Hepatocyte growth factor combined with adenosine deaminase as biomarker for diagnosis of tuberculous pleural effusion.

Background: The simple, rapid, and accurate diagnosis of tuberculous pleural effusion (TPE) remains difficult. This study aimed to determine the accuracy of hepatocyte growth factor (HGF) in the diagnosis of TPE. Methods: We quantified the expression of HGF, adenosine deaminase (ADA), and interferon gamma (IFN-γ) in pleural effusion (PE) in 97 TPE subjects and 116 non-TPE subjects using an enzyme-linked immunosorbent assay (ELISA) or a fully automatic biochemical analyzer. The diagnostic performance of these three biomarkers was evaluated using a receiver operating characteristic (ROC) curve of subjects by age and gender. Results: We discovered that the TPE group had much higher levels of HGF than the non-TPE group, regardless of age or gender, and that there was no statistically significant difference between the two groups' levels of HGF expression in peripheral plasma. In female TPE patients aged ≤65 years, the AUCs of TPE and non-TPE diagnosed by HGF, ADA or IFN-γ were 0.988, 0.964, and 0.827, respectively. HGF plus ADA had the highest diagnostic efficacy in female TPE patients aged ≤65 years. With HGF plus ADA having a cut-off value of 0.219 for distinguishing TPE from non-TPE, the area under the curve (AUC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV) were, respectively, 0.998 (95% confidence interval [CI], 0.993-1.000), 100 (95% CI, 89.997-100.000), 96.667 (95% CI, 82.783-99.916), 97.222 (95% CI, 83.594-99.586), and 100. Conclusion: This study confirmed that HGF plus ADA has high diagnostic efficacy in younger female TPE patients and has the potential to be an excellent biomarker.

Characterization of the alternative splicing landscape in lung adenocarcinoma reveals novel prognosis signature associated with B cells.

BACKGROUND: Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death. Malignant pleural effusion (MPE) is a special microenvironment for lung cancer metastasis. Alternative splicing, which is regulated by splicing factors, affects the expression of most genes and influences carcinogenesis and metastasis. METHODS: mRNA-seq data and alternative splicing events in lung adenocarcinoma (LUAD) were obtained from The Cancer Genome Atlas (TCGA). A risk model was generated by Cox regression analyses and LASSO regression. Cell isolation and flow cytometry were used to identify B cells. RESULTS: We systematically analyzed the splicing factors, alternative splicing events, clinical characteristics, and immunologic features of LUAD in the TCGA cohort. A risk signature based on 23 alternative splicing events was established and identified as an independent prognosis factor in LUAD. Among all patients, the risk signature showed a better prognostic value in metastatic patients. By single-sample gene set enrichment analysis, we found that among tumor-infiltrating lymphocytes, B cells were most significantly correlated to the risk score. Furthermore, we investigated the classification and function of B cells in MPE, a metastatic microenvironment of LUAD, and found that regulatory B cells might participate in the regulation of the immune microenvironment of MPE through antigen presentation and promotion of regulatory T cell differentiation. CONCLUSIONS: We evaluated the prognostic value of alternative splicing events in LUAD and metastatic LUAD. We found that regulatory B cells had the function of antigen presentation, inhibited naïve T cells from differentiating into Th1 cells, and promoted Treg differentiation in LUAD patients with MPE.

Interleukin 32 as a Potential Marker for Diagnosis of Tuberculous Pleural Effusion.

