Malignant pleural effusion: current understanding and therapeutic approach.

Malignant pleural effusion (MPE) is a common complication of thoracic and extrathoracic malignancies and is associated with high mortality and elevated costs to healthcare systems. Over the last decades the understanding of pathophysiology mechanisms, diagnostic techniques and optimal treatment intervention in MPE have been greatly advanced by recent high-quality research, leading to an ever less invasive diagnostic approach and more personalized management. Despite a number of management options, including talc pleurodesis, indwelling pleural catheters and combinations of the two, treatment for MPE remains symptom directed and centered around drainage strategy. In the next future, because of a better understanding of underlying tumor biology together with more sensitive molecular diagnostic techniques, it is likely that combined diagnostic and therapeutic procedures allowing near total outpatient management of MPE will become popular. This article provides a review of the current advances, new discoveries and future directions in the pathophysiology, diagnosis and management of MPE.

ERS/ESTS statement on the management of pleural infection in adults.

Pleural infection is a common condition encountered by respiratory physicians and thoracic surgeons alike. The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) established a multidisciplinary collaboration of clinicians with expertise in managing pleural infection with the aim of producing a comprehensive review of the scientific literature. Six areas of interest were identified: 1) epidemiology of pleural infection, 2) optimal antibiotic strategy, 3) diagnostic parameters for chest tube drainage, 4) status of intrapleural therapies, 5) role of surgery and 6) current place of outcome prediction in management. The literature revealed that recently updated epidemiological data continue to show an overall upwards trend in incidence, but there is an urgent need for a more comprehensive characterisation of the burden of pleural infection in specific populations such as immunocompromised hosts. There is a sparsity of regular analyses and documentation of microbiological patterns at a local level to inform geographical variation, and ongoing research efforts are needed to improve antibiotic stewardship. The evidence remains in favour of a small-bore chest tube optimally placed under image guidance as an appropriate initial intervention for most cases of pleural infection. With a growing body of data suggesting delays to treatment are key contributors to poor outcomes, this suggests that earlier consideration of combination intrapleural enzyme therapy (IET) with concurrent surgical consultation should remain a priority. Since publication of the MIST-2 study, there has been considerable data supporting safety and efficacy of IET, but further studies are needed to optimise dosing using individualised biomarkers of treatment failure. Pending further prospective evaluation, the MIST-2 regimen remains the most evidence based. Several studies have externally validated the RAPID score, but it requires incorporating into prospective intervention studies prior to adopting into clinical practice.

Expert Review on Contemporary Management of Common Benign Pleural Effusions.

Heart failure (HF) and cirrhosis are frequently associated with pleural effusions (PEs). Despite their apparently benign nature, both HF-related effusions and hepatic hydrothorax (HH) have poor prognosis because they represent an advanced stage of the disease. Optimization of medical therapy in these two entities involve not only the use of diuretics, but also other pharmacological therapies. For instance, all HF patients with reduced or mildly reduced left ventricular ejection fraction can benefit from angiotensin receptor-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors. Conversely, it is better for HH patients to avoid nonselective beta blockers. Refractory cardiac- and cirrhosis-related PEs are commonly managed by iterative therapeutic thoracentesis. When repeated aspirations are needed, thereby diminishing quality of life, the insertion of an indwelling pleural catheter (IPC) may be warranted. However, in selected HH patients who are diuretic-resistant or diuretic-intractable, placement of transjugular intrahepatic portosystemic shunts should be considered as a bridge to liver transplantation, whereas in transplant candidates the role of IPC is debatable. Another benign condition, pleural tuberculosis (TB) is a serious health problem in developing countries. Diagnostic certainty is still a concern due to the paucibacillary nature of the infection, although the use of more sensitive nucleic acid amplification tests is becoming more widespread. Its treatment is the same as that of pulmonary TB, but the potential drug interactions between antiretroviral and anti-TB drugs in HIV-coinfected patients as well as the current recommended guidelines for the different types of anti-TB drugs resistance should be followed.

MicroRNAs Present in Malignant Pleural Fluid Increase the Migration of Normal Mesothelial Cells In Vitro and May Help Discriminate between Benign and Malignant Effusions.

