| BACKGROUND Lung cancer is one of the severest malignancies dangerous for human’s health, whose incidence and mortality are both highly increasing in all countries, especially in the latest half century. In2014, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States. Lung cancer mortality only inferior to prostate cancer and breast cancer, and its death rate ranks the top of cancer.Malignant pleural effusion (MPE), the accumulation of pleural fluid due to metastasis of cancer to the pleural space, is a common clinical manifestations of advanced lung cancer with an annual incidence rate of approximately500patients/million in the United States. Most patients with pleural effusions (PE) present with progressive dyspnea, cough, or chest pain that compromises their quality of life. Malignancies account for approximately40%of all pleural effusions; lung cancer is the most common metastatic tumor associated with MPE. In fact, at the time of diagnosis,14%of patients with non-small-cell lung cancer have a pleural effusion, because this cancer disseminates to the pleura, approximately50%will eventually develop a pleural effusion. Whereas, the most common causes of benign pleural effusion (BPE) are tuberculosis and pneumonia. Therapeutic management differs for these two types of effusions; therefore, it is clinically important to differentiate between them rapidly and accurately. Finding malignant cells, in either the pleural fluid by cyto logical examination or in a pleural biopsy, has traditionally been the primary diagnostic method for MPE. However, it is often difficult to find malignant cells in MPE, and because pleural biopsy is an invasive procedure it is not readily accepted by some patients. Although several tumor markers, such as carcinoembryonic antigen (CEA), cancer antigen125(CA-125), and cytokeratin fragment19(CYFRA21-1), can assist the diagnosis of MPE, their specificity and sensitivity are limited. Therefore, new indices that are more accurate are needed. Several factors that participate in the formation of pleural effusion been identified; however, our current understanding of the basic mechanisms by which effusion accumulates within the pleural space is poor. Metastasis of tumor cells into the pleural space may lead to production of large amounts of MPE. In addition, angiogenic factors released by the infiltrated tumor cells or stromal cells play an important role in the development of MPE.Lysophosphatidic acid (LPA) is one of the simplest natural phospholipids and it consists of a single fatty acyl chain, a glycerol backbone and a free phosphate group, and unlike most other phospholipids, it is also water soluble. Although originally known for its rather unglamorous role as an intermediate in intracellular lipid metabolism, LPA is now recognized as an extracellular lipid mediator that evokes growth-factor-like responses in almost every cell type. The first indication that LPA was an important bio active lipid came several decades ago, when it was found to induce smooth-muscle contraction, platelet aggregation and alterations in blood pressure. At this time, LPA was shown to have growth-factor-like activities, to signal through specific cell-surface receptors in a G-protein-dependent manner, and to be a major active constituent of serum. LPA have been detected extracellularly in biological fluids such as serum, saliva, seminal fluid, follicular fluid, hen egg white and ascites from ovarian cancer patients. LPA can be produced by at least two distinct enzymatic mechanisms. LPA can be produced by the sequential removal of a fattyacyl chain from phosphatidic acid by phospholipase A1(PLA1) or phospholipase A2(PLA2), or by the removal of choline from membrane phosphatidylcholine by ATX/lysoPLD (lyso phospholipase D).The excess LPA was degradated into acylglycerol lipase and osphatidie acid by lipid phosphate phosphohydrolases (LPPS). When the balance is broken, there will be a high level of LPA which leads to diseases. Platelets, fibroblasts and tumor cells can generate lysophospholipids acid, combined with serum protein and present in blood circulation. Increasing evidence shows that LPA can stimulate cancer cell proliferation and promote tumor invasion and metastasis and it can anti-apoptosis and regulate tumor angiogenesis. In vitro experiments found that A549lung carcinoma cells express endogenous LPA receptors and that LPA can activate this receptor, enhance the degradation of the p53tumor suppressor and thereby promote cancer cell proliferation and motility. Therefore, LPA also plays an important role in lung cancer. Previous studies reported that malignant effusions contained LPA-like activity, but they primarily evaluated ascites of ovarian cancer patients, and the method for detecting LPA, by the neurite retraction assay, was limited. Most importantly, whether LPA is actually present in MPE and whether there is a significant difference in LPA levels between MPE and BPE remained unknown. Our study will explore the LPA expression level in MPE and