Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Epstein-Barr Virus Infections/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Neoplasms, Multiple Primary/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biopsy , Bone Marrow/pathology , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methylation/drug effects , DNA Methyltransferase 3A , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Dioxygenases , Epigenesis, Genetic/drug effects , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/virology , Gene Expression Regulation, Neoplastic/drug effects , Herpesvirus 4, Human/isolation & purification , Humans , Leukemia, Myelomonocytic, Chronic/diagnosis , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/virology , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/virology , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/drug therapy , Neoplasms, Multiple Primary/virology , Positron-Emission Tomography , Proto-Oncogene Proteins/genetics , Treatment OutcomeABSTRACT
BACKGROUND: BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man. CASE PRESENTATION: While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation. CONCLUSION: These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.
Subject(s)
Indoles/adverse effects , MAP Kinase Signaling System/drug effects , Pneumonia/chemically induced , Protein Kinase Inhibitors/adverse effects , Pyridones/adverse effects , Pyrimidinones/adverse effects , Sulfonamides/adverse effects , Bronchoalveolar Lavage Fluid/cytology , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , Male , Melanoma/drug therapy , Middle Aged , Pneumonia/diagnosis , Pneumonia/metabolism , Recurrence , Tomography, X-Ray Computed , VemurafenibABSTRACT
INTRODUCTION: Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging. OBJECTIVE: To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma. METHODS: K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors. RESULTS: In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001). CONCLUSION: MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer.