The sensitivity of pleural fluid (PF) analyses for the diagnosis of malignant pleural effusions (MPEs) is low to moderate. Knowledge about the pathobiology and molecular characteristics of this condition is limited. In this study, the crosstalk between stromal cells and tumor cells was investigated in vitro in order to reveal factors that are present in PF which can mediate MPE formation and aid in discriminating between benign and malignant etiologies. Eighteen PF samples, in different proportions, were exposed in vitro to mesothelial MeT-5A cells to determine the biological effects on these cells. Treatment of normal mesothelial MeT-5A cells with malignant PF increased cell viability, proliferation, and migration, and activated different survival-related signaling pathways. We identified differentially expressed miRNAs in PF samples that could be responsible for these changes. Consistently, bioinformatics analysis revealed an enrichment of the discovered miRNAs in migration-related processes. Notably, the abundance of three miRNAs (miR-141-3p, miR-203a-3, and miR-200c-3p) correctly classified MPEs with false-negative cytological examination results, indicating the potential of these molecules for improving diagnosis. Malignant PF produces phenotypic and functional changes in normal mesothelial cells. These changes are partly mediated by certain miRNAs, which, in turn, could serve to differentiate malignant from benign effusions.

Nonmalignant Pleural Effusions.

Although the potential causes of nonmalignant pleural effusions are many, the management of a few, including complicated pleural infections and refractory heart failure and hepatic hydrothoraces, can be challenging and requires the assistance of interventional pulmonologists. A pragmatic approach to complicated parapneumonic effusions or empyemas is the insertion of a small-bore chest tube (e.g., 14-16 Fr) through which fibrinolytics (e.g., urokinase and alteplase) and DNase are administered in combination. Therapeutic thoracenteses are usually reserved for small to moderate effusions that are expected to be completely aspirated at a single time, whereas video-assisted thoracic surgery should be considered after failure of intrapleural enzyme therapy. Refractory cardiac and liver-induced pleural effusions portend a poor prognosis. In cases of heart failure-related effusions, therapeutic thoracentesis is the first-line palliative therapy. However, if it is frequently needed, an indwelling pleural catheter (IPC) is recommended. In patients with hepatic hydrothorax, repeated therapeutic thoracenteses are commonly performed while a multidisciplinary decision on the most appropriate definitive management is taken. The percutaneous creation of a portosystemic shunt may be used as a bridge to liver transplantation or as a potential definitive therapy in nontransplant candidates. In general, an IPC should be avoided because of the high risk of complications, particularly infections, that may jeopardize candidacy for liver transplantation. Even so, in noncandidates for liver transplant or surgical correction of diaphragmatic defects, IPC is a therapeutic option as valid as serial thoracenteses.

EV-associated miRNAs from peritoneal lavage as potential diagnostic biomarkers in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Current systematic methods for diagnosing have inherent limitations so development of a minimally-invasive diagnosis, based on the identification of sensitive biomarkers in liquid biopsies could therefore facilitate screening among population at risk. METHODS: In this study, we aim to develop a novel approach to identify highly sensitive and specific biomarkers by investigating the use of extracellular vesicles (EVs) isolated from the peritoneal lavage as a source of potential miRNA diagnostic biomarkers. We isolated EVs by ultracentrifugation from 25 ascitic fluids and 25 peritoneal lavages from non-cancer and CRC patients, respectively. Analysis of the expression of EV-associated miRNAs was performed using Taqman OpenArray technology through which we could detect 371 miRNAs. RESULTS: 210 miRNAs were significantly dysregulated (adjusted p value < 0.05 and abs(logFC) ≥ 1). The top-10 miRNAs, which had the AUC value higher than 0.95, were miRNA-199b-5p, miRNA-150-5p, miRNA-29c-5p, miRNA-218-5p, miRNA-99a-3p, miRNA-383-5p, miRNA-199a-3p, miRNA-193a-5p, miRNA-10b-5p and miRNA-181c-5p. CONCLUSIONS: This finding opens the avenue to the use of EV-associated miRNA of peritoneal lavages as an untapped source of biomarkers for CRC.

Diagnosis and characterization of malignant effusions through pleural fluid cytological examination.

