cheaper and most effective in lung cancer staging.

The use of endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA) as the initial diagnostic and staging procedure in patients with suspected, non-metastatic lung cancer has gained substantial support, and is now recommended by numerous guidelines. Whereas considerable attention has been pointed to the reductions in costs achieved by EBUS-TBNA, that has not been the case for some of its more significant benefits, namely the reduction of the diagnostic work-up time and its ability to accurately assess and restage lymph nodes, which were previously stated incorrectly by CT or PET scan. Both these benefits translate into improved outcomes for patients, as delays are reduced, futile surgeries are prevented and curable operations can be performed on patients previously excluded by CT or PET scan. Indeed, the use of EBUS as the initial diagnostic and staging procedure has been proven to significantly increase survival, compared with conventional diagnostic and staging procedures, in a pragmatic, randomised controlled trial (Navani N. et al, 2015). The instalment of EBUS will have the greatest effect on overwhelmed, suboptimally functioning national healthcare systems, by decreasing the number of required diagnostic and staging procedures, therefore reducing both treatment delays and costs. The improved selection of surgical candidates by EBUS will result in improved patient outcomes. The latest findings regarding the benefits of EBUS are outlined in this review, which, to the best of our knowledge, is the first to emphasise the impact of the procedure, both on timing and costs of lung cancer staging, as well as on survival.

Bronchoscopy-related outbreaks and pseudo-outbreaks: A systematic review.

OBJECTIVE: To identify and report the pathogens and sources of contamination associated with bronchoscopy-related outbreaks and pseudo-outbreaks. DESIGN: Systematic review. SETTING: Inpatient and outpatient outbreaks and pseudo-outbreaks after bronchoscopy. METHODS: PubMed/Medline databases were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the search terms "bronchoscopy," "outbreak," and "pseudo-outbreak" from inception until December 31, 2022. From eligible publications, data were extracted regarding the type of event, pathogen involved, and source of contamination. Pearson correlation was used to identify correlations between variables. RESULTS: In total, 74 studies describing 23 outbreaks and 52 pseudo-outbreaks were included in this review. The major pathogens identified in these studies were Pseudomonas aeruginosa, Mycobacterium tuberculosis, nontuberculous mycobacteria (NTM), Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, Legionella pneumophila, and fungi. The primary sources of contamination were the use of contaminated water or contaminated topical anesthetics, dysfunction and contamination of bronchoscopes or automatic endoscope reprocessors, and inadequate disinfection of the bronchoscopes following procedures. Correlations were identified between primary bronchoscope defects and the identification of P. aeruginosa (r = 0.351; P = .002) and K. pneumoniae (r = 0.346; P = .002), and between the presence of a contaminated water source and NTM (r = 0.331; P = .004) or L. pneumophila (r = 0.280; P = .015). CONCLUSIONS: Continued vigilance in bronchoscopy disinfection practices remains essential because outbreaks and pseudo-outbreaks continue to pose a significant risk to patient care, emphasizing the importance of stringent disinfection and quality control measures.

Interstitial Lung Diseases and Non-Small Cell Lung Cancer: Particularities in Pathogenesis and Expression of Driver Mutations.

INTRODUCTION: Interstitial lung diseases are a varied group of diseases associated with chronic inflammation and fibrosis. With the emerging and current treatment options, survival rates have vastly improved. Having in mind that the most common type is idiopathic pulmonary fibrosis and that a significant proportion of these patients will develop lung cancer as the disease progresses, prompt diagnosis and personalized treatment of these patients are fundamental. SCOPE AND METHODS: The scope of this review is to identify and characterize molecular and pathogenetic pathways that can interconnect Interstitial Lung Diseases and lung cancer, especially driver mutations in patients with NSCLC, and to highlight new and emerging treatment options in that view. RESULTS: Common pathogenetic pathways have been identified in sites of chronic inflammation in patients with interstitial lung diseases and lung cancer. Of note, the expression of driver mutations in EGFR, BRAF, and KRAS G12C in patients with NSCLC with concurrent interstitial lung disease is vastly different compared to those patients with NSCLC without Interstitial Lung Disease. CONCLUSIONS: NSCLC in patients with Interstitial Lung Disease is a challenging diagnostic and clinical entity, and a personalized medicine approach is fundamental to improving survival and quality of life. Newer anti-fibrotic medications have improved survival in IPF/ILD patients; thus, the incidence of lung cancer is going to vastly increase in the next 5-10 years.

Effect of spironolactone on pharmacological treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) was recently renamed to metabolic (dysfunction)-associated fatty liver disease (MAFLD) to better characterize its pathogenic origin. NAFLD represents, at least in western societies, a potential epidemic with raising prevalence. Its multifactorial pathogenesis is partially unraveled and till now there is no approved pharmacotherapy for NAFLD. A plethora of various choices are investigated in clinical trials, targeting an arsenal of different pathways and molecules. Since the mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) appear to be implicated in NAFLD, within this concise review, we focus on a rather classical and inexpensive pharmacological agent, spironolactone. We present the current lines of evidence of MR and RAAS-related preclinical models and human trials reporting an association with NAFLD. In conclusion, evidence about spironolactone of RAAS is commented, as potential future pharmacological management of NAFLD.

