Signaling protein signature predicts clinical outcome of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application. METHODS: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort. RESULTS: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018). CONCLUSIONS: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

Role of circulating tumor DNA in the management of early-stage lung cancer.

Lung cancer is one of the most common cancers and the predominant cause of cancer-related death in the world. The low accuracy of early detection techniques and high risk of relapse greatly contribute to poor prognosis. An accurate clinical tool that can assist in diagnosis and surveillance is urgently needed. Circulating tumor DNA (ctDNA) is free DNA shed from tumor cells and isolated from peripheral blood. The genomic profiles of ctDNA have been shown to closely match those of the corresponding tumors. With the development of approaches with high sensitivity and specificity, ctDNA plays a vital role in the management of lung cancer as a result of its reproducible, non-invasive, and easy-to-obtain characteristics. However, most previous studies have focused on advanced lung cancer. Few studies have investigated ctDNA in the early stages of the disease. In this review, we focus on ctDNA obtained from patients in the early stage of lung cancer, provide a summary of the related literature to date, and describe the main approaches to ctDNA and the clinical applications.

Shp2 regulates migratory behavior and response to EGFR-TKIs through ERK1/2 pathway activation in non-small cell lung cancer cells.

In the clinical treatment of lung cancer, therapy failure is mainly caused by cancer metastasis and drug resistance. Here, we investigated whether the tyrosine phosphatase Shp2 is involved in the development of metastasis and drug resistance in non-small cell lung cancer (NSCLC). Shp2 was overexpressed in a subset of lung cancer tissues, and Shp2 knockdown in lung cancer cells inhibited cell proliferation and migration, downregulated c-Myc and fibronectin expression, and upregulated E-cadherin expression. In H1975 cells, which carry double mutations (L858R + T790M) in epidermal growth factor receptor (EGFR) that confers resistance toward the tyrosine kinase inhibitor gefitinib, Shp2 knockdown increased cellular sensitivity to gefitinib; conversely, in H292 cells, which express wild-type EGFR and are sensitive to gefitinib, Shp2 overexpression increased cellular resistance to gefitinib. Moreover, by overexpressing Shp2 or using U0126, a small-molecule inhibitor of extracellular signal-regulated kinase 1/2 (ERK1/2), we demonstrated that Shp2 inhibited E-cadherin expression and enhanced the expression of fibronectin and c-Myc through activation of the ERK1/2 pathway. Our findings reveal that Shp2 is overexpressed in clinical samples of NSCLC and that Shp2 knockdown reduces the proliferation and migration of lung cancer cells, and further suggest that co-inhibition of EGFR and Shp2 is an effective approach for overcoming EGFR T790M mutation acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Thus, we propose that Shp2 could serve as a new biomarker in the treatment of NSCLC.

Circulating Tumor DNA Detection in Early-Stage Non-Small Cell Lung Cancer Patients by Targeted Sequencing.

Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC.

Diagnostic value of endobronchial ultrasound guided transbronchial needle aspiration in superior vena cava syndrome.

BACKGROUND: The pathological diagnosis is of critical importance to the subsequent treatment for the pathients with superior vena cava syndrome (SVCS). The aim of this study is to report our experience in the diagnosis of SVCS by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). METHODS: The data of 520 patients who underwent EBUS-TBNA from September 2009 to May 2012 at our institution were reviewed. Of these, there were 14 males and 6 females (mean age of 59.1 years) with SVCS who received EBUS-TBNA that were included in the analysis. RESULTS: The mean short axis diameter of the paratracheal lesions was (3.32 ± 1.79) cm (range, 1.69 to 9.50 cm) and 6 cases also had subcarinal lymph node enlargement with a mean short axis diameter of (2.14 ± 0.49) cm (range, 1.73 to 3.01 cm). An average of 4.3 punctures was performed per lesion. Malignancy was confirmed in 16 cases (10 small cell carcinomas, 4 adenocarcinomas, 1 squamous cell carcinoma and 1 Hodgkin lymphoma). In two patients, pathological examination of tissue revealed no evidence of malignancy and for 13 to 24 months of follow-up. One patient from whom adequate tissue was not obtained refused further surgical biopsy since he had undergone endovascular stenting of the SVC. One patient in whom a diagnosis was not obtained by EBUS-TBNA underwent thoracoscopic biopsy and the final diagnosis was B cell non-Hodgkin's lymphoma. The diagnosis accuracy of EBUS-TBNA in SVCS was 18/20 patients. CONCLUSION: EBUS-TBNA is a highly effective and safe procedure for the diagnosis of SVCS.

