Biological toxicities as surrogate markers of efficacy in patients treated with mTOR inhibitors for metastatic renal cell carcinoma.

BACKGROUND: Metabolic toxicities of mTOR inhibitors (mTORi) are well characterized. The purpose of the study was to investigate the relationship between these metabolic toxicities and mTORi efficacy. METHODS: From