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Evidence to date suggests that a significant proportion of COVID-19 patients experience adverse psychological outcomes and neuropsychiatric complications. The aim of this study was to evaluate the effect of SARS-CoV-2 infection and subsequent hospitalization on the mental health, sleep, and quality of life of COVID-19 survivors. Patients were assessed 1–2 months after hospital discharge using standardized screening tools for depression and anxiety (HADS), post-traumatic stress disorder (IES-R), insomnia (AIS), and quality of life (EQ-5D-5L). Sociodemographic factors, comorbidities, disease severity and type of hospitalization were also collected. Amongst the 143 patients included, mental health symptoms were common (depression—19%; anxiety—27%; traumatic stress—39%; insomnia—33%) and more frequently reported in female than in male patients. Age, smoking status, comorbidities and illness severity were not found to significantly correlate with the presence of mood, sleep, or stress disorders. Finally, quality of life was worse for patients requiring ICU (p = 0.0057) or a longer hospital stay (p < 0.001) but was unaffected by factors such as sex and other measured outcomes. These findings highlight the need for appropriate intervention to properly manage the immediate and enduring mental health complications of COVID-19. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Background: During COVID-19 pandemic, people who developed pneumonia and needed supplemental oxygen, where treated with low-flow oxygen therapy systems and non-invasive methods, including oxygen therapy using high flow nasal cannula (HFNC) and the application of bi-level or continuous positive airway pressure (BiPAP or CPAP). We aimed to investigate the outcomes of critical COVID-19 patients treated with HFNC and unveil predictors of HFNC failure. Methods: We retrospectively enrolled patients admitted to COVID-19 wards and treated with HFNC for COVID-19-related severe hypoxemic respiratory failure. The primary outcome of this study was treatment failure, such as the composite of intubation or death during hospital stay. The association between treatment failure and clinical features was evaluated using logistic regression models. Results: One hundred thirty-two patients with a median (IQR) PaO2/FiO2 ratio 96 (63-173) mmHg at HFNC initiation were studied. Overall, 45.4% of the patients were intubated. Hospital mortality was 31.8%. Treatment failure (intubation or death) occurred in 50.75% and after adjustment for age, gender, Charlson Comorbidity index (CCI) score and National Early Warning Score 2 (NEWS2) score on admission and PaO2/FiO2 ratio and acute respiratory distress syndrome (ARDS) severity at the time of HFNO initiation, it was significantly associated with the presence of dyspnea [adjusted OR 2.48 (95% CI: 1.01-6.12)], and higher Urea serum levels [adjusted OR 1.25 (95% CI: 1.03-1.51) mg/dL]. Conclusions: HFNC treatment was successful in almost half of the patients with severe COVID-19-related acute hypoxemic respiratory failure (AHRF). The presence of dyspnea and high serum Urea levels on admission are closely related to HFNC failure. © 2022 AME Publishing Company. All rights reserved.

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. © 2022 European Sleep Research Society.

INTRODUCTION Telehealth for COVID-19 patients is still limited. We aimed to assess the clinical effects of a home-based tele-rehabilitation exercise program following hospital discharge during the first lockdown in Greece, April to July 2020. METHODS A pre-and post-intervention design was applied in two stages. Firstly, patients were instructed to use a specially designed for COVID-19, e-book during four tele-health sessions. Afterwards, a 2-month home-based program consisted of self-practice exercise and one-hour supervised tele-rehabilitation exercise sessions every 10 days, was delivered. At baseline and at the end of the program, participants were interviewed about their physical, psychological status and quality of life (QoL) during the post-hospitalization period. The IPAQ-Gr, the HADS and the SF-36 questionnaires were used, respectively, and the participants were functionally assessed via teleconferences, using the 60 sec Sit to Stand Test (60secSTS), the Short Physical Performance Battery (SPPB) and the 3 min Step Test (3MST). RESULTS Seventy-four patients, median age 52.5 (IQR: 43–61) years were included at the first stage. From those, only 22 patients, mean ± SD age 50.1 ± 13.2 years completed the 2-month exercise program. The training program was well tolerated by all 22 patients. The mean number of unsupervised exercise sessions was 18.4 ± 3.5. No adverse effects were observed either during initial and follow-up assessment via tele-communication or during home-exercise sessions. Training improved significantly (p

