Prognostic value of the dynamics of M-type phospholipase A2 receptor antibody titers in patients with idiopathic membranous nephropathy treated with two different immunosuppression regimens.

CONTEXT: The dynamics of anti-phospholipase A2 antibody titers during treatment could predict clinical responses in patients with membranous nephropathy. OBJECTIVES: We analyzed the predictive value of the dynamics of these antibodies on clinical responses. MATERIALS AND METHODS: The serum antibody levels were measured before and during treatment in 79 patients with anti-phospholipase A2 receptor antibody membranous nephropathy treated with two different immunosuppression regimens RESULTS: In both groups of patients, the relative reduction in antibody titers at 3 and 6 months preceded and predicted the clinical responses. CONCLUSIONS: Antibody titer dynamics was useful for predicting clinical responses.

Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma.

Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic ß-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non-Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.