Yizhuo Zhao

Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis.

STUDY OBJECTIVES Recently, less invasive methods have emerged as potential alternatives for staging with tissue confirmation of suspected metastatic mediastinal lymph nodes in lung cancer. The objective of this review was to assess the overall diagnostic accuracy of EBUS-TBNA in detecting metastatic mediastinal lymph node in lung cancer with a meta-analysis. METHODS The MEDLINE, EMBASE, Cancerlit and Cochrane Library database, from January 1995 to September 2008, were searched for studies evaluating EBUS-TBNA accuracy. Meta-analysis methods were used to pool sensitivity and specificity and to construct summary receiver-operating characteristic. RESULTS A total of 11 studies with 1299 patients, who fulfilled all of the inclusion criteria, were considered for the analysis. No publication bias was found. EBUS-TBNA had a pooled sensitivity of 0.93 (95% CI, 0.91-0.94) and a pooled specificity of 1.00 (95% CI, 0.99-1.00). The subgroup of patients who were selected on the basis of CT or PET positive results had higher pooled sensitivity (0.94, 95% CI 0.93-0.96) than the subgroup of patients without any selection of CT or PET (0.76, 95% CI 0.65-0.85) (p<0.05). Study sensitivity was not correlated with the prevalence of lymph node metastasis. Only two complications occurred (0.15%). CONCLUSION EBUS-TBNA was an accurate, safe and cost-effective tool in lung cancer staging. The selection of patients who had positive results of suspected lymph node metastasis in CT or PET may improve the sensitivity of EBUS-TBNA. High-quality prospective studies regarding EBUS-TBNA in lung cancer staging are still needed to be conducted.

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

Capture-based next-generation sequencing (NGS) is a potentially useful diagnostic method to measure tumor tissue DNA in blood as it can identify concordant mutations between cell-free DNA (cfDNA) and primary tumor DNA in lung cancer patients. In this study, the sensitivity, specificity and accuracy of capture-based NGS for detecting ALK fusion in plasma cfDNA was assessed. 24 patients with tissue ALK-positivity and 15 who did not harbor ALK fusion were enrolled. 13 ALK-positive samples were identified by capture-based NGS among the 24 samples with tissue ALK-positivity. In addition to EML4-ALK, 2 rare fusion types (FAM179A-ALK and COL25A1-ALK) were also identified. The overall sensitivity, specificity and accuracy for all cases were 54.2%, 100% and 71.8%, respectively. For patients without distant metastasis (M0-M1a) and patients with distant metastasis (M1b), the sensitivities were 28.6% and 64.7%, respectively. In the 15 patients who received crizotinib, the estimated median PFS was 9.93 months. Thus, captured-based NGS has acceptable sensitivity and excellent specificity for the detection of ALK fusion in plasma cfDNA, especially for patients with distant metastasis. This non-invasive method is clinically feasible for detecting ALK fusion in patients with advanced-stage NSCLC who cannot undergo traumatic examinations or have insufficient tissue samples for molecular tests.

Is there a progression-free survival benefit of first-line crizotinib versus standard chemotherapy and second-line crizotinib in ALK-positive advanced lung adenocarcinoma? A retrospective study of Chinese patients

Although crizotinib has demonstrated promising efficacy and acceptable toxicity in patients with advanced non‐small cell lung cancer (NSCLC), the available evidence in Chinese populations is currently limited. This study compared the progression‐free survival (PFS) of Chinese patients with anaplastic lymphoma kinase (ALK)‐positive, advanced lung adenocarcinoma who received first‐line crizotinib therapy with that of patients who received first‐line standard chemotherapy, and also the PFS benefit of first‐line versus second‐line crizotinib treatment. Data on 80 patients with ALK‐positive, advanced lung adenocarcinoma who received crizotinib or standard chemotherapy as first‐line treatments between June 2013 and December 2014 were retrospectively collected; 26 of the patients received crizotinib as second‐line therapy after progressive disease (PD) occurred on first‐line chemotherapy. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The median PFS was 13.3 months (95% CI: 6.5–20.0 months) in patients who received first‐line crizotinib as compared with 5.4 months (95% CI: 4.4–6.5 months) in patients who received first‐line standard chemotherapy (adjusted hazard ratio for progression or death with crizotinib, 0.20; 95% CI: 0.11–0.36; P < 0.001). In patients who received second‐line crizotinib therapy, the median PFS was 9.9 months (95% CI: 6.4–13.4 months). The difference between first‐line and second‐line crizotinib treatment was not statistically significant (adjusted hazard ratio for progression, 0.56; 95% CI: 0.29–1.11; P = 0.092). Thus, there was a significant PFS benefit of first‐line crizotinib versus first‐line standard chemotherapy in Chinese patients with ALK‐positive lung adenocarcinoma. Additionally, crizotinib showed promising efficacy in patients who received it as second‐line therapy after PD had occurred on first‐line chemotherapy.

