Serum and pleural fluid tumor markers are well-recognized auxiliary diagnostic tools for malignant pleural effusion (MPE). Here, we discuss some pearls and pitfalls regarding the role of tumor markers in MPE management. The following issues are discussed in this article: What is the appropriate clinical scenario for evaluating pleural tumor markers? Which tumor markers should be advocated for diagnosing MPE? Can extremely high levels of tumor markers be employed to establish a diagnosis of MPE? Does the serum-to-pleural fluid ratio of a tumor marker have the same diagnostic efficacy as the measurement of that marker alone in the pleural fluid? Can tumor markers be used to estimate the risk of specific cancers? What should be considered when interpreting the diagnostic accuracy of tumor markers? How should tumor marker studies be performed? We addressed these issues with published works, particularly systematic reviews and meta-analyses.

UNASSIGNED: Many cancers metastasize to the pleura, resulting in effusions that cause dyspnea and discomfort. Regardless of the tissue of origin, pleural malignancies are aggressive and uniformly fatal, with no treatment shown to prolong life. The pleural mesothelial monolayer is joined by tight junctions forming a contained bioreactor-like space, concentrating cytokines and chemokines secreted by the mesothelium, tumor, and infiltrating immune cells. This space represents a unique environment that profoundly influences tumor and immune cell behavior. Defining the pleural secretome is an important step in the rational development localized intrapleural immunotherapy.
UNASSIGNED: We measured cytokine/chemokine content of 252 malignant pleural effusion (MPE) samples across multiple cancers using a 40-analyte panel and Luminex multiplexing technology.
UNASSIGNED: Eleven analytes were consistently present in concentrations ≥ 10.0 pM: CXCL10/IP10 (geometric mean = 672.3 pM), CCL2/MCP1 (562.9 pM), sIL-6Rα (403.1 pM), IL-6 (137.6 pM), CXCL1/GRO (80.3 pM), TGFβ1 (76.8 pM), CCL22/MDC (54.8 pM), CXCL8/IL-8 (29.2 pM), CCL11/Eotaxin (12.6 pM), IL-10 (11.3 pM), and G-CSF (11.0 pM). All are capable of mediating chemotaxis, promotion of epithelial to mesenchymal transition, or immunosuppression, and many of are reportedly downstream of a pro-inflammatory cytokine cascade mediated by cytokine IL-6 and its soluble receptor.
UNASSIGNED: The data indicate high concentrations of several cytokines and chemokines across epithelial cancers metastatic to the pleura and support the contention that the pleural environment is the major factor responsible for the clinical course of MPE across cancer types. A sIL-6Rα to IL-6 molar ratio of 2.7 ensures that virtually all epithelial, immune and vascular endothelial cells in the pleural environment are affected by IL-6 signaling. The central role likely played by IL-6 in the pathogenesis of MPE argues in favor of a therapeutic approach targeting the IL-6/IL-6R axis.

Malignant pleural effusions (MPEs) are hard to treat, and their onset usually signals terminal cancer. Immunotherapies hold promise but must overcome the immunosuppressive MPE microenvironment. Herein, we treat MPEs via synergistically combining two emerging cancer therapy modalities: enzyme-dynamic therapy (EDT) and metalloimmunotherapy. To do so, a nanoplatform termed \"A-R-SOME\" was developed which comprises MPE-targeted M1 type extracellular vesicles (EVs) loaded with (1) a manganese-based superoxide dismutase (SOD) enzyme, (2) stimulator of interferon genes (STING) agonist diABZI-2, and (3) signal transducer and an activator of transcription 3 (STAT3) small interfering RNA. Endogenous reactive oxygen species within tumors induced immunogenic cell death by EDT, along with STING activation by both Mn and diABZI-2, and suppression of the STAT3 pathway. Systemically administered A-R-SOME alleviated the MPE immunosuppressive microenvironment, triggered antitumor systemic immunity, and long-term immune memory, leading to the complete eradication of MPE and pleural tumors with 100% survival rate in an aggressive murine model. A-R-SOME-induced immune effects were also observed in human patient-derived MPE, pointing toward the translation potential of A-R-SOME as an experimental malignancy treatment.