Accurate differential diagnosis is the key to choosing the correct treatment for pleural effusion. The present study aimed to assess whether interleukin 32 (IL-32) could be a new biomarker of tuberculous pleural effusion (TPE) and to explore the biological role of IL-32 in TPE. IL-32 levels were evaluated in the pleural effusions of 131 patients with undetermined pleural effusion from Wuhan and Beijing cohorts using an enzyme-linked immunosorbent assay method. Macrophages from TPE patients were transfected with IL-32-specific small interfering RNA (siRNA), and adenosine deaminase (ADA) expression was determined by real-time PCR and colorimetric methods. With a cutoff value of 247.9 ng/mL, the area under the curve of the receiver operating characteristic (ROC) curve for IL-32 was 0.933 for TPE, and the sensitivity and specificity were 88.4% and 93.4%, respectively. A multivariate logistic regression model with relatively good diagnostic performance was established. IL-32-specific siRNA downregulated ADA expression in macrophages, and IL-32γ treatment significantly induced ADA expression. Our results indicate that IL-32 in pleural effusion may be a novel biomarker for identifying patients with TPE. In addition, our multivariate model is acceptable to rule in or rule out TPE across diverse prevalence settings. Furthermore, IL-32 may modulate ADA expression in the tuberculosis microenvironment. (This study has been registered at ChiCTR under registration number ChiCTR2100051112 [https://www.chictr.org.cn/index.aspx].) IMPORTANCE Tuberculous pleural effusion (TPE) is a common form of extrapulmonary tuberculosis, with manifestations ranging from benign effusion with spontaneous absorption to effusion with pleural thickening, empyema, and even fibrosis, which can lead to a lasting impairment of lung function. Therefore, it is of great significance to find a rapid method to establish early diagnosis and apply antituberculosis therapy in the early stage. This study indicates that interleukin 32 (IL-32) in pleural effusion is a new high-potency marker to distinguish TPE from pleural effusions with other etiologies. A multivariate model combining age, adenosine deaminase (ADA), lactic dehydrogenase, and IL-32 may reliably rule in TPE in intermediate- or high-prevalence areas. Additionally, we observed that IL-32 might regulate ADA expression in macrophages in the tuberculosis microenvironment. Therefore, this study provides new insights into the role of IL-32 in the tuberculosis microenvironment.

Prognostic biomarkers of malignant patients with pleural effusion: a systematic review and meta-analysis.

BACKGROUND: Pleural effusion is a common clinical problem in patients with cancer. We aimed to summarize all the known prognostic indicators of malignant pleural effusion. METHODS: We did a systematic review and meta-analysis with a systematic literature search. All prospective or retrospective cohort studies that estimated the prognostic factors of malignant pleural effusion were enrolled. Mantel-Haenszel method was used to calculate the pooled hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Eventually, we identified 82 studies with a total of 10,748 patients that met our inclusion criteria. The LENT score showed a good prognostic value (HR 1.97, 95% CI 1.67-2.31) so did the LENT score item. In addition, clinical parameters like stage (HR 1.68, 95% CI 1.25-2.25), distant metastasis (HR 1.62, 95% CI 1.38-1.89), EGFR mutation (HR 0.65, 95% CI 0.56-0.74), serum biological parameters like hemoglobin (HR 1.56, 95% CI 1.17-2.06), albumin (HR 1.71, 95% CI 1.25-2.34), C-reaction protein (HR 1.84, 95% CI 1.49-2.29), VEGF (HR 1.70, 95% CI 1.18-2.43) and pleural effusion biological parameters like PH (HR 1.95, 95% CI 1.46-2.60), glucose (HR 1.75, 95% CI 1.18-2.61), VEGF (HR 1.99, 95% CI 1.67-2.37), and survivin (HR 2.90, 95% CI 1.17-7.20) are also prognostic factors for malignant pleural effusion. CONCLUSIONS: For malignant pleural effusion, LENT score and its items are valuable prognostic biomarkers, so do the clinical parameters like stage, distant metastasis, EGFR mutation, the serum biological parameters like hemoglobin, albumin, C-reaction protein, VEGF and the pleural effusion biological parameters like PH, glucose, VEGF and survivin.

Prognostic impact of pleural effusion in patients with malignancy: A systematic review and meta-analysis.