The coronavirus disease 2019 (COVID-19) pandemic, related to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial burden in public health due to an enormous increase in hospitalizations for pneumonia with the multiorgan disease. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care, and ongoing trials are testing the efficacy of antiviral therapies, immune modulators and anticoagulants in the prevention of disease progression and complications, while monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Consensus suggestions can standardize care, thereby improving outcomes and facilitating future research. This review discusses current evidence regarding the pharmacotherapy of COVID-19. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Although coagulation disorders and immune/inflammatory response have been associated with the final outcome of patients with sepsis, their link with thetemporaryclinical deterioration or improvement of patients is unknown. We aimed to investigate this link. We prospectively included consecutive patients admitted to the intensive care unit (ICU) with a suspected diagnosis of infection and evaluated within the first 24 h from admission. Blood levels of many cytokines and inflammatory and coagulation factors were measured and their predictive value was assessed by calculating the Area Under the Receiver Operating Characteristic (AUROC) curves. Patients (n = 102) were allocated in five groups, i.e., sepsis (n = 14), severe sepsis (n = 17), septic shock (n = 28), Systemic Inflammatory Response Syndrome (SIRS) without infection (n = 17), and trauma/surgery without SIRS or infection (n = 26). In septic shock, coagulation factors FVII and FIX and Protein C had AUROCs 0.67–0.78. In severe sepsis, Antithrombin III, Protein C, C-reactive protein, Procalcitonin and Thrombopoietin had AUROCs 0.73–0.75. In sepsis, Tumor Necrosis Factor a, and Interleukins 1β and 10 had AUROCs 0.66–0.72. In patients admitted to the ICU with a suspected diagnosis of infection, coagulation factors and inhibitors, as well as cytokine and inflammatory marker levels, have substantial predictive value in distinct groups of septic patients. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Background: Community-acquired pleural infection (CAPI) is a growing health problem worldwide. Although most CAPI patients recover with antibiotics and pleural drainage, 20% require surgical intervention. The use of inappropriate antibiotics is a common cause of treatment failure. Awareness of the common causative bacteria along with their patterns of antibiotic resistance is critical in the selection of antibiotics in CAPI-patients. This study aimed to define CAPI bacteriology from the positive pleural fluid cultures, determine effective antibiotic regimens and investigate for associations between clinical features and risk for death or antibiotic-resistance, in order to advocate with more invasive techniques in the optimal timing. Methods: We examined 158 patients with culture positive, CAPI collected both retrospectively (2012-2013) and prospectively (2014-2018). Culture-positive, CAPI patients hospitalized in six tertiary hospitals in Greece were prospectively recruited (N=113). Bacteriological data from retrospectively detected patients were also used (N=45). Logistic regression analysis was performed to identify clinical features related to mortality, presence of certain bacteria and antibiotic resistance. Results: Streptococci, especially the non-pneumococcal ones, were the most common bacteria among the isolates, which were mostly sensitive to commonly used antibiotic combinations. RAPID score (i.e., clinical score for the stratification of mortality risk in patients with pleural infection; parameters: renal, age, purulence, infection source, and dietary factors), diabetes and CRP were independent predictors of mortality while several patient co-morbidities (e.g., diabetes, malignancy, chronic renal failure, etc.) were related to the presence of certain bacteria or antibiotic resistance. Conclusions: The dominance of streptococci among pleural fluid isolates from culture-positive, CAPI patients was demonstrated. Common antibiotic regimens were found highly effective in CAPI treatment. The predictive strength of RAPID score for CAPI mortality was confirmed while additional risk factors for mortality and antibiotic resistance were detected. © 2021 Journal of Thoracic Disease. All rights reserved.