BACKGROUND: Pleural effusion is due to the pathological accumulation of pleural fluid in the pleural space, 25%-30% of which may remain undiagnosed despite the combination of biochemical, microbiological, and pathological tests and closed pleural biopsy. Medical thoracoscopy may help physicians diagnose such cases. We aimed to study the diagnostic yield of medical thoracoscopy in patients with undiagnosed exudative pleural effusion and assess the safety profile of the medical thoracoscopy.
METHODS: A cross-sectional descriptive study was conducted on 105 patients with undiagnosed pleural effusion. Medical thoracoscopy was performed using an Olympus semi-rigid thoracoscope (LTF 160 Evis Pleurovideoscope, Japan) as per standard protocol. Multiple pleural biopsies were taken and sent for histopathology examination, NAAT (nucleic acid amplification test), and MGIT (mycobacteria growth indicator tube). Post-procedure, the patients were evaluated for any complications.
RESULTS: A total of 105 patients were enrolled in the study. The mean ± SD age was 55.1 ± 13.6 years. Sixty-three (60%) patients were males. The diagnostic utility of medical thoracoscopy was found in 94 (89.5%) patients. The diagnosis of tuberculosis (TB) was made in 34 (32.3%) patients, and 48 (45.7%) patients were diagnosed with malignant pleural effusion. Adenocarcinoma of the lung was the most common malignancy diagnosed (32 patients, 66.6%). Five (5.31%) patients had dual etiology of pleural effusion: tubercular and malignancy. The most common complication was chest pain following the procedure (99.4%). One patient developed pneumomediastinum and was managed conservatively. There were no major adverse events after the procedure.
CONCLUSIONS: Medical thoracoscopy has a high diagnostic yield and favorable safety profile with minimal complications. Excessive reliance on the level of ADA (adenosine deaminase) may further delay the diagnosis. Dual etiologies like TB coexisting with malignancy should be considered in TB high-burden countries.

Malignant pleural effusion (MPE) from patients with advanced non-small-cell lung cancer (NSCLC) has been proven valuable for molecular analysis; however, simultaneous detection of driver fusions in MPE is still challenging. In this study, we investigated the Idylla™ GeneFusion Panel, a stand-alone test in tissue samples, in the evaluation of ALK, ROS1, RET and MET ex14 skipping mutations in MPE and compared its performance with routine reference methods (Real-time-based and Next-generation Sequencing-NGS). The inclusion criteria for sample selection were as follows: advanced NSCLC harboring ALK, ROS1, RET fusions or MET exon-skipping alterations and the availability of MPE collected at diagnosis or disease progression. Molecular alterations have been investigated on tissue by fluorescence in situ hybridization (FISH) or Real-time PCR or NGS. For molecular profiling with the Idylla™ GeneFusion, 200 µL of MPE supernatants combined with 50 µL of RNA Later solution were loaded into the Idylla™ cartridge without cfRNA extraction. The Idylla™ GeneFusion Assay performed on MPEs was able to confirm molecular profile, previously diagnosed with conventional methods, in all cases. Our data confirm that MPE are suitable material for investigating fusion alterations. The Idylla™ GeneFusion, although indicated for investigation of tissue samples, offers the possibility of performing a molecular characterization of supernatants without undertaking the entire cfRNA extraction procedure providing a rapid and reliable strategy for the detection of actionable genetic alterations.

Isolation of tumor-specific T cells and their antigen receptors (TCRs) from malignant pleural effusions (MPE) may facilitate the development of TCR-transduced adoptive cellular immunotherapy products for advanced lung cancer patients. However, the characteristics and markers of tumor-specific T-cells in MPE are largely undefined. To this end, to establish the phenotypes and antigen specificities of CD8+ T cells, we performed single-cell RNA and TCR sequencing of samples from three advanced lung cancer patients. Dimensionality reduction on a total of 4,983 CD8+ T cells revealed 10 clusters including naïve, memory, and exhausted phenotypes. We focused particularly on exhausted T cell clusters and tested their TCR reactivity against neoantigens predicted from autologous cancer cell lines. Four different TCRs specific for the same neoantigen and one orphan TCR specific for the autologous cell line were identified from one of the patients. Differential gene expression analysis in tumor-specific T cells relative to the other T cells identified CXCL13, as a candidate gene expressed by tumor-specific T cells. In addition to expressing CXCL13, tumor-specific T cells were present in a higher proportion of T cells co-expressing PDCD1(PD-1)/TNFRSF9(4-1BB). Furthermore, flow cytometric analyses in advanced lung cancer patients with MPE documented that those with high PD-1/4-1BB expression have a better prognosis in the subset of 57 adenocarcinoma patients (p = .039). These data suggest that PD-1/4-1BB co-expression might identify tumor-specific CD8+ T cells in MPE, which are associated with patients\' prognosis. (233 words).

UNASSIGNED: Malignant pleural effusion (MPE) is a common and debilitating condition seen in advanced cancer disease, and life-expectancy is short. Symptoms include pain and severe shortness of breath. Current first-line treatment options include pleural drainage using catheters as well as pleurodesis. However, these treatment modalities are often inefficient and patients need repeated procedures. Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) is a minimally invasive procedure, where antineoplastic agents are nebulized under pressure into the pleural space.
UNASSIGNED: We present the preliminary safety, feasibility, and response assessment data for PITAC based on a comprehensive literature review.
UNASSIGNED: Five retrospective studies reported data on 38 PITACs in 21 patients. Data were heterogeneous and incomplete on several important aspects such as procedure, safety, local effect and long-term outcomes. PITAC seems technically feasible with a low risk of complications and may provide some reduction in MPE in selected cases.
UNASSIGNED: PITAC seems feasible, but prospective phase I and II studies are needed to define safety, indications, and efficacy.