The exact role of pleural effusion in the prognosis of cancer patients remains unclear. We aimed to systematically review the prognostic value of pleural effusion in patients with cancer. We performed a systematic review and meta-analysis with a systematic literature search. All cohort studies with available overall survival (OS) and progression-free survival (PFS) results for patients with cancer with or without pleural effusion were included. The Mantel-Haenszel method was used to calculate the pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Heterogeneity and publication bias were examined. Subgroup analysis and sensitivity analysis were performed. A total of 47 studies with 146,117 patients were included in the analysis. For OS, pleural effusion was a prognostic factor associated with a poor prognosis for patients with cancer (HR, 1.58, 95% CI, 1.43-1.75; I2 94.8%). In the subgroup analysis, pleural effusion was a prognostic factor associated with poor survival for patients with lung cancer (HR, 1.44, 95% CI, 1.35-1.54; I2 60.8%), hematological cancer (HR, 2.79, 95% CI, 1.63-4.77; I2 29.4%) and other types of cancer (HR, 2.08, 95% CI, 1.43-3.01; I2 55.1%). For PFS, pleural effusion was a prognostic factor associated with a poor prognosis for patients with cancer (HR, 1.61, 95% CI, 1.28-2.03; I2 42.9%). We also observed that massive pleural effusion was a prognostic factor associated with a poorer prognosis compared to minimal pleural effusion. Pleural effusion had prognostic value in both OS and PFS of patients with cancer, except for patients with malignant pleural mesothelioma, regardless of whether the malignant effusion was confirmed histologically or cytologically. However, future evidence of other pleural effusion characteristics is still needed.

Single-cell analysis of diverse immune phenotypes in malignant pleural effusion.

The complex interactions among different immune cells have important functions in the development of malignant pleural effusion (MPE). Here we perform single-cell RNA sequencing on 62,382 cells from MPE patients induced by non-small cell lung cancer to describe the composition, lineage, and functional states of infiltrating immune cells in MPE. Immune cells in MPE display a number of transcriptional signatures enriched for regulatory T cells, B cells, macrophages, and dendritic cells compared to corresponding counterparts in blood. Helper T, cytotoxic T, regulatory T, and T follicular helper cells express multiple immune checkpoints or costimulatory molecules. Cell-cell interaction analysis identifies regulatory B cells with more interactions with CD4+ T cells compared to CD8+ T cells. Macrophages are transcriptionally heterogeneous and conform to M2 polarization characteristics. In addition, immune cells in MPE show the general up-regulation of glycolytic pathways associated with the hypoxic microenvironment. These findings show a detailed atlas of immune cells in human MPE and enhance the understanding of potential diagnostic and therapeutic targets in advanced non-small cell lung cancer.

An update of the long-term outcome of patients with nonspecific pleurisy at medical thoracoscopy.

BACKGROUND: Medical thoracoscopy (MT) is recommended in patients with undiagnosed exudative pleural effusion and offers a degree of diagnostic sensitivity for pleural malignancy. However, not all patients who undergo MT receive an exact diagnosis. Our previous investigation from 2014 summarized the long-term outcomes of these patients with nonspecific pleurisy (NSP); now, we offer updated data with the goal of refining our conclusions. METHODS: Between July 2005 and August 2018, MT with pleural biopsies were performed in a total of 1,254 patients with undiagnosed pleural effusions. One hundred fifty-four patients diagnosed with NSP with available follow-up data were included in the present study, and their medical records were reviewed. RESULTS: A total of 154 patients were included in this study with a mean follow-up duration of 61.5 ± 43.7 months (range: 1-180 months). No specific diagnosis was established in 67 (43.5%) of the patients. Nineteen patients (12.3%) were subsequently diagnosed with pleural malignancies. Sixty-eight patients (44.2%) were diagnosed with benign diseases. Findings of pleural nodules or plaques during MT and the recurrence of pleural effusion were associated with malignant disease. CONCLUSIONS: Although most NSP patients received a diagnosis of a benign disease, malignant disease was still a possibility, especially in those patients with nodules or plaques as noted on the MT and a recurrence of pleural effusion. One year of clinical follow-up for NSP patients is likely sufficient. These updated results further confirm our previous study's conclusions.

Predicting Survival for Patients with Malignant Pleural Effusion: Development of the CONCH Prognostic Model.