Tolerability and toxicity of adjuvant cisplatin and gemcitabine for treating non-small cell lung cancer.

BACKGROUND: The combination of cisplatin and vinorelbine is an evidence-supported regimen for adjuvant chemotherapy for treating non-small cell lung cancer (NSCLC). But this doublet has considerable toxicity and unfavorable tolerability, and results in poor compliance. The cisplatin and gemcitabine regimen is one of the most active and well-tolerated regimens against advanced NSCLC, but its toxicity and tolerability has not been adequately evaluated in the adjuvant setting. METHODS: From a lung cancer database we retrospectively reviewed NSCLC patients receiving adjuvant chemotherapy of cisplatin (75 mg/m(2)) and gemcitabine (1250 mg/m(2)) between January 2005 and December 2011. Postoperative demographics, compliance to adjuvant therapy and toxicity were retrieved from medical records. RESULTS: A total of 132 patients met the criteria and were included in the study, 96 were male (72.7%) and 36 were female (27.3%). Median age was 60.5 years old, range 29 - 75 years, and 41.7% of patients were ≥ 65 years old. Overall, 68.2% patients received all four planned cycles, and the cumulative dose delivered for gemcitabine was 8333 mg (83.3% of the planned dose) and cisplatin 248 mg (82.7% of the planned dose). There were no treatment-related deaths. Grade 3/4 neutropenia developed in 47 patients (35.6%) and was the predominant hematologic toxicity. Common grade 3/4 non-hematologic toxicities were nausea/vomiting (22.0%), infection (12.3%), and febrile neutropenia (11.4%). CONCLUSION: Cisplatin and gemcitabine are feasible for use in the adjuvant setting with a favorable toxicity profile and superior tolerability compared with published data on cisplatin and vinorelbine.

[Application of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of isolated mediastinal lesions].

OBJECTIVE: To evaluate the role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of isolated mediastinal lesions. METHODS: A retrospective study was conducted of 73 consecutive patients with isolated mediastinal lesions of unknown origin without parenchymal lung abnormalities, who underwent EBUS-TBNA from September 2009 to April 2011. The patients who were nondiagnostic with EBUS-TBNA subsequently underwent surgical biopsies and a minimum of 6 months'clinical and radiologic follow-up. RESULTS: EBUS-TBNA achieved definitive diagnoses in 60 patients of the 73 patients (82.2%, 60/73). Malignancies were diagnosed in 23 patients and benignancies in 37. The sensitivity, specificity, and accuracy of EBUS-TBNA in distinguishing malignant mediastinal lesions were 95.8%(23/24), 100%(49/49) and 98.6%(72/73), respectively. EBUS was well tolerated by all of the patients with no complications. CONCLUSION: EBUS-TBNA of isolated mediastinal lesions is a minimally invasive and safe diagnostic technique with high yield.

Development and validation of a clinical prediction model to estimate the probability of malignancy in solitary pulmonary nodules in Chinese people.