Corrigendum: Post-COVID-19 interstitial lung disease: Insights from a machine learning radiographic model.

[This corrects the article DOI: 10.3389/fmed.2022.1083264.].

Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial.

OBJECTIVE: Randomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need. METHODS: To determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10. RESULTS: We assigned 251 patients with COVID-19 and a PaO2/FiO2 ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56-1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61-1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0-0.0] vs. 0.0 [95% CI, 0.0-1.0]; p 0.83). DISCUSSION: In the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.

Fanconi syndrome-associated interstitial lung disease.

A middle-aged man was referred to our respiratory department with dyspnoea progressively deteriorating and non-productive cough over the past 8 months. High-resolution CT revealed multiple bilateral consolidations, traction bronchiectasis, reticular pattern and honeycombing with basal and peripheral predominance. Serology tests were negative. Pulmonary function tests showed moderate restrictive functional impairment and severe reduction in diffusing capacity for carbon monoxide. Meticulous evaluation of patient's medical history revealed recent administration of oral corticosteroid due to pulmonary fibrosis potentially in the context of Fanconi syndrome diagnosed at childhood. The working diagnosis of interstitial lung disease (ILD) as a rare complication of Fanconi syndrome was proposed following multidisciplinary discussion. Despite combination treatment with low doses of corticosteroids and antifibrotic compound, the patient exhibited clinical, radiological and functional deterioration, was admitted to intensive care unit due to respiratory failure following infection-driven progression of fibrotic ILD and finally died.

High-flow versus conventional nasal cannula oxygen supplementation therapy and risk of hypoxia in gastrointestinal endoscopies: a systematic review and meta-analysis.

BACKGROUND: Gastrointestinal endoscopy (GIE) represents a mainstay diagnostic and therapeutic procedure in clinical practice. Hypoxemia constitutes a major complication for endoscopists. Emerging evidence supports the utilization of high-flow nasal cannula (HFNC) over conventional nasal cannula (CNC) for avoidance of hypoxemia. Our aim was to compare the hypoxemia risk in patients undergoing GIE with HFNC versus CNC oxygen supplementation recruited by randomized controlled trials (RCTs). METHODS: We searched in medical databases PubMed, EMBASE and Cochrane to identify RCTs investigating the abovementioned association. Enrolled studies were evaluated for risk of bias and inserted into a random effects model for meta-analysis; subgroup analyses and publication bias were also assessed. RESULTS: Out of 271 articles, five RCTs were eligible (patients n=2656, HFNC 1299 and CNC 1357). A statistically significant reduced relative risk (RR) of hypoxemia among HFNC patients was revealed (RR=0.18, CI95%: 0.05-0.61), whilst with high heterogeneity (I2:79.94%, p<0.01). Patients undergoing upper GIE with HFNC displayed a significantly lower hypoxemia risk (96%, p<0.001, I2:15.59%), even after exclusion of endoscopic retrograde cholangiopancreatography cases (RR:0.03, CI95%:0.01-0.21), albeit with higher heterogeneity (I2:41.82%).    . CONCLUSION: Patients undergoing upper GIE with HFNC experience significantly less hypoxemia burden than CNC counterparts. Further research is warranted to target optimal safety during endoscopy.Abbreviations: ASA, American Society of Anesthesiologists; ASGE, American Society for Gastrointestinal Endoscopy; BMI, Body Mass Index; CI, confidence interval; CNC, conventional nasal cannula; ERCP, endoscopic retrograde cholangiopancreatography; FiO2, fraction of inspired O2; GI, gastrointestinal; GIE, gastrointestinal endoscopies; HFNC, High-Flow nasal cannula; ICU, intensive care unit; PEEP, positive end-expiratory pressure; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis; RCTs, randomized control trials; RR, relative risk (or risk ratio).

High-Flow vs. Low-Flow Nasal Cannula in Reducing Hypoxemic Events During Bronchoscopic Procedures: A Systematic Review and Meta-Analysis.

Introduction: High-flow nasal cannula (HFNC) oxygenation method has been proven to be successful in oxygenation of patients with respiratory failure and has exhibited clinical superiority compared to low-flow nasal cannula (LFNC). Methods: We performed a systematic review and meta-analysis to evaluate the potential favorable impact of HFNC oxygenation during bronchoscopy and related procedures like endobronchial ultrasound-transbronchial needle aspiration. Only randomized control trials (RCTs) were included in the meta-analysis. Results: Six randomized control trials with 1,170 patients were included in this meta-analysis. Patients who underwent bronchoscopy with the use of high-flow nasal cannula experienced less hypoxemic events/desaturations, less procedural interruptions and pneumothoraxes compared to patients under low-flow nasal cannula treatment. This beneficial effect of HFNC in hypoxemic events was persistent 10 min after the end of procedure. Conclusion: The high-flow nasal cannula (HFNC) oxygenation method could reduce hypoxemic events and related peri- and post-bronchoscopic complications.