BACKGROUND: Malignant pleural effusion (MPE) is a frequent complication of advanced malignancies that leads to a poor quality of life and limits treatment options. OBJECTIVE: The objective of this study was to identify biomarkers of survival in patients with MPE, which will greatly facilitate the clinical management of this complication. METHODS: This retrospective study recruited patients who had been pathologically diagnosed with MPE, regardless of the type of primary cancer, at Beijing Chao-Yang Hospital over 158 months. Demographic, clinical, hematological, and pleural fluid data were collected and analyzed as potential predictors of survival, and a new predictive model was developed based on Cox and logistic regression analyses. RESULTS: In our alternative prognostic model (n = 281), four routinely detected variables, namely, carcinoembryonic antigen (CEA) level, monocyte count, N-terminal pro B-type natriuretic peptide (NT-pro-BNP) level, and pleural effusion chloride level on admission, were identified as predictors (the CONCH prognostic score). Patients were divided into three prognosis subgroups based on risk stratification, with median survival periods of 17, 11, and 5 months, respectively. In comparison with the low-risk group, patients in the medium- and high-risk groups showed significantly poorer survival (medium-risk group: hazard ratio [HR], 1.586; 95% confidence interval [CI], 1.047-2.402; P = 0.029; high-risk group: HR, 4.389; 95% CI, 2.432-7.921; P < 0.001). CONCLUSION: Four routinely detected variables were used to develop the CONCH scoring system, which was confirmed to be an accurate prognostic score for patients with MPE. This system can guide the selection of interventions and management for MPE.

Pleural effusion-based nomogram to predict outcomes in unselected patients with multiple myeloma: a large single center experience.

Pleural effusion (PE) is prevalent in unselected "real-life" populations of multiple myeloma (MM). However, its prognostic value on MM is currently elusive. This study aimed to explore the role of PE on MM prognosis and to develop a novel prognostic nomogram for a cohort of Chinese patients with MM. Patients diagnosed with MM form 2000 through 2017 were retrospectively enrolled. PE was evaluated by chest computed tomography (CT) scans. Independent predictors of overall survival (OS) were identified using a multivariable Cox regression model performed on variables selected by the least absolute shrinkage and selection operator (LASSO) algorithm. A nomogram was constructed based on these variables. The concordance index (C-index) and the calibration curve were used to evaluate the predictive performance of the nomogram. Among 861 patients analyzed, 368 patients developed PE. Multivariate cox regression and restricted mean survival time (RMST) analyses revealed that patients with PE experienced worse OS vs. patients without PE. A nomogram predictive of OS was constructed using PE, plasma cell proportion, international staging system (ISS) stage, Charlson comorbidity index (CCI), 1q21 gain, and autologous hematopoietic stem cell transplantation (HSCT). The nomogram showed satisfactory discrimination in the derivation cohort (C-index=0.729) and the validation cohort (C-index=0.684), outperforming the Durie-Salmon (DS) and ISS staging systems. Moreover, the nomogram accurately classified patients into two distinct high- and low-risk groups. PE is frequently encountered in the disease course for MM patients. We derivated and validated a novel nomogram for MM based on PE, outperforming the DS/ISS staging systems.

Clinical Characteristics and Risk Factors for Pleural Effusion in Patients with Multiple Myeloma.

PURPOSE: Pleural effusion (PE) is prevalent in "real-life" populations of multiple myeloma (MM), a common hematologic malignancy. Development of PE likely has prognostic implications. The aim of this study was to investigate the characteristics and identify risk factors for occurrence of PE in MM. PATIENTS AND METHODS: We reviewed electronic medical records of 907 patients diagnosed with MM. RESULTS: Incidence of PE in MM patients was 42.7%. Small and bilateral PE in most cases. PE developed in all MM subtypes, the median time from diagnosis of multiple myeloma to pleural effusion was 6.8 months (range 0.8-33.6 months). Patients with PE showed worse survival than those without PE (unadjusted hazard ratio with 95% confidence interval: 2.249 [1.774-2.852]). No difference in survival was found between patients with small PE and those with moderate to large PE (unadjusted HR, 1.402; 95% CI, 1.037-1.896). Plasma cell proportion (OR, 1.373; 95% CI, 1.153-1.634; P = 0.009) and amyloidosis (OR, 1.791; 95% CI, 1.408-2.279; P = 0.024) were risk factors for the occurrence of PE at the initial diagnosis of MM. Plasma cell proportion (OR, 1.853; 95% CI, 1.451-2.368; P = 0.038), pneumonia (OR, 1.309; 95% CI, 1.143-1.498; P = 0.008) and heart failure (OR, 1.815; 95% CI, 1.387-2.374; P = 0.031) were risk factors for the occurrence of PE at relapse of MM. CONCLUSION: The incidence of PE in MM patients is notable and PE can occur in all MM subtypes. PE indicates a poor prognosis, even small amounts of effusion. PE is a problem worthy of attention, especially in patients with high plasma cell proportion, amyloidosis or complicated with pneumonia and heart failure.