Case Presentation: A 27-year-old man from Eritrea presented to the ED complaining about a progressively worse blunt chest pain in the anterior right hemithorax. Chest pain started 4 years ago and was intermittent. During the last 6 months, symptoms got worse, and the patient experienced shortness of breath in mild exercise. For this purpose, he visited another institution, where a chest radiograph was performed (Fig 1). He was advised to visit a pulmonologist for further evaluation, with the diagnosis of a loculated pleural effusion in the right upper hemithorax. © 2020 American College of Chest Physicians

Background and aim: Pleural effusions (PE) are a common clinical entity resulting from pathologies that affect the pleural space such as congestive heart failure, malignancy and pneumonia. The osmolality of the pleural fluid has never been studied as well as the effects of its changes on the pleural membrane. The purpose of this study was to identify the osmolality levels of PEs of different etiologies and to assess the potential effects of osmolality imbalance on the pleural permeability. Materials and methods: We measured the osmolality of the PEs of 64 consecutive patients (6 with transudative, 11 with parapneumonic and 47 with malignant pleural effusions) that were hospitalized in the University Hospital of Larissa. Subsequently, we selected clinically relevant hyper- and hypo- osmolality levels and performed assessment of the permeability of sheep parietal pleura by means of Ussing chamber experiments. Results: The mean pleural fluid osmolality was 291.7 ± 24.89 mOms/Kg (95 % CI: 285.4–297.9), and it varied among the three groups of PEs (p = 0.05). Transformed osmolality values were associated with pH and glucose levels in the PEs. After exposure of the sheep parietal pleura to 240 mOsm/kg (hyposmolar) the transmesothelial resistance (RTM) significantly increased (p < 0.05) while at 340 mOsm/kg (hyperosmolar) the RTM was not significantly altered. Conclusions: PEs osmolality differs depending on the underlying pathology and is linked to PE pH and glucose. Hypo-osmotic PEs can lead to decreased pleural permeability. These results warrant further study of the PEs osmolality levels on the function of the pleural mesothelial cells. © 2020 Elsevier B.V.

Background: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. Methods: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). Findings: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20–0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2/FiO2. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17–0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12–0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37–1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59–3·10]). Interpretation: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. Funding: Sobi. © 2021 Elsevier Ltd

COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

COVID-19 is a global pandemic associated with increased morbidity and mortality. Convalescent plasma (CP) infusion is a strategy of potential therapeutic benefit. We conducted a multicenter phase II study to evaluate the efficacy and safety of CP in patients with COVID-19, grade 4 or higher. To evaluate the efficacy of CP, a matched propensity score analysis was used comparing the intervention (n = 59) to a control group (n = 59). Sixty patients received CP within a median time of 7 days from symptom onset. During a median follow-up of 28.5 days, 56/60 patients fully recovered and 1 patient remained in the ICU. The death rate in the CP group was 3.4% vs. 13.6% in the control group. By multivariate analysis, CP recipients demonstrated a significantly reduced risk of death [HR: 0.04 (95% CI: 0.004–0.36), p: 0.005], significantly better overall survival by Kaplan–Meir analysis (p < 0.001), and increased probability of extubation [OR: 30.3 (95% CI: 2.64–348.9), p: 0.006]. Higher levels of antibodies in the CP were independently associated with significantly reduced risk of death. CP infusion was safe with only one grade 3 adverse event (AE), which easily resolved. CP used early may be a safe and effective treatment for patients with severe COVID-19 (trial number NCT04408209). © 2021 by the au-thors. Licensee MDPI, Basel, Switzerland.

In the version of this Article initially published, there was an error in the author affiliations. Specifically, affiliation 27, corresponding to author Carlo Selmi, has been corrected from “Humanitas Research Hospital, Milan, Italy” to read: “Department of Biomedical Sciences, Humanitas University, Milan, Italy & IRCCS Humanitas Research Hospital, Milan, Italy.” The change has been made to the online version of the Article. © The Author(s) 2021.

Malignant pleural effusions usually manifest in the course of metastatic cancer disease. Primary pleural tumours are rare with mesothelioma being by far the most common. Primary squamous cell carcinoma of the pleura (PSCCP) is extremely rare. It is usually asymptomatic, until it invades the pleura presenting pain as the first symptom. Our knowledge about its treatment or prognosis is limited due to its rarity. We present the case of a 48-year-old man who presented with persistent right-sided thoracic pain with chest computed tomography (CT) scan demonstrating a right-sided pleural effusion and pleural mass invading the ribs. Ultrasound-guided biopsy revealed a PSCCP. Positron emission tomography staging demonstrated metastatic lung and lymph node involvement precluding surgical therapy. We provide information about treatment, including immunotherapy as well as extended follow-up course. Immunotherapy with nivolumab resulted in prolongation of survival with good quality of life. © 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology

Increased expression of osteopontin (secreted phosphoprotein 1, SPP1) is associated with aggressive human lung adenocarcinoma (LADC), but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced LADC. We combined mouse models of tobacco carcinogen-induced LADC, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis. Co-expression of Spp1 and mutant KrasG12C in benign cells was employed to investigate SPP1/KRAS interactions in oncogenesis. Finally, intratracheal adenovirus encoding Cre recombinase was delivered to LSL.KRASG12D mice lacking endogenous or overexpressing transgenic Spp1 alleles. SPP1 was overexpressed in experimental and human LADC and portended poor survival. In response to two different smoke carcinogens, Spp1-deficient mice developed fewer and smaller LADC with decreased cellular survival and angiogenesis. Both lung epithelial- A nd macrophage-secreted SPP1 drove tumor-associated inflammation, while epithelial SPP1 promoted early tumorigenesis by fostering the survival of KRAS-mutated cells. Finally, loss and overexpression of Spp1 was, respectively, protective and deleterious for mice harboring KRASG12D-driven LADC. Our data support that SPP1 is functionally involved in early stages of airway epithelial carcinogenesis driven by smoking and mutant KRAS and may present an important therapeutic target. © 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: Journals.permissions@oup.com.

For critically ill patients with coronavirus disease 2019 (COVID-19) who require intensive care unit (ICU) admission, extremely high mortality rates (even 97%) have been reported. We hypothesized that overburdened hospital resources by the extent of the pandemic rather than the disease per se might play an important role on unfavorable prognosis. We sought to determine the outcome of such patients admitted to the general ICUs of a hospital with sufficient resources. We performed a prospective observational study of adult patients with COVID-19 consecutively admitted to COVID—designated ICUs at Evangelismos Hospital, Athens, Greece. Among 50 patients, ICU and hospital mortality was 32% (16/50). Median PaO2 /FiO2 was 121 mmHg (interquartile range (IQR), 86–171 mmHg) and most patients had moderate or severe acute respiratory distress syndrome (ARDS). Hospital resources may be an important aspect of mortality rates, since severely ill COVID-19 patients with moderate and severe ARDS may have understandable mortality, provided that they are admitted to general ICUs without limitations on hospital resources. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Background and objective: Mesothelial cells and cardiomyocytes have shared embryonic mesodermal origin. Cardiomyocytes release BNP under stretch. We searched whether malignant mesothelioma cells also secrete BNP and if so, this has a meaningful impact. Methods: Part I: Prospectively, patients with pleural lesions on CT having malignant mesothelioma effusions (MME, n = 13) were compared to patients with malignant effusions with pleural lesions (MEa, n = 14). Age-matched patients with ME without pleural lesions (MEb, n = 16) and non-malignant effusions (NME, n = 25) were analysed. Part II: Retrospectively, samples from patients with mesothelioma (n = 14), lung cancer (n = 8) or heart failure (n = 9) were used. BNP was measured in pleural fluid and blood/plasma. Part III: BNP was assessed in the culture supernatants of benign (MeT-5A) and malignant mesothelioma cell lines (M14K-epithelioid, MSTO-biphasic and ZL34-sarcomatoid) (n = 10 per cell line in three different biological replicates). Results: In vitro, BNP concentration was significantly higher in the supernatant of all malignant cell lines than benign ones (P < 0.01), denoting BNP's production from the former. The pleural fluid to blood BNP ratio in MME was extremely high in Part I and Part II subjects (28.3 ± 12.1 and 25.9 ± 8.6, respectively) versus 1.1 ± 0.3 and 0.4 ± 0.1 in Part I ME and NME, respectively (P < 0.0001), and 0.8 ± 0.1 and 0.4 ± 0.1 in Part II ME and NME, respectively (P < 0.0001). BNP ratio ≥2.11 in Part I had 92% sensitivity and 94.5% specificity for MME (P < 0.0001). Conclusion: BNP is secreted from malignant mesothelial cells. In clinical practice, the pleural fluid to blood BNP ratio can help in the diagnosis of malignant mesothelioma. © 2020 Asian Pacific Society of Respirology