G4-Tetra DNA Duplex Induce Lung Cancer Cell Apoptosis in A549 Cells

The specific DNA is typically impermeable to the plasma membrane due to its natural characters, but DNA tetra structures (DTNs) can be readily uptake by cells in the absence of transfection agents, providing a new strategy to deliver DNA drugs. In this research, the delivery efficiency of tetrahedral DNA nanostructures was measured on adenocarcinomic human alveolar basal epithelial (A549) cells via delivering AS1411 (G4). The DNA tetra-AS1411 complex was rapidly and abundantly uptake by A549 cells, and the induced apoptosis was enhanced. Furthermore, biodistribution in mouse proved the rapid clearance from non-targeted organs in vivo. This study improved the understanding of potential function in DNA-based drug delivery and proved that DTNs-AS1411 could be potentially useful for the treatment of lung cancer.

The evaluation of efficacy and safety of sunitinib on EGFR‐TKI pretreated advanced non‐small cell lung cancer patients in China

Sunitinib is an oral multitargeted tyrosine kinase inhibitor (TKI) exhibiting antiagiogenic and antitumor effects.

Clinical outcomes of patients with metachronous second primary lung adenocarcinomas

Background The incidence of adenocarcinomas as multiple primary lung cancers (MPLCs) is increasing. How to determine the treatment strategies of MPLCs, especially second primary lung adenocarcinomas (SPLACs), and the prognostic factors associated with it are unclear. Methods The clinical records of patients undergoing surgery for second adenocarcinomas based on Martini–Melamed criteria between 2001 and 2014 were retrospectively reviewed. Survival rates were calculated by the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis was conducted using the Cox proportional hazards model. Results A total of 115 patients with SPLACs were identified based on Martini–Melamed criteria. With respect to the second resections, three subgroups with low- (adenocarcinoma in situ, n=6; minimally invasive adenocarcinoma, n=19), intermediate- (lepidic, n=9; acinar, n=40; papillary, n=23), and high-grades (solid, n=9; micropapillary, n=2; invasive mucinous, n=7) were assigned. The 5-year overall survival (OS) rates from the time of the first and the second resections were 86.5% and 69.5%, respectively. Cox multivariate analysis identified computed tomography (CT) morphology of SPLACs (ground glass opacity predominant versus solid predominant; hazard ratio [HR]=0.42; P=0.036), histologic classification (same/similar vs different; HR=0.06; P<0.001), pathologic stage of the primary (stage I vs II; HR=0.20; P=0.015) and second tumors (stage I vs IIIa; HR=0.21; P=0.002), and histologic grade of SPLACs (low- vs high-grade, HR=0.05, P=0.016; intermediate- vs high-grade, HR=0.37, P=0.027) as significantly favorable prognostic factors for OS. Conclusion In addition to pathologic stage of the initial tumors and histologic classification, pathologic stage and CT morphology of SPLACs were identified as predictors of survival. The histologic grade of SPLACs based on the new adenocarcinoma classification could provide additional prognostic information.

[The Clinical Analysis of 21 Patients with Lymphoepithelioma-like Carcinoma after Operation.].

BACKGROUND Lung lymphoepithelioma-like carcinoma is a rare subtype of large cell carcinomas of the lung. The aim of this study is to retrospectively analyze the clinical characteristics, surgical methods, laboratory inspection, chemotherapy, radiotherapy and prognosis of LELC. METHODS From 2004 to 2008, clinical data were collected from 21 patients who were treated in Shanghai Chest Hospital. The correlation between clinicopathological characteristics and prognosis was evaluated. RESULTS Of the 21 patients, 15 patients had lobectomy; 4 patients had wedge resection; 1 patient had pneumonectomy and 1 patient had sleeve resection. 12 patients received chemotherapy and 3 patients received radiotherapy after operation. Until 2009-4-31, 4 patients died, and the median survival time (MST) was 49 months. CONCLUSIONS Lymphoepitheliomalike carcinoma of the lung is a very rare and unique subtype of large cell carcinomas of the lung, which has a better prognosis with surgical, chemotherapy and radiotherapy.

