Diagnostic Values Of SVEGFR-1 And Endostatin In Malignant Pleural Effusions In Patients With Lung Cancer

Background: Malignant pleural effusion(MPE)occurs in over 175,000 patients each year,and it is a frequent complication of various malignancies.Lung cancer is the major cause.Approximately 15% of lung cancer patients have an MPE at presentation and an additional 50% develop pleural effusion(PE)later in the process of their disease.MPE also implies an end stage disease and a dismal prognosis with a median survival time of approximately 4-6 months.Therefore,the differentiation of malignant from benign effusions is important for receiving timely treatment and improving prognoses.However,this remains a major clinical challenge.Cytology is the most specific,rapid,and minimally invasive diagnostic method,but it has a sensitivity of only 60%,which is insufficient for clinical needs.Thoracoscopy achieves a diagnosis with approximately 95% accuracy,but it may not be adoptable in all hospitals.Moreover,it is often too invasive for patients in poor physical condition.Recently,with the development of molecular biology in cancer,especially in the mechanism of tumor angiogenesis,tumor markers are widely used for the identification of PE.Therefore,we should identify new and less invasive biomarkers for the differentiation of MPE.Angiogenesis plays a principal role in the formation of MPE and is regulated by the quantity of angiogenic cytokines and anti-angiogenic cytokines.Many known angiogenic cytokines,including VEGF and matrix metalloproteinase-9,are present in the pleural fluid and may serve as diagnostic and prognostic biomarkers for MPE.The relative levels of anti-angiogenic cytokines,such as sVEGFR-1 and endostatin in PE,have been performed in only a few researches.To our knowledge,this is the first study focused on these two anti-angiogenic cytokines(sVEGFR-1 and endostatin)in pleural fluid to evaluate the diagnostic value of MPE and the possible links between them.A VEGF-specific tyrosine kinase receptor,VEGFR-1,is an intermediary of angiogenesis in malignancy and is involved in cancer growth and metastasis.A soluble form of VEGFR-1(sVEGFR-1)has been detected in the circulation.sVEGFR-1 is a critical inhibitor of VEGF activity and thus plays a key role in tumor angiogenesis as an endogenous anti-angiogenic cytokine.Clinical observations have demonstrated that the pleural levels of sVEGFR-1 might be helpful for MPE diagnosis.Endostatin is characterized as an efficient endogenously produced inhibitor of angiogenesis and is closely related with malignancies occurrence and development,invasion and metastasis.Serum endostatin levels have widely been evaluated in malignancies;however,only a few studies have investigated why pleural endostatin levels are elevated in MPE and may contribute to its diagnosis.Objective:1.To determine the concentration of sVEGFR-1 and endostatin in pleural effusion,and analyze whether there is statistical difference between the two groups in MPE and BPE.2.To assess the diagnostic value of sVEGFR-1 and endostatin in lung cancer combined with MPE according to the ROC operating(receiver characteristic curve).3.to analyze whether there is correlation between sVEGFR-1,endostatin and the laboratory parameters of pleural effusions.4.In this study,we further compared the concentration levels of sVEGFR-1 and endostatin in bloody pleural effusions and non-bloody pleural effusions.Methods: Between April 2014 and November 2016,effusion samples from 44 patients with MPE caused by lung cancer and from 36 patients with benign pleural effusion(BPE)were collected in our institute.The detailed clinical information of the patients were collected and analysis processing.Fresh PE samples were obtained by diagnostic thoracentesis before any treatment and the supernatants were immediately frozen at -80oC until the enzyme-linked immunosorbent assay(ELISA)was performed.The concentrations of sVEGFR-1 and endostatin in pleural fluid were determined by ELISA.The diagnostic performance was analyzed by receiver operating characteristic curves(ROCs).Results: 1.The detection of sVEGFR-1 and endostatin in pleural effusion: The levels of sVEGFR-1 and endostatin in MPE due to lung cancer were significantly higher than those in BPE(p <0.05).2.Diagnostic value of sVEGFR-1 and endostatin in MPE: The sensitivity and specificity of endostatin were 52.27% and 86.11%,respectively,while for sVEGFR-1,the sensitivity was 88.64% and the specificity was 58.33%.Interestingly,the combination of sVEGFR-1 and endostatin produced better sensitivity and specificity of 72.73% and 83.33%,respectively.3.The correlation between sVEGFR-1,endostatin and laboratory parameters of pleural effusion: there is a positive correlation between endostatin and sVEGFR-1 in pleural effusion.The level of endostatin was positively correlated with RBC.The levels of sVEGFR-1 and endostatin in pleural effusion were negatively correlated with ADA levels.4.The expression of sVEGFR-1 and endostatin in bloody and non-bloody pleural effusion: Pleural fluid endostatin concentrations in bloody effusions were significantly higher than those in non-bloody effusions(p < 0.05).However,the sVEGFR-1 levels showed no significant difference between bloody effusions and non-bloody effusions(p > 0.05)Conclusion: Pleural fluid sVEGFR-1 and endostatin showed higher levels in MPE due to lung cancer than in BPE,indicating that high pleural levels are suggestive of MPE.The combined detection of sVEGFR-1 and endostatin had better sensitivity and specificity and may be effective biological markers for diagnosis of MPE.In addition,Pleural fluid endostatin concentrations in bloody effusions were significantly higher than those in non-bloody effusions.However,the sVEGFR-1 levels showed no significant difference between bloody effusions and non-bloody effusions.Furthermore,there is a significant correlation between sVEGFR-1 and endostatin concentrations in pleural effusions.These findings may be important to clarify the role of anti-angiogenic cytokines in pleural effusions and merit further investigation.Background: Pleural effusion is a common and frequently occurring disease.The etiology of pleural effusion is complicated and can be caused by a variety of malignant or benign diseases.Traditionally,pleural effusion can be divided into extravasation and exudate according to the Light’s standard,extravasation pleural effusion can be secondary to heart failure,nephrotic syndrome or cirrhosis and so on.The most common causes of exudation are malignant tumors,tuberculosis,followed by pulmonary infection.MPE implies an end stage disease and a dismal prognosis with a median survival time of approximately 4-6 months.Therefore,the diagnosis of pleural effusion is important for the improvement of prognosis.However,it still a great challenge for clinicians.The diagnosis of pleural effusion is a stepwise clinical diagnosis and treatment process.Cytological is the most common and rapid methods for MPE diagnosis,but its sensitivity is only 60%.It is relatively difficult to diagnosis TPE by routine clinical diagnostic method,Sensitivity of pleural fluid smear for acid-fast bacilli is very low,only 0-1%.Pleural biopsies have been demonstrated to be helpful for the diagnosis of TPE,but the sensitivity is less than 45%.Approximately 15–20% of all pleural effusions remain undiagnosed after thoracentesis and or pleural biopsy.Surgical thoracoscopy,namely video-assisted thoracoscopic surgery(VATS)achieves a diagnostic sensitivity with approximately 90%-95%,but it should be carried out by a thoracic surgeon in the operation room under general anesthesia,Moreover,it is often too invasive.Therefore,a minimally invasive,effective method to the diagnosis of pleural effusion,has become the urgent need to solve.Unlike VATS,MT is a less invasive and safer endoscopic procedure that is performed by a Pulmonologist under local anaesthesia through a single port.Thoracoscopy permits large biopsy under direct visualisation that increases the diagnostic yield.It has been proven that MT is highly sensitive and safe for diagnosing and treatment of pleural diseases.The sensitivity of the diagnosis of pleural effusion ranges from 92% to 97% and specificity from 99% to 100% has become the “gold standard” for the diagnosis of pleural effusion of unknown origin.It has now become an excellent tool for the diagnostic and therapeutic exploration of pleural cavity in pleural effusions of undetermined aetiology when routine procedures have failed.MT has become a