Background and objective: Anti-angiogenic treatment has been recently shown to be clinically beneficial for mesothelioma patients. Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. Ang-1 is mainly known to promote angiogenesis and vessel stability, while Ang-2 could serve as an antagonist of Ang-1 causing vessel regression and destabilization or enhance angiogenesis in a context-dependent manner. We hypothesized that Ang-1 would promote and Ang2 would halt experimental mesothelioma by affecting tumor angiogenesis. Methods: To examine the effects of angiopoietins in mesothelioma angiogenesis and in vivo growth we constructed Ang-1 or Ang-2 overexpressing AE17 and AB1 mesothelioma cells and implanted them in the respective syngeneic animals. We also explored the clinical relevance of our observations using the human tumoral mRNAseq data available in the TCGA database. Results and conclusions: Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Low Ang-1 levels in human mesotheliomas are associated with the epitheloid subtype. Tumors of high Ang-1, or concurrent high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression, markers of vascularity and vascular stability, respectively. Our results highlight the importance of angiopoietins in mesothelioma pathophysiology and pave the way for the clinical development of novel anti-angiogenic strategies. © 2018 Elsevier Ltd

Purpose of ReviewTo provide an updated summary of the pleurotoxic drugs and their manifestations.Recent FindingsNovel antineoplastic agents for the treatment of hematologic and non-hematologic malignancies have been associated with the induction of pleural disorders. Moreover, the list of agents that have been associated with drug-induced lupus pleuritis is steadily increasing.SummaryPleurotoxic medications are agents that may cause pleural disorders, most commonly pleural effusions. Connecting a pleural disorder to a specific drug requires the exclusion of other potential causes combined with resolution of the disorder after drug discontinuation while previous literature reports on similar cases may be of assistance. The incorporation of new therapies into clinical practice over the last few years has exposed medical professionals to areas devoid of a historic evidence base. Thus, drug-induced pleurotoxicity should be always included in the diagnostic approach to the patient with a pleural effusion.

Versican promotes experimental tumor growth through cell- and non cell-autonomous mechanisms. Its role in mesothelioma progression has not been investigated so far. In this study we investigated the impact of tumor-derived versican in mesothelioma progression and the underlying mechanism of its action. For this purpose, versican-silenced or control ΑΕ17 and ΑΒ1 murine mesothelioma cells were intrapleuraly injected into syngeneic mice, in order to create pleural mesotheliomas and pleural effusions. Intratumoral and pleural immune subsets were assessed using flow cytometry. Mesothelioma cells were co-cultured with syngeneic macrophages to examine versican’s impact on their interaction and endothelial cells to assess the effect of versican in endothelial permeability. Versican expression was assessed in human mesotheliomas and mesothelioma-related pleural effusions and benign pleural tissue and effusions. We observed that, versican silencing reduced mesothelioma mass and pleural fluid volume by affecting tumor cell proliferation and apoptosis in vivo, while tumor cell growth remained intact in vitro, and limited pleural vascular permeability. Mice harboring versican-deficient tumors presented fewer tumor/pleural macrophages and neutrophils, and fewer pleural T-regulatory cells, compared to the control animals. Macrophages co-cultured with versican-deficient mesothelioma cells were polarized towards M1 anti-tumor phenotype and demonstrated increased tumor cell phagocytic capacity, compared to macrophages co-cultured with control tumor cells. In co-culture, endothelial monolayer permeability was less effectively stimulated by versican-deficient cells than control cells. Versican was over-expressed in human mesothelioma tissue and mesothelioma-associated effusion. In conclusion, tumor cell-derived versican stimulates mesothelioma progression by shaping a tumor friendly inflammatory milieu, mainly by blunting macrophage anti-tumor activities. © 2018, © 2018 Taylor & Francis Group, LLC.