Dynamics of EGFR mutations in plasma recapitulates the clinical response to EGFR-TKIs in NSCLC patients

Objectives Genomic profiling using plasma cell-free DNA (cfDNA) represents a non-invasive alternative to tumor re-biopsy, which is challenging in clinical practice. The feasibility of dynamically monitoring epidermal growth factor receptor (EGFR) mutation status using serial plasma samples from non-small cell lung cancer (NSCLC) patients treated by tyrosine kinase inhibitors (TKIs) and its application in tracking clinical response and detection of resistance were investigated. Patients and methods Forty-five NSCLC patients with EGFR mutation-positive pre-TKI plasma and at least two post-TKI plasma collections were recruited to this study. EGFR mutations including L858R, exon 19 deletion (19-del) and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples. Results We observed a significant reduction in plasma EGFR mutation abundance during the first two-month of TKI treatment. Acquiring of secondary T790M gatekeeper mutation or completed “loss” of EGFR mutations represented two major categories of resistance profiles. Moreover, we demonstrated that levels of plasma EGFR mutations highly correlated with changes of tumor diameter as determined by radiographic imaging, or development of new lesions. In a subset of patients, we further showed that reappearance of EGFR mutations could be detected in plasma up to 5 months ahead of progressive disease (PD), suggesting an early detection of drug resistance. Conclusions Our findings suggest that genomic analysis using plasma cfDNA may offer an effective approach to monitor clinical response and emergence of resistance.

Use of SuperARMS EGFR Mutation Detection Kit to Detect EGFR in Plasma Cell-free DNA of Patients With Lung Adenocarcinoma

Micro‐Abstract We assessed the performance of SuperARMS for the detection of EGFR mutations using plasma cell‐free DNA in 180 patients with advanced lung adenocarcinoma in the present study. SuperARMS and ARMS‐based methods have shown highly concordant results. SuperARMS can identify more mutation sites than ARMS. SuperARMS is a promising method for the clinical detection of EGFR mutations, especially for patients with insufficient biopsy samples. Background The SuperARMS EGFR Mutation Detection Kit (SuperARMS) is highly selective and sensitive and able to detect 41 of the most common somatic mutations in exons 18 to 21 of the epidermal growth factor receptor gene (EGFR). It allows for the detection of 0.2% to 0.8% mutant DNA in a background of 99.8% to 99.2% normal DNA. The present study assessed the performance of SuperARMS in detecting EGFR mutations in cell‐free DNA (cfDNA) samples derived from plasma in patients with advanced lung adenocarcinoma. Materials and Methods A total of 180 patients with advanced clinical stage lung adenocarcinoma were retrospectively registered. The concordance between the EGFR mutations detected by SuperARMS and ARMS (AmoyDx EGFR 29 Mutations Detection Kit) was analyzed. Results Of the 180 samples, 57 (31.7%) were positive for EGFR mutations using SuperARMS, with 38 (21.1%) positive using ARMS. For the entire cohort, the positive, negative, and overall concordance rates were 97.3% (95% confidence interval [CI], 86.2%‐99.5%), 85.3% (95% CI, 78.6%‐90.2%), and 87.8% (95% CI, 82.2%‐91.8%), respectively. The kappa value was 0.69 (95% CI, 0.57‐0.81). For the 61 treatment‐naive patients and 119 previously treated patients, the kappa values were 0.59 (95% CI, 0.37‐0.79) and 0.74 (95% CI, 0.60‐0.87), respectively. SuperARMS identified 9 samples harboring the T790M mutation; of these, only 1 (11.1%) was detected using ARMS. Conclusion SuperARMS is a promising plasma‐based assay for EGFR mutations, including T790M. It might be useful in advanced‐stage lung adenocarcinoma patients whose tissue biopsy samples are insufficient for a traditional diagnostic EGFR assay or for patients with a poor performance status.