A cluster of health care workers with COVID-19 pneumonia caused by SARS-CoV-2.

BACKGROUND: The current outbreak of coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, Hubei, China, spreads across national and international borders. METHODS: We prospectively collected medical records of 14 health care workers (HCWs) who were infected with SARS-CoV-2, in neurosurgery department of Wuhan Union Hospital, China. RESULTS: Among the 14 HCWs, 12 were conformed cases, the other 2 were suspected cases. Most of them were either exposed to the two index patients or infected coworkers, without knowing they were COVID-19 patients. There were 4 male and 10 female infected HCWs in this cohort, whose mean age was 36 years (SD, 6 years). The main symptoms included myalgia or fatigue (100%), fever (86%) and dry cough (71%). On admission, 79% of infected HCWs showed leucopenia and 43% lymphopenia. Reduced complement C3 could be seen in 57% of the infected HCWs and IL-6 was significantly elevated in 86% of them. The proportion of lymphocytes subsets, concentrations of immunoglobulins, complement C4, IL-2, IL-4, IL-10, TNF-α and IFN-γ were within normal range in these 14 infected HCWs. The most frequent findings on pulmonary computed tomographic images were bilateral multifocal ground-glass opacifications (86%). CONCLUSIONS: Human-to-human transmission of COVID-19 pneumonia has occurred among HCWs, and most of these infected HCWs with confirmed COVID-19 are mild cases. Our data suggest that in the epidemic area of COVID-19, stringent and urgent surveillance and infection-control measures should be implemented to protect doctors and nurses from COVID-19 infection.

Helper T cells in malignant pleural effusion.

Malignant pleural effusion (MPE) is a frequent complication of malignancies and poses a clinical problem. CD4+ T lymphocytes are the most frequent cell population in MPE. Traditionally, CD4+ T cells are classified into two subsets based on cytokine production profiles, type 1 (Th1) and type 2 (Th2) helper T cells, which exhibit distinct functions. Recently, other T-cell subsets have been added to the Th-cell "portfolio", including regulatory T, Th17, Th9, and Th22 cells. The current review focuses on summarizing the Th-cell phenotypic characteristics, mechanism of Th-cell differentiation, and their pleural space recruitment, based on recent research. We also describe the interplay in MPE among different Th cells, as well as Th cells and lung cancer cells or mesothelial cells. Future research should expand the landscape map of human MPE immune cells, explore the immuno-regulation of B cells, and investigate the communication between macrophages and Th cells in MPE, which may facilitate meaningful advancements in the diagnoses and therapeutics of MPE.

TSAd Plays a Major Role in Myo9b-Mediated Suppression of Malignant Pleural Effusion by Regulating TH1/TH17 Cell Response.