Electronic cigarettes (e-cigs) are advertised as a less harmful nicotine delivery system or as a new smoking cessation tool. We aimed to assess the in vivo effects of e-cig vapor in the lung and to compare them to those of cigarette smoke (CS). We exposed C57BL/6 mice for either 3 days or 4 wk to ambient air, CS, or e-cig vapor containing 1) propylene glycol/vegetable glycerol (PG:VG-Sol; 1:1), 2) PG:VG with nicotine (G:VG-N), or 3) PG:VG with nicotine and flavor (PG:VG-N+F) and determined oxidative stress, inflammation, and pulmonary mechanics. E-cig vapors, especially PG:VG-N+F, increased bronchoalveolar lavage fluid (BALF) cellularity, Muc5ac production, as well as BALF and lung oxidative stress markers at least comparably and in many cases more than CS. BALF protein content at both time points studied was only elevated in the PG:VG-N+F group. After 3 days, PG:VG-Sol altered tissue elasticity, static compliance, and airway resistance, whereas after 4 wk CS was the only treatment adversely affecting these parameters. Airway hyperresponsiveness in response to methacholine was increased similarly in the CS and PG:VG-N+F groups. Our findings suggest that exposure to e-cig vapor can trigger inflammatory responses and adversely affect respiratory system mechanics. In many cases, the added flavor in e-cigs exacerbated the detrimental effects of e-cig vapor. We conclude that both e-cig vaping and conventional cigarette smoking negatively impact lung biology. © 2018 American Physiological Society. All rights reserved.

Malignant pleural mesothelioma is resistant to currently used treatment. Angiopoieitn-1 directly promotes mesothelioma cell growth in a Tie-2-dependent fashion. Angiopoietin/Tie-2 axis may thus be valid targets for therapeutic interventions against mesothelioma. We hypothesized that a soluble angiopoietin inhibitor (Murine Tek-deltaFc) would halt mesothelioma progression in vivo by enhancing mesothelioma cell proliferation and inhibiting tumor angiogenesis. Our hypothesis was challenged on two syngeneic mesothelioma in vivo models (AB1 cells- Balb/c mice and AE17 cells-C57BL/6 mice. Even though both mesothelioma cell lines express the Angiopoietin-1/-2 and Tie-2, murine Tek-deltaFc hampered AB1 but not AE17 mesothelioma growth in vivo by enhancing tumor cell apoptosis and limiting tumor angiogenesis. Neither angiopoietins (Angs)-1 and -2 nor the inhibitor affected mesothelioma cell growth in vitro. AB1 (responding) tumors were more vascularized and displayed higher endothelial Tie-2 and lower tumor Ang-1 expression than the (non-responding) AE17 tumors. Angiopoietins-1 and -2 are expressed in tumors and pleural cavity of mesothelioma patients demonstrating the clinical relevance of our experimental observations. In conclusion, disrupting Ang-Tie-2 signaling limits mesothelioma angiogenesis and halts tumor progression. Tumor vascularity, endothelial Tie-2 expression and tumor Ang-1 expression may predict mesothelioma response to Tek-deltaFc. © Magkouta et al.

SETTING: Data on the relationship between pleural tuberculosis (TB) and anti-tuberculosis drug resistance are scarce. OBJECTIVE: To determine the patterns of drug resistance among pleural Mycobacterium tuberculosis isolates in Greece and the incidence of tuberculous pleural effusion (TPE) among patients with multidrug-resistant (MDR) or extensively drug-resistant (XDR) pulmonary TB. DESIGN: Drug susceptibility testing (DST) results recorded in the database of the National Reference Centre for Tuberculosis in Athens, Greece, over a 9-year period (2003-2011) were reviewed. Chest X-rays from hospitalised patients with pulmonary MDR/XDR-TB during the same period were also reviewed for the presence of TPE. RESULTS: Resistance to at least one first-line drug was observed in 11% of the cases (MDR-TB 3%, XDR-TB 1%), while 29% of the patients with pulmonary MDR/XDR-TB presented with TPE during the course of their disease, the majority ipsilateral to the lung lesions, which responded to guided anti-tuberculosis treatment. CONCLUSION: The prevalence of drug resistance among pleural M. tuberculosis isolates in Greece highlights the importance of DST prior to treatment selection in TPE patients. In our study population, TPE that developed in one third of the patients with pulmonary MDR/XDR-TB usually resolved with DST guided anti-tuberculosis treatment.

