Anti-ALK monoclonal antibody, clone 2C3

Background: Deregulated signal transduction pathways play a key role in development, progression and therapeutic resistance of non-small cell lung cancers (NSCLC). The purpose of this study is to assess the downstream markers of two well-characterized pathways and to correlate them with clinical outcome. Design: 670 patients with metastatic NSCLC were prospectively enrolled in a comprehensive biomarker profiling program at a single center from 2012 to 2016. Phosphorylation of extracellular signal-regulated kinase (p-ERK), and protein kinase B (p-AKT) was assessed by standardized immunohistochemistry. Product of scores for quantity and quality of staining were calculated (immunoreactive score, 0-9). Somatic mutations of Kirsten rat sarcoma viral oncogene homolog [KRAS], epithelial growth factor receptor [EGFR], v-Raf murine sarcoma viral oncogene homolog B [BRAF] and phosphatidylinositol 3-kinase [PIK3CA]) were detected by Sanger (2012-03/2015) and amplicon NGS (04/2015-02/2016). Patients enrolled during the first year (2012) were used as discovery cohort. Patients enrolled from 2013 to 02/2016 were used as validation cohort. Clinical data were retrieved from the electronic medical records and were analyzed retrospectively. Results: Using a discovery cohort, we identified an immunoreactive score of p-ERK >= 3 to be prognostically relevant. The validation cohort confirmed that higher levels of p-ERK correlated with worse overall survival (OS) and higher proportion of RAS mutations. Multivariate analysis including established risk factors such EGFR, ALK or ROS mutations and metastatic disease showed a trend of a detrimental effect of high p-ERK on OS (HR 1.23, CI 0.94-1.59, p = 0.131 for p-ERK immunoreactive score >= 3) and time to treatment failure after first-line therapy in the validation cohort. Phosphorylated AKT did not correlate with clinical outcome. Conclusion: While serving as a prognosticator in univariate analysis, highly phosphorylated ERK does not convey a significant prognostic effect for OS in the presence of other prognostic factors. Phosphorylated ERK indicates a higher activity of RAS in advanced NSCLC.

Objective. The aim of this study was to unveil the reciprocal relation of tumor characteristics and inflammation in inflammatory myofibroblastic tumor in the head and neck. Study Design. The study included a retrospective cohort of patients with inflammatory myofibroblastic tumors treated between 2005 and 2017 in a tertiary hospital. Tumor features and inflammation were assessed through the expression of anaplastic lymphoma kinase (ALK), the degree of inflammation and cyclooxygenase-2 (COX-2) expression. The prognostic factors were analyzed for overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analyses. Results. Forty-one patients diagnosed with inflammatory myofibroblastic tumors were followed up, and 41 paraffin sections were obtained. The positive rate of ALK expression was 21 (51.2%) of 41 patients. Nineteen patients had high-grade ALK expression, and 22 patients had low-grade ALK expression. Thirty-nine patients had high-grade inflammation, and 2 had low-grade inflammation. The positive rate of COX-2 expression was 100%. Tumors with both high-grade ALK expression and inflammation had worse DFS (P =.015). The multivariate Cox analysis showed that the grades of ALK expression and inflammation (P =.004) were independent risk factors for DFS. Conclusions. Because of the latent synergistic effects of ALK and inflammation in the tumorigenesis of inflammatory myofibroblastic tumor, the combined therapy of ALK and COX-2 inhibitors shows promise.