PURPOSE OF REVIEW: Malignancy accounts for a substantial proportion of pleural effusions, and cytologic examination of pleural fluid is the easiest way to establish the diagnosis. This review summarizes relevant advances in the diagnostic cytopathology of pleural effusions for the practicing pulmonologist. RECENT FINDINGS: Cytologic analysis using a stained smear and cell block preparation is able to provide the diagnosis in about 55% of malignant effusions. Processing a maximum of two separate specimens (provided the initial examination is negative) with an approximate volume of 40 ml each is the most accepted recommendation. Cytologic identification of mesothelioma is particularly challenging, but testing for BAP1 nuclear expression (immunocytochemistry) and p16 deletion (fluorescence in situ hybridization) has greatly improved our diagnostic capabilities. Similarly, in patients with advanced nonsmall cell lung cancer a comprehensive molecular testing on pleural fluid samples, which should include at a minimum epidermal growth factor receptor/v-raf murine sarcoma viral oncogene homolog B/anaplastic lymphoma kinase/reactive oxygen species 1/programmed death-ligand 1 alterations, is highly advocated to identify patients who may benefit from targeted therapies. SUMMARY: A judicious use of pleural fluid cytologic specimens, which includes immunocytochemistry and molecular testing, eliminates the need for more invasive tissue sampling.

Epithelial cell adhesion molecule (EpCAM) from pleural fluid cell lysates is a highly accurate diagnostic biomarker of adenocarcinomatous effusions.

BACKGROUND AND OBJECTIVE: The discovery of highly accurate pleural fluid (PF) biomarkers of malignancy remains elusive. We assessed the operating characteristics of the PF epithelial cell adhesion molecule (EpCAM), claudin 4 (CL4) and human epididymis protein 4 (HE4) as potential markers of epithelial malignancies. METHODS: The three markers were quantified by immunoassays in the supernatants (s) and cell lysates (cl) of 175 PF samples. The cut-off values with 100% specificity were selected for malignant-benign discrimination. An immunocytochemical staining index score for each marker was also evaluated on PF cell blocks. The resulting best biomarker was further validated in two independent populations of 73 and 48 patients with pleural effusions (PE). RESULTS: An EpCAM(cl) >98 pg/g total lysate protein yielded 75% sensitivity, 100% specificity, negative likelihood ratio of 0.25 and area under the curve of 0.94 for labelling adenocarcinomatous effusions. Sensitivity reached 88% if EpCAM(cl) was combined with EpCAM immunostaining. One-third or more of the malignant effusions exhibiting a false-negative cytological fluid examination were correctly classified by EpCAM(cl) concentrations. Immunoassays for CL4 and HE4 were diagnostically useless. CONCLUSION: EpCAM(cl) is a new biomarker of adenocarcinomatous PE with meaningful discriminating properties.

Pleural Effusions in Diffuse Large B-Cell Lymphoma: Clinical and Prognostic Significance.

PURPOSE: Pleural effusion (PEs) may complicate diffuse large B-cell lymphomas (DLBCL). However, their real prevalence and prognostic significance have seldom been approached systematically. METHODS: Retrospective single-center evaluation of consecutive patients with DLBCL was conducted. Baseline characteristics, PEs on CT imaging, pleural fluid analyses, and outcome until death or censoring date were collected. RESULTS: Of 185 DLBCL patients, 55 (30%) had PEs, of which 27 (49%) were analyzed. Most tapped PEs were malignant (n = 24) and cytological and/or flow cytometric analyses provided the diagnosis in about 70% of the cases. Malignant PEs were exudates with adenosine deaminase levels > 35 U/L in 35% of the cases. More than one-third of lymphomatous PEs required definitive pleural procedures for symptomatic relief. PEs greater than 200 mL on CT scans were an independent predictor of poor survival in Cox regression modeling (hazard ratio 1.9). CONCLUSIONS: PEs are common in DLBCL and foreshadow a poor prognosis.

ERS/EACTS statement on the management of malignant pleural effusions.