INTRODUCTION: This study evaluated the clinical factors affecting the probability of malignancy of solitary pulmonary nodules (SPNs) using multivariate logistic regression analysis. A clinical prediction model was subsequently developed to estimate the probability of malignancy. This model was then validated. METHODS: Medical records from 371 patients (197 men, 174 women) with a pathologic diagnosis of SPN made between January 2000 and September 2009, were reviewed. Clinical data were collected to estimate the independent predictors of malignancy of SPN with multivariate analysis. A clinical prediction model was subsequently created. Between October 2009 and March 2010, data from an additional 62 patients with a pathologic diagnosis of SPN were used to validate this clinical prediction model. The model was also compared with two previously described models. RESULTS: Median patient age was 57.1 years old. Fifty-three percent of the nodules were malignant and 46% were benign. Logistic regression analysis identified six clinical characteristics (age, diameter, border, calcification, spiculation, and family history of tumor) as independent predictors of malignancy in patients with SPN. The area under the receiver operating characteristic (ROC) curve for our model (0.89; 50% confidence interval [CI], 0.78-0.99) was higher than those generated using another two reported models. In our model, sensitivity was 92.5%, specificity was 81.8%,positive predictive value was 90.2%, and negative predictive value was 85.7%). CONCLUSIONS: Age of the patient, diameter, border, calcification, spiculation, and family history of tumors were independent predictors of malignancy in patients with SPN. Our prediction model was more accurate than the two existing models and was sufficient to estimate malignancy in patients with SPN.

[Establishment of a mathematical prediction model to evaluate the probability of malignancy or benign in patients with solitary pulmonary nodules].

OBJECTIVE: To evaluate the clinical factors affecting the definite pathological diagnosis of solitary pulmonary nodules (SPN) with multivariate Logistic regression analysis, and to build the clinical prediction model to estimate the probability of malignancy. METHODS: A retrospective cohort study in our institution included 371 patients (197 males and 174 females) with definite pathological diagnosis of solitary pulmonary nodules from Jan 2000 to Sep 2009 (group A). Clinical data included age, gender, course of disease, symptoms, history and quantity of smoking history, history of tumor, family history of tumor, site, diameter, calcification, speculation, border, lobulation, traction of pleural, vascular convergence sign, and cavity. The independent predictors of malignancy were estimated with multivariate analysis, then the clinical prediction model was built. Other 62 SPN patients (group B) with definite pathological diagnosis in our institute from Oct 2009 to Mar 2010, were used to validate value of this clinical prediction model. RESULTS: 53.1% of the nodules were malignant, and 46.9% were benign in goup A. Logistic regression analysis showed that seven clinical characteristics [age of patient (OR: 1.073), diameter (OR: 1.966), border (OR: 0.245), calcification (OR: 0.199), spiculation (OR: 2.088) and the family history of tumor (OR: 3.550)] were independent predictors of malignancy in patients with SPN (P<0.05). The cut-off value was 0.463. The sensitivity in group B was 92.5%, specificity 81.8%, positive predictive value 90.2%, and negative predictive value 85.7%. The area under the ROC curve for our model was 0.888±0.054. CONCLUSION: Age of patient, diameter, border, calcification, spiculation and the family history of tumor are independent predictors of malignancy in patients with SPN. Our prediction model is accurate and sufficient to estimate the malignancy of patients with SPN.

Application of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of mediastinal lesions.

BACKGROUND: Mediastinal lesions are often difficult to diagnose in clinical practice because of the unique anatomical position of the mediastinum, which makes performance of biopsy difficult. The value of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lung cancer and mediastinal lymph node staging has been widely accepted. However, few studies have been conducted on the value of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis and differential diagnosis of mediastinal lesions. The current study was conducted to investigate the value of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis and differential diagnosis of isolated mediastinal lesions without lung abnormalities. METHODS: We retrospectively analyzed the data of patients with isolated mediastinal lesions without lung abnormalities for whom endobronchial ultrasound-guided transbronchial needle aspiration examination was performed at the Department of Thoracic Surgery of Peking University People's Hospital, between September 2009 and December 2010. For patients who could not be diagnosed with endobronchial ultrasound-guided transbronchial needle aspiration, surgical biopsy or more than 6 months of clinical and imaging follow-up was carried out. RESULTS: Endobronchial ultrasound-guided transbronchial needle aspiration was performed for 60 patients with isolated mediastinal lesions. Correct diagnosis was made in 48 cases. Nineteen cases were malignant, and 29 were benign. The rate of correct diagnosis was 80%. The sensitivity, specificity, and accuracy of endobronchial ultrasound-guided transbronchial needle aspiration in distinguishing benign from malignant mediastinal lesions were 95%, 100%, and 98%, respectively. The examination was tolerable for all patients. No associated complications were observed. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration is a safe and effective method of diagnosing mediastinal lesions.