Emerging evidence indicates that Myo9b is a cancer metastasis-related protein and functions in a variety of immune-related diseases. However, it is not clear whether and how Myo9b functions in malignant pleural effusion (MPE). In this study, our data showed that Myo9b expression levels correlated with lung cancer pleural metastasis, and nucleated cells in MPE from either patients or mice expressed a lower level of Myo9b than those in the corresponding blood. Myo9b deficiency in cancer cells suppressed MPE development via inhibition of migration. Myo9b deficiency in mice suppressed MPE development by decreasing TH1 cells and increasing TH17 cells. CD4+ naive T cells isolated from Myo9b-/- mouse spleens exhibited less TH1 cell differentiation and more TH17 cell differentiation in vitro. mRNA sequencing of nucleated cells showed that T cell-specific adaptor protein (TSAd) was downregulated in Myo9b-/- mouse MPE, and enrichment of the H3K27me3 mark in the TSAd promoter region was found in the Myo9b-/- group. Naive T cells purified from wild type mouse spleens transfected with TSAd-specific small interfering RNAs (siRNAs) also showed less TH1 cell differentiation and more TH17 cell differentiation than those from the siRNA control group. Furthermore, downregulation of TSAd in mice using cholesterol-conjugated TSAd-specific siRNA suppressed MPE development, decreased TH1 cells, and increased TH17 cells in MPE in vivo. Taken together, Myo9b deficiency suppresses MPE development not only by suppressing pleural cancer metastasis but also by regulating TH1/TH17 cell response via a TSAd-dependent pathway. This work suggests Myo9b and TSAd as novel candidates for future basic and clinical investigations of cancer.

Salivary microRNAs show potential as biomarkers for early diagnosis of malignant pleural effusion.

BACKGROUND: Malignant pleural effusion (MPE) is a common medical problem caused by multiple malignancies, especially lung cancers, and always comes along with a poor outcome. Early detection and diagnosis are important for improving the prognosis in patients with MPE. Salivary microRNAs (miRNAs) may represent a relatively convenient way for diagnosing MPE. We investigated the characteristics of salivary miRNAs of MPE patients, benign pleural effusion (BPE) patients, patients with a malignant tumor but without pleural effusion (MT), and healthy controls (HCs). We believe that they may show potential as a non-invasive and convenient biomarker for diagnosing MPE. METHODS: From January 1, 2019, to July 1, 2019, 57 MPE patients, 33 BPE patients, 50 MT patients, and 49 HCs were enrolled. To select candidate biomarkers, in the discovery phase, the salivary miRNA profiles were detected in three MPE patients and three HCs. Then, qPCR was used in the validation phase with 54 MPE patients, 33 BPE patients, 50 MT patients, and 46 HCs to assay the selected miRNAs. RESULTS: hsa-miR-4484 and hsa-miR-3663-3p were identified as potential biomarkers to diagnose MPE patients, with areas under the curve (AUC) of 0.768 and 0.666, respectively. The diagnostic efficacy was higher when the combination of both miRNAs was used, with an AUC of 0.802. No correlation was found between the volume of MPE and the expression of salivary miRNAs. CONCLUSIONS: This study reports the characterization of salivary miRNAs collected from MPE patients. A combination of hsa-miR-4484 and hsa-miR-3663-3p showed potential discriminatory power for MPE detection, and it may be helpful for the early diagnosis of MPE, i.e., before the pleural effusion volume is too large.

IL-10 promotes malignant pleural effusion by regulating TH 1 response via an miR-7116-5p/GPR55/ERK pathway in mice.

IL-10, produced by a wide variety of cells, is a highly pleiotropic cytokine that plays a critical role in the control of immune responses. However, its regulatory activity in tumor immunity remains poorly understood. In this study, we report that IL-10 deficiency robustly suppressed the formation of malignant pleural effusion (MPE) and significantly enhanced miR-7116-5p expression in pleural CD4+ T cells. We demonstrated that miR-7116-5p suppressed IL-10-mediated MPE formation by inhibiting pleural vascular permeability as well as tumor angiogenesis and tumor growth. IL-10 promoted MPE formation by suppressing miR-7116-5p that enhances TH 1 response. We identified G protein-coupled receptor 55 (GPR55) as a potential target of miR-7116-5p, and miR-7116-5p promoted TH 1 cell function by downregulating GPR55. Moreover, GPR55 promoted MPE formation by inhibiting TH 1 cell expansion through the ERK phosphorylation pathway. These results uncover an IL-10-mediated pathway controlling TH 1 cells and demonstrate a central role for miR-7116-5p/GPR55/ERK signaling in the physiological regulation of IL-10-driven pro-malignant responses.