Small GTPases are pivotal regulators of several aspects of tumor progression. Their implication in angiogenesis, vascular permeability and tumor-associated inflammatory responses is relevant to the pathobiology of Malignant Pleural Effusion (MPE). Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt) abrogates small GTPase activation. We therefore hypothesized that cysmethynil, an Icmt inhibitor would limit pleural fluid accumulation in two models, a lung-adenocarcinoma and a mesothelioma-induced MPE. Cysmethynil significantly reduced MPE volume in both models and tumor burden in the adenocarcinoma model. It inhibited pleural vascular permeability and tumor angiogenesis in vivo and reduced endothelial cell proliferation, migration and tube formation in vitro. Cysmethynil also promoted M1 anti-tumor macrophage homing in the pleural space in vivo, and inhibited tumor-induced polarization of macrophages towards a M2 phenotype in vitro. In addition, the inhibitor promoted adenocarcinoma cell apoptosis in vivo. Inhibition of small GTPase might thus represent a valuable strategy for pharmacotherapy of MPE.

Malignant pleural effusion (MPE) is a common but serious condition that is related with poor quality of life, morbidity and mortality. Its incidence and associated healthcare costs are rising and its management remains palliative, with median survival ranging from 3 to 12 months. During the last decade there has been significant progress in unravelling the pathophysiology of MPE, as well as its diagnostics, imaging, and management. Nowadays, formerly bed-ridden patients are genotyped, phenotyped, and treated on an ambulatory basis. This article attempts to provide a comprehensive overview of current advances in MPE from bench to bedside. In addition, it highlights unanswered questions in current clinical practice and suggests future directions for basic and clinical research in the field. © ERS 2016.

Background and objective The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu. Methods We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20-mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation. Results Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration. Conclusions In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo. We used syngeneic in vivo mesothelioma models to show that temsirolimus, an mTOR inhibitor, curtailed mesothelioma growth by inducing tumour cell apoptosis, by targeting tumour angiogenesis and by modulating host immune response. This is the first report on the effects of temsirolimus impact on mesothelioma-related immune response and mesothelioma vascularization. © 2015 Asian Pacific Society of Respirology.

The impact of temsirolimus was investigated in a murine model of malignant pleural effusion (MPE) created with intrapleural injection of Lewis Lung Cancer (LLC) cells. Temsirolimus (1 or 20 mg/kg) did not affect the pleural fluid volume or the number of pleural tumour foci. In addition, temsirolimus did not affect vascular endothelial growth factor expression by LLC cells in vitro. In conclusion, temsirolimus did not curtail experimental lung-adenocarcinoma- induced MPE. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated angiogenesis and inflammation, both central to the pathogenesis of malignant pleural effusion (MPE). Here, we examined the impact of tumor- and host-derived SPP1 in MPE formation and explored the mechanisms by which the cytokine exerts its effects. We used a syngeneic murine model of lung adenocarcinoma-induced MPE. To dissect the effects of tumor- versus host-derived SPP1, we intrapleurally injected wild-type and SPP1-knockout C57/BL/6 mice with either wild-type or SPP1-deficient syngeneic lung cancer cells. We demonstrated that both tumor- and host-derived SPP1 promoted pleural fluid accumulation and tumor dissemination in a synergistic manner (P

Background and objective The role of pro-inflammatory interleukin-17A (IL-17A), in pleural diseases is unknown. We sought to investigate IL-17A expression and its clinical implications in patients with pleural effusion (PE) and IL-17A involvement in the pathobiology of pleural inflammation elicited by bacterial products. Methods Pleural and blood IL-17A content was examined in 84 patients with PE of different aetiologies, and the diagnostic value of pleural IL-17A was explored in 92 patients with neutrophil-predominant PE. IL-17A contribution in pleural inflammation was evaluated in mice injected intrapleurally with either IL-17A or bacterial products with or without IL-17A-neutralizing antibodies. Results IL-17A was upregulated in the pleural space of patients with parapneumonic PE. It was detected in a minority of patients with tuberculous PE and very uncommonly in patients with malignant or other pleural exudates. Pleural fluid (PF) IL-17A levels were correlated with markers of acute pleural inflammation, as well as vascular endothelial growth factor and IL-8 levels. Among patients with neutrophil-predominant PE, PF IL-17A was detected only in those with parapneumonic PE, although the sensitivity of the test was low (