routine endoscopic procedure for respiratory physicians after bronchoscopy.Objective: 1.To investigate the value of MT in the diagnosis of patients with undiagnosed pleural effusions of and to analyze the etiological distribution of pleural effusion diagnosed by MT.2.To review and summarize the morphological features of pleural diseases of different pathological types under MT and improve its tecognition.3.To analyze the complications,safety and efficacy of MT procedures,and evaluate the clinical value of MT in the diagnosis of pleural effusion.4.To analyze the sensitivity,specificity and accuracy of pleural CEA in the diagnosis of MPE,and the diagnostic value of MPE in adenocarcinoma.Methods: 1.Between February 2015 and July 2017,82 patients of undiagnosed pleural effusions who underwent semi-rigid MT in our Institute(Department of cadre of respiratory and critical care of respiratory and critical care West ward)were included in the present study.According to the pathological results of thoracoscopy,the 77 diagnosed patients were divided into MPE group and BPE group,the relevant clinical indexes were calculated and the differences between the groups were compared.We further evaluated the diagnostic value of pleural fluid CEA in MPE.2.The characteristics of patients and pleural fluid are presented as the mean ± standard deviation(SD).The differences between MPE and BPE were analyzed using an independent Student’s t-test for measurement data and the χ2 test for numeration data.P <0.05 were considered statistically significant.Results: The pathological diagnosis in patients who had undergone MT: in the 82 patients of pleural effusion,77 patients were diagnosed by MT examination,so the diagnostic rate of MT was 93.9%.MT revealed MPE in 32 patients(39.02%)and BPE in 45 patients(54.88%),the most common pathological type of MPE was adenocarcinoma in 22 patients,followed by small cell carcinoma(5 patients),squamous cell carcinoma(3 patients)and pleural mesothelioma(2 patients).The most frequent cause of BPE is TPE(41 patients),followed by inflammatory pleural effusion(4 patients),5 patients still unable to achieve definite diagnoses.Characteristics of the study population: a total of 82 patients were enrolled,including 61 male patients(74.4%)and 21 female patients(25.6%),with an average age of 54.26 + 1.60 years.The difference of gender and clinical symptoms between the MPE and BPE groups was not statistically significant(both p > 0.05).The age of patients with MPE was significantly higher than that of patients with BPE(p < 0.001).The percentage of smokers in lung cancer patients with MPE appeared higher in comparison to patients with BPE.(p < 0.05),and the bloody pleural effusion in MPE was more common than that in BPE(p < 0.05).The Morphological features under MT : MPE showed that multiple or single nodule,a cauliflower like nodules,extensive white pleural plaques,congestion and erosion.The view appearance of TPE in pleura was diffuse military nodules,single or multiple pleural nodules,necrosis,cellulose adhesion obviously.While inflammatory pleural effusion under the thoracoscopy can be seen no abnormalities or local congestion and edema and cord-like adhesive bands.Complications of thoracoscopy: in this study,no serious complications were observed,minor complications observed in 28 patients(34.15%)that include intraoperative or postoperative chest pain(22 patients),mild subcutaneous emphysema(4 patients)and fever(2 patients).The diagnosis value of pleural CEA: Pleural CEA gave a diagnostic sensitivity of 65.63% and specificity of 97.78% in MPE,while had a better sensitivity and specificity of 86.36% and 92.73% of MPE in adenocarcinoma.Conclusion: MT has important clinical value in the diagnosis of pleural effusion,When the routine examinations cannot identify the pathogenesis of pleural effusion,the thoracoscopy should be applied.In this study,diagnostic yield of MT is high(93.7%).Among undiagnosed pleural the most common causes are MPE and TPE.MT is a safe,minimally invasive with small trauma and minor complications.Thus,it is worthy being popularized and applied in respiratory medicine.In addition,the pleural fluid CEA level can be used as an important tumor marker to aid the diagnosis of MPE,especially in adenocarcinoma.