ABSTRACT
OBJECTIVES: Tumor mutation screening is standard of care for patients with stage IV NSCLC. Since a couple of years, widespread NGS approaches used in routine diagnostics to detect driver mutations such as EGFR, KRAS, BRAF or MET allows the identification of other alterations that could modulated the intensity or duration of response to targeted therapies. The prevalence of co-occurring alterations that could affect response or prognosis as not been largely analyzed in clinical settings and large cohorts of patients. Thanks to the IFCT program "Biomarkers France", a collection of samples and data at a nation-wide level was available to test the impact of co-mutations on first line EGFR TKI in patients with EGFR mutated cancers. MATERIALS AND METHODS: Targeted NGS was assessed on available (n = 208) samples using the Ion AmpliSeq™ Cancer Hotspot Panel v2 to screen for mutations in 50 different cancer genes. RESULTS: This study showed that PTEN inactivating mutations, ATM alterations, IDH1 mutations and complex EGFR mutations were predictors of short PFS in patients with a stage 4 lung adenocarcinoma receiving first line EGFR TKI and that PTEN, ATM, IDH1 and KRAS mutations as well as alterations in the MAPK pathway were related to shorter OS. CONCLUSION: These findings may lead to new treatment options in patients with unfavorable genotypes to optimize first line responses.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Protein Kinase Inhibitors , Ataxia Telangiectasia Mutated Proteins , Biomarkers , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , France/epidemiology , Humans , Isocitrate Dehydrogenase , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , PTEN Phosphohydrolase , Protein Kinase Inhibitors/therapeutic useABSTRACT
Basement membrane collagens or derived fragments are measured in biological fluids such as blood and urine of patients and appear to be useful for diagnosis, prognostication, or treatment monitoring as proposed for endostatin, a fragment of collagen XVIII, or tumstatin, a fragment of collagen IV. Tetrastatin, the NC1 alpha 4 collagen IV domain, was previously reported to inhibit tumor growth and angiogenesis. The aim of this study was to develop and validate a method to measure tetrastatin concentrations in human fluids. We developed a competitive enzyme-linked immunosorbent assay (ELISA). It allowed measuring tetrastatin levels in human serum, bronchial aspiration and bronchoalveolar lavage fluids, and lung tissue extracts. The tetrastatin level was significantly higher in tumor tissues than in healthy lung tissues. Tetrastatin competitive ELISA could be useful to quantify tetrastatin in tissues and biological fluids for the diagnosis or prognostication of diseases in which basement membrane metabolism may be altered, especially tumor progression.
Subject(s)
Collagen Type IV/analysis , Collagen Type IV/blood , Enzyme-Linked Immunosorbent Assay/methods , Lung Neoplasms/blood , Lung Neoplasms/diagnosis , Lung/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Bronchoalveolar Lavage Fluid/chemistry , Child , Female , Humans , Lung/chemistry , Lung Neoplasms/pathology , Male , Middle Aged , Protein Structure, Tertiary , Young AdultABSTRACT
Type XIX collagen is a minor collagen associated with basement membranes in vascular, neuronal, mesenchymal, and epithelial tissues. We demonstrated that the NC1, C-terminal, domain of collagen XIX inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Other basement membrane collagens or derived fragments were measured in biological fluids such as blood and urine of patients and appeared to be useful for diagnosis, prognosis, or treatment monitoring. The aim of this study was to develop and validate methods to measure collagen XIX and its fragments in human cell cultures, tissue extracts, and human biological fluids. For that purpose, we developed real-time PCR, Western blot, and competitive enzyme-linked immunosorbent assays. We demonstrated that the methods developed in this paper are specific for collagen XIX. We showed that it is expressed in human cell cultures, tissue extracts, and various biological fluids. These methods may be used in various human tissue extracts and biological fluids such as serum, amniotic fluid, cord blood, and many other fluids. Collagen XIX or its fragments could constitute new biomarkers for human diseases as well as for diagnosis and/or prognosis.
Subject(s)
Body Fluids/chemistry , Collagen/classification , Collagen/metabolism , Epithelial Cells/metabolism , Fibroblasts/metabolism , Tissue Extracts/chemistry , Cell Line , Collagen/chemistry , Enzyme-Linked Immunosorbent Assay , Epithelial Cells/chemistry , Fibroblasts/chemistry , Gene Expression Regulation/physiology , Humans , Osteosarcoma/chemistry , Osteosarcoma/metabolismABSTRACT
Polypropyleneimines (PPIs) functionalized by glycerol-based entities are prepared and characterized by diffusion-ordered spectroscopy NMR. Showing low cytotoxicity against MRC5 fibroblasts, their encapsulation capacities of gadolinium complexes was evaluated. T(1) measurements were performed to determine the relaxivity of the encapsulated gadopentetate dimeglumine (GdBOPTA) in dendrimers of fourth and fifth generation (GD-PPI-4 and GD-PPI-5). Comparison of the GdBOPTA relaxivity and the relaxivity of GdBOPTA-loaded dendrimers showed a slight increase of the gadolinium chelate relaxivity.
