Purpose: FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ATPcompetitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR)1-3, in patients with FGFR2-amplified gastric cancer.Experimental Design: Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2.Results: Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI 50 values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents.Conclusion: FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification. Clin Cancer Res; 19(9); 2572-83. Ó2013 AACR.
BACKGROUND: The prognosis of amyopathic dermatomyositis (ADM)-associated interstitial lung disease (ILD) is poor. A mortality risk score model is needed to predict survival in patients with ADM-ILD and to guide clinical treatment. RESEARCH QUESTION: How to identify patients with ADM-ILD who are at high risk and to predict patient outcome based on a risk stratification model? STUDY DESIGN AND METHODS: We evaluated 207 patients with ADM-ILD in this prospective inception study. We used a multivariable Cox proportional hazards model to identify the independent prognostic risk factors and created a risk score model according to patient data from January 2012 to December 2016. We used the index of prediction accuracy that uses the Brier score to reflect both discrimination and calibration of the model. The model was validated in an independent group of patients from January 2017 to June 2018. RESULTS: We developed a combined risk score, the FLAIR score, that included the following values and scores: ferritin (<636 ng/mL, 0; $636 ng/mL, 2), lactate dehydrogenase (<355 U/ L, 0; $355 U/L, 2), antimelanoma differentiation-associated gene 5 antibody (negative, 0; þ, 2; þþ, 3; þþþ, 4), high-resolution CT imaging score (<133, 0; $133, 3), and rapidly progressive ILD (RPILD) (non-RPILD, 0; RPILD, 2). We divided patients into three risk groups according to the FLAIR score: low, 0 to 4; medium, 5 to 9; and high, 10 to 13. In both discovery and validation cohorts, high-risk patients had significantly higher mortality rates than low-and medium-risk patients (P < .001). INTERPRETATION: The FLAIR risk score model could help to predict survival in patients with ADM-ILD and to guide further clinical research on risk-based treatment.
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