Influence of age on the diagnostic accuracy of soluble biomarkers for tuberculous pleural effusion: a post hoc analysis.

BACKGROUND: Accurately diagnosing pleural effusion is a frequent and significant problem in clinical practice. Combining pleural biomarkers with patients' age may be a valuable method for diagnosing TPE. We sought to evaluate the influence of age on diagnostic values of pleural adenosine deaminase (ADA), interferon-gamma (IFN-γ), and interleukin 27 (IL-27) for tuberculous pleural effusion (TPE). METHODS: Two hundred seventy-four consecutive adult patients with pleural effusion were selected from Beijing and Wuhan between January 1, 2014 and June 30, 2015, and their pleural fluid concentrations of ADA, IFN-γ, and IL-27 were tested. Biomarker performance was analyzed by standard receiver operating characteristic (ROC) curves according to different ages. RESULTS: Data from the Beijing cohort showed that ADA, IFN-γ, and IL-27 could all accurately diagnose TPE in young patients (≤ 40 years of age). With a cutoff of 21.4 U/L, the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ADA for diagnosing TPE were 1.000 (95% confidence interval: 0.884-1.000), 100.0, 100.0%, 100.0, and 100.0, respectively. In older patients (> 40 years of age), IL-27 and IFN-γ were excellent biomarkers for discriminating TPE versus non-TPE cases. With a cutoff of 591.4 ng/L, the AUC, sensitivity, specificity, PPV, and NPV of IL-27 for diagnosing TPE were 0.976 (95% confidence interval: 0.932-0.995), 96.3, 99.0%, 96.3, and 99.0, respectively. Similar diagnostic accuracy among the three pleural biomarkers was validated in the Wuhan cohort. CONCLUSIONS: Among young patients, ADA is reliable for diagnosing TPE. Conversely, in older patients, IL-27 and IFN-γ are excellent biomarkers to differentiate TPE versus non-TPE cases.

Diagnostic value of CD206+CD14+ macrophages in diagnosis of lung cancer originated malignant pleural effusion.

BACKGROUND: Pleural effusions are common complications of various diseases. Patients with malignant pleural effusion (MPE) usually face poor prognosis and short life expectancy. Discriminating between MPE and benign pleural effusion remains to be difficult. The aim of our current study was to evaluate whether CD206+CD14+ macrophages could be a diagnostic biomarker for MPE. METHODS: The percentages of CD14+, CD86+CD14+ and CD206+CD14+ macrophages in pleural effusions were determined by flow cytometry in 34 patients with MPE and 26 with benign pleural effusion, and their diagnostic performances were evaluated by receiver operating characteristic (ROC) curves. RESULTS: The percentages of CD14+, CD86+CD14+ and CD206+CD14+ macrophages were remarkably higher in MPE than in benign pleural effusion (all P<0.05). With a cutoff value of 39.8%, a high sensitivity of 88.2% and high specificity of 100.0% were found in CD206+CD14+ macrophages to diagnose MPE. The area under the curve, positive predictive value and negative predictive value of CD206+CD14+ macrophages were 0.980 (95% CI, 0.905 to 0.999), 100.0 (88.4 to 100.0) and 86.7 (69.3 to 96.2), respectively. The diagnostic performance of CD206+CD14+ macrophages was more accurate than those of CD14+ and CD86+CD14+ macrophages. CONCLUSIONS: CD206+CD14+ macrophages could be used to discriminate MPE from benign pleural effusion.

Development and validation of the PET-CT score for diagnosis of malignant pleural effusion.

PURPOSE: Although some parameters of positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG) and computed tomography (PET-CT) are somehow helpful in differentiating malignant pleural effusion (MPE) from benign effusions, no individual parameter offers sufficient evidence for its implementation in the clinical practice. The aim of this study was to establish the diagnostic accuracy of a scoring system based on PET-CT (the PET-CT score) in diagnosing MPE. METHODS: One prospective derivation cohort of patients with pleural effusions (84 malignant and 115 benign) was used to develop the PET-CT score for the differential diagnosis of malignant pleural effusion. The PET-CT score was then validated in another independent prospective cohort (n = 74). RESULTS: The PET-CT parameters developed for discriminating MPE included unilateral lung nodules and/or masses with increased 18F-FDG uptake (3 points); extrapulmonary malignancies (3 points); pleural thickening with increased 18F-FDG uptake (2 points); multiple nodules or masses (uni- or bilateral lungs) with increased 18F-FDG uptake (1 point); and increased pleural effusion 18F-FDG uptake (1 point). With a cut-off value of 4 points in the derivation cohort, the area under the curve, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of the PET-CT score to diagnose MPE were 0.949 (95% CI: 0.908-0.975), 83.3% (73.6%-90.6%), 92.2% (85.7%-96.4%), 10.7 (5.6-20.1), and 0.2 (0.1-0.3), respectively. CONCLUSIONS: A simple-to-use PET-CT score that uses PET-CT parameters was developed and validated. The PET-CT score can help physicians to differentiate MPE from benign pleural effusions.

IL-10 promotes malignant pleural effusion in mice by regulating TH 1- and TH 17-cell differentiation and migration.

The role of IL-10 in malignant pleural effusion (MPE) remains unknown. By using murine MPE models, we observed that an increase in pleural IL-10 was a significant predictor of increased risk of death. We noted that TH 1- and TH 17-cell content in MPE was higher in IL-10-/- mice than in WT mice, and IL-10 deficiency promoted differentiation into TH 1 but not into TH 17 cells. A higher fraction of TH 1 and TH 17 cells in the MPE of IL-10-/- mice expressed CXCR3 compared with WT mice. We also demonstrated that Lewis lung cancer and colon adenocarcinoma cells secreted large amounts of CXCL10, a ligand of CXCR3, which induced the migration of TH 1 and TH 17 cells into the MPE, and IFN-γ could promote this signaling cascade. Furthermore, intrapleural injection of mice with CXCL10-deficient tumor cells led to decreased TH 1- and TH 17-cell content in MPE, increased MPE volume, and reduced survival of MPE-bearing mice. Taken together, we demonstrated that IL-10 deficiency promoted T-cell differentiation into TH 1 cells and upregulated the CXCR3-CXCL10 signaling pathway that recruits TH 1 and TH 17 cells into MPE, ultimately resulting in decreased MPE formation and longer survival time of mice-bearing MPE.

IL-17A-Producing γδT Cells Inhibit the Formation of Malignant Pleural Effusions.

γδT cells are an important source of IL-17A and play an anti- or protumor role depending on the surrounding microenvironment. The precise role of γδT cells in the development of malignant pleural effusions (MPE) remains unknown. Using flow cytometry, we analyzed the distribution and differentiation of γδT cells in wild-type (WT) and IL-10-∕- mice. We carefully elucidated the influence of γδT cells on the formation of MPE by depleting γδT cells from WT, IL-10-∕-, and IL-17a-∕- mice. The distribution of γδT17 cells in human MPE and peripheral blood was also determined. Our data showed that both γδT cells and IL-17A-producing γδT (γδT17) cells accumulated in murine MPE, and IL-10 deficiency enhanced their accumulation. γδT cells were the main source of IL-17A in MPE for both WT and IL-10-∕- mice. IL-10 inhibited the chemotactic response of γδT cells to MPE and the proliferation of these cells. IL-10 suppressed γδT cell secretion of IL-17A via RORγt. The ablation of γδT cells accelerated MPE accumulation in both WT and IL-10-∕- mice, but it did not influence MPE accumulation in IL-17a-∕- mice. Patients with higher frequencies of γδT17 cells had significantly longer survival times than patients with lower frequencies of γδT17 cells. Taken together, our data demonstrate that γδT17 cells play an inhibitory role in the progression of MPE, and the accumulation of γδT17 cells in MPE is suppressed by IL-10.