BPE, meanwhile we will evaluate the diagnostic and prognostic significance of LPA in MPE.OBJECTIVETo detect LPA of PE in the patients with BPE and patients with MPE caused by lung cancer, and to evaluate the diagnostic value of LPA in differentiating between MPE and BPE and to evaluate the association between the level of LPA in MPE and the prognosis of lung cancer patients. Try to find a new biomarker for the diagnosis of MPE caused by lung cancer and provide a new way for therapy. PATIENTS AND METHODSThis retrospective cohort study included123patients with PE who were hospitalized in the Respiratory Department, Nanjing General Hospital of Nanjing Military Command in China, from September2009through September2013. Written consent was obtained from all the patients who participated in this study. Pleural effusions were collected by routine thoracentesis performed after patients gave written the consent. Samples were centrifuged at1500×g for10min at-4℃. The supernatants were dispensed into1.5mL Eppendorf tubes and were stored at-80℃.In our study, twenty-nine patients (20males and9females; mean age,61.21years) had BPEs, and94had MPEs caused by lung cancer (55males and39females; mean age,63.29years). BPE mainly included tuberculosis PE (TPE) and parapneumonic PE. The diagnostic criteria for TPE were as follows:Identification of M. tuberculosis, pleural biopsy revealing granulomatous tissue and positive response to anti-tuberculosis treatment. Pleural effusions were considered pneumonic if they had the following these characteristics:an acute febrile condition along with cough, yellow sputum, chest CT with pulmonary infiltration, leukocytosis with neutrophilic predominance in the PE and response to antibiotic treatment. The diagnostic criteria for MPE were malignant cells present either in the cytology of the pleural fluid or seen on histopathologic examination of a biopsy specimen of the pleura. Only patients diagnosed with primary malignancies were included; otherwise they were excluded.LPA was determined using a commercial human LPA ELISA Kit (CUSABIO, China; Catalog Number CSB-EQ028005HU).The performance of LPA was analyzed by standard ROC analysis methods, using the area under the curve (AUC) as a measure of accuracy. Overall survival (OS) curves and progression-free survival (PFS) curves were based on the Kaplan-Meier method, and the survival differences between subgroups were analyzed using the log-rank or Breslow test (SPSS software). A multivariate Cox proportional hazards model was used to assess whether LPA independently predicted lung cancer survival. For the above comparisons, P<0.05was considered statistically significant.RESULTSOur study was carried out with123patients (75males and48females; age range,17-83years) with MPE (94) caused by lung cancer or BPE (29) caused by tuberculous pleuritis or pneumonia. There were19patients with TBE and10with pneumonic PE in BPE group. There were no significant differences in gender, age, and smoking history between the MPE and BPE groups (P>0.05). Of the MPE cases,74(78.7%) had adenocarcinoma,12(12.8%) squamous carcinoma and8(8.5%) small cell lung cancer. The MPE cytology results were28(29.8%) positive and66(70.2%) negative.The level of LPA was significantly higher in patients with MPE (22.08±8.72μg/L) than in those with BPE (14.61±5.12μg/L; P=0.000). Subgroup analysis found that the mean levels of LPA in MPEs caused by adenocarcinoma, squamous cell carcinoma and small cell lung carcinoma,22.01±9.28μg/L,20.76±4.65μg/L, and24.75±8.72μg/L, respectively, were not significantly different (P=0.603).We evaluated the relationship between the levels of LPA and gender, age, smoking history, histologic type of tumor, and a positive cytology result. However, no significant associations between LPA concentration and these clinicopathologic factors were found.Using a cutoff point of18.93μg/L, LPA had a sensitivity of60%and a specificity of83%to distinguish MPEs from BPEs with an AUC of0.769±0.045(SE)(P=0.000)(95%CI0.68-0.857). In the three pathological types of lung cancer patients with MPE, there were no significant associations between LPA levels and the length of PFS and OS (P=0.58and P=0.186, respectively). Interestingly, in the patients with MPE caused by lung adenocarcinoma there were significant associations between the LPA levels and the PFS and OS (P=0.018and0.026, respectively). Multivariate analysis showed that the LPA level was an independent prognostic factor for PFS in lung adenocarcinoma.CONCLUSIONOur results indicate that LPA can be used as a new biomarker for the diagnosis of MPE caused by lung cancer and the level of LPA in MPE is inversely related to the length of OS and PFS in lung adenocarcinoma. LPA may contribute to the progression of MPE caused by lung adenocarcinoma. We believe that LPA may be a therapeutic target to reduce or inhibit MPE. Additional studies that are more extensive are needed to understand the role and mechanism of LPA in the formation of MPE. |
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