Malignant pleural effusions (MPE) are a common pathology, treated by respiratory physicians and thoracic surgeons alike. In recent years, several well-designed randomised clinical trials have been published that have changed the landscape of MPE management. The European Respiratory Society (ERS) and the European Association for Cardio-Thoracic Surgery (EACTS) established a multidisciplinary collaboration of clinicians with expertise in the management of MPE with the aim of producing a comprehensive review of the scientific literature.Six areas of interest were identified, including the optimum management of symptomatic MPE, management of trapped lung in MPE, management of loculated MPE, prognostic factors in MPE, whether there is a role for oncological therapies prior to intervention for MPE and whether a histological diagnosis is always required in MPE.The literature revealed that talc pleurodesis and indwelling pleural catheters effectively manage the symptoms of MPE. There was limited evidence regarding the management of trapped lung or loculated MPE. The LENT score was identified as a validated tool for predicting survival in MPE, with Brims' prognostic score demonstrating utility in mesothelioma prognostication. There was no evidence to support the use of oncological therapies as an alternative to MPE drainage, and the literature supported the use of tissue biopsy as the gold standard for diagnosis and treatment planning.

Chest imaging for the diagnosis of complicated parapneumonic effusions.

PURPOSE OF REVIEW: To provide an overview of the contribution of thoracic ultrasound (TUS) and computed tomography (CT) in the identification of complicated parapneumonic effusions (CPPE), defined as those which need chest tube drainage for resolution. RECENT FINDINGS: A recent retrospective study found that visualization of complex (nonanechoic) effusions on TUS (likelihood ratio positive = 6.92) outperformed the recognition of loculated/septated effusions on CT (likelihood ratio = 2.20) or chest radiographs (likelihood ratio = 1.54) for predicting a CPPE. In another retrospective study, a weighted CT scoring system consisting of pleural contrast enhancement (three points), pleural microbubbles, increased extrapleural fat attenuation, and fluid volume at least 400 ml (one point each) had relatively good accuracy for labeling CPPE (likelihood ratio positive = 3.4; likelihood ratio negative = 0.22) when four or more points were achieved. SUMMARY: Although a gold standard for CPPE diagnosis is lacking, bedside TUS primarily, and CT scan in certain circumstances, may help to drive clinical decisions regarding chest tube placement in parapneumonic effusions (PPE). However, recommendations are limited by the absence of prospective trials.

Malignant Pleural Effusions: Management Options.

Malignant pleural effusion (MPE) represents advanced metastatic malignancy and is associated with poor median survival. Incidence remains high and continues to rise, in part due to changing population demographics. This therefore represents a significant health care burden. Management is predominantly palliative in nature and multiple interventions are available within conventional treatment paradigms, all of which are proven to result in statistically significant patient benefit. This article further explores the methods available in the management of MPE along with the pitfalls, complications, and alternatives. Recent advances within the field are discussed with an exploration of likely future directions, including the role of ultrasound as a prospective predictor and the role of intrapleural fibrinolytic therapy.

Pleural effusions in acute idiopathic pericarditis and postcardiac injury syndrome.

PURPOSE OF REVIEW: Pleural effusions are frequent in the context of acute idiopathic pericarditis and following pericardiotomy, but they have seldom been characterized. This review summarizes their most relevant clinical features. RECENT FINDINGS: In acute idiopathic pericarditis, pleural effusions tend to be left-sided and, if bilateral, they are usually larger on the left. Less than 5% are unilateral right-sided. About 90% of the effusions occupy less than one-third of the hemithorax, and 99% meet Light's exudative criteria with a predominance of lymphocytes in three fourths of the cases. Although postcardiac injury syndrome (PCIS)-related effusions share similar characteristics, they present some differential features: more than 15% are unilateral on the right (except for Dressler syndrome), one-fourth opacify half or more of the hemithorax, and nearly two thirds are bloody. The combination of nonsteroidal anti-inflammatory drugs and colchicine, along with therapeutic thoracenteses for moderate-to-large effusions, is the mainstay treatment approach. The postoperative use of colchicine is also a reasonable option for preventing PCIS in patients who have undergone cardiac surgery. SUMMARY: Pleural effusions because of pericardial diseases remain a clinical diagnosis. If unilateral right-sided, massive, or transudative effusions are seen, an alternative diagnosis to acute pericarditis should be considered.