UNASSIGNED: Malignant pleural effusion (MPE) is prevalent among cancer patients, indicating pleural metastasis and predicting poor prognosis. However, accurately identifying MPE in clinical settings is challenging. The aim of this study was to establish an innovative nomogram-derived model based on clinical indicators and serum metal ion levels to identify MPE.
UNASSIGNED: From July 2020 to May 2022, 428 patients diagnosed with pleural effusion (PE) were consecutively recruited. Comprehensive demographic details, clinical symptoms, imaging data, pathological information, and laboratory results, including serum metal ion levels, were systematically collected. The nomogram was created by incorporating the most significant predictors identified through LASSO and multivariate logistic regression analysis. The predictors were assigned weighted points based on their respective regression coefficients, allowing for the calculation of a total score that corresponds to the probability of MPE. Internal validation using bootstrapping techniques assessed the nomogram\'s performance, including calibration, discrimination, and clinical applicability.
UNASSIGNED: Seven key variables were identified using LASSO regression and multiple regression analysis, including dyspnea, fever, X-ray/CT compatible with malignancy, pleural carcinoembryonic antigen(pCEA), serum neuron-specific enolase(sNSE), serum carcinoembryonic antigen(sCEA), and pleural lactate dehydrogenase(pLDH). Internal validation underscored the superior performance of our model (AUC=0.940). Decision curve analysis (DCA) analysis demonstrated substantial net benefit across a probability threshold range > 1%. Additionally, serum calcium and copper levels were significantly higher, while serum zinc levels were significantly lower in MPE patients compared to benign pleural effusion (BPE) patients.
UNASSIGNED: This study effectively developed a user-friendly and reliable MPE identification model incorporating seven markers, aiding in the classification of PE subtypes in clinical settings. Furthermore, our study highlights the clinical value of serum metal ions in distinguishing malignant pleural effusion from BPE. This significant advancement provides essential tools for physicians to accurately diagnose and treat patients with MPE.

BACKGROUND: Malignant pleural effusion (MPE) is frequently observed in patients with advanced lung adenocarcinoma (LUAD). Pleural fluid cytology is a less invasive procedure compared to pleural biopsy. Therefore, it is crucial to identify novel effective biomarkers for LUAD-associated pleural fluid cytology.
METHODS: The RNA sequencing (RNA-Seq) and clinical data of LUAD cases were downloaded from TCGA and OncoSG databases. Differential gene expression analysis, survival analysis and immune cell infiltration analysis were performed on the LUAD datasets. The expression levels of FAM83A, TFF-1, and NapsinA in 94 paired LUAD and adjacent normal tissues, and in the pleural effusion specimens of 40 LUAD and 21 non-neoplastic patients were evaluated by immunohistochemistry.
RESULTS: FAM83A expression levels were significantly different between the LUAD and normal tissue datasets, and correlated with overall or disease-free survival, and histological grade of the tumors. Furthermore, the in-situ expression of FAM83A was higher in 89/94 LUAD tissues compared to the paired normal tissues. FAM83A expression was significantly correlated with immune cell infiltration, and showed a positive association with macrophage infiltration. In addition, FAM83A staining was positive in 37 LUAD pleural effusion samples, and negative in 20 non-neoplastic pleural effusion samples. The expression pattern of FAM83A in the pleural effusion of LUAD patients was relatively consistent with that of TFF-1 and NapsinA, and even stronger in some specimens that were weakly positive or negative for TTF1/NapsinA.
CONCLUSIONS: FAM83A is a promising immune-related biomarker in LUAD biopsy specimens and pleural fluid, and can distinguish between malignant and benign pleural effusion.

BACKGROUND: Malignant pleural effusion (MPE) affects up to 15% of patients with malignancy, and the prevalence is increasing. Non-expandable lung (NEL) complicates MPE in up to 30% of cases. However, it is not known if patients with malignant pleural effusion and NEL are more symptomatic in activities of daily living compared to patients with MPE with expandable lung.
METHODS: This was an observational study on consecutively recruited patients with MPE from our pleural clinic. Before thoracentesis, patients completed patient-reported outcomes on cancer symptoms (ESAS), health-related quality of life (5Q-5D-5L), and dyspnoea scores. Following thoracentesis, patients scored dyspnoea relief and symptoms during thoracentesis. Data on focused lung ultrasound and pleural effusion biochemistry were collected. The non-expandable lung diagnosis was made by pleural experts based on radiological and clinical information.
RESULTS: We recruited 43 patients, including 12 with NEL (28%). The NEL cohort resembled those from previous studies concerning ultrasonography, pleural fluid biochemistry, and fewer cases with high volume thoracentesis. Patients with and without NEL were comparable concerning baseline demography. The 5Q-5D-5L utility scores were 0.836 (0.691-0.906) and 0.806 (0.409-0.866), respectively, for patients with and without NEL. We observed no between-group differences in symptom burden or health-related quality of life.
CONCLUSIONS: While the presence of NEL affects the clinical management of recurrent MPE, the presence of NEL seems not to affect patients\' overall symptom burden in patients with MPE.