Efficacy and Safety of Gefitinib as Third-line Treatment in NSCLC Patients With Activating EGFR Mutations Treated With First-line Gefitinib Followed by Second-line Chemotherapy: A Single-Arm, Prospective, Multicenter Phase II Study (RE-CHALLENGE, CTONG1304).

OBJECTIVE: There is no standard care for advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation in the third line. Our study aimed to assess the efficacy and safety of gefitinib as a third-line re-challenge treatment for advanced NSCLC patients with EGFR mutation. MATERIALS AND METHODS: It was a multicenter, open-label, single-arm, phase II study. Stage IIIB/IV NSCLC patients with EGFR exon 19del/L858R mutation, who had benefited from first-line gefitinib treatment followed by second-line chemotherapy, received gefitinib 250 mg/d. The primary objective was disease control rate (DCR) at week 8. RESULTS: Predefined DCR was achieved in 69.8% (95% confidence interval, 49.87-74.91) patients and objective response rate was reported in 4.7% (95% confidence interval, 0.78-13.06) patients. Median progression-free survival (PFS) was 4.4 months and overall survival (OS) was 10.3 months. Baseline T790M-negative patients achieved favorable DCR compared with T790M-positive patients (78.1% vs. 45.5%, P=0.0418), significantly longer median PFS (4.7 vs. 2.0 mo, P=0.0009) and median OS (15.2 vs. 7.7 mo, P=0.0132). We observed a negative correlation of PFS (r=-0.4396, P=0.0032), and OS (r=-0.3630, P=0.0167) with mutation abundance of exon 19del/L858R at baseline. CONCLUSIONS: Re-challenge with gefitinib is effective and could be a choice for third-line patients after the first-line EGFR-TKI treatment and second-line chemotherapy, especially for the T790M-negative patients.

Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non-Small Cell Lung Cancer.

Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood.Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM.Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development.Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209-16. ©2017 AACR.

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.

[Research on automatic external defibrillator based on DSP].

Electrical defibrillation is the most effective way to treat the ventricular tachycardia (VT) and ventricular fibrillation (VF). An automatic external defibrillator based on DSP is introduced in this paper. The whole design consists of the signal collection module, the microprocessor controlingl module, the display module, the defibrillation module and the automatic recognition algorithm for VF and non VF, etc. This automatic external defibrillator has achieved goals such as ECG signal real-time acquisition, ECG wave synchronous display, data delivering to U disk and automatic defibrillate when shockable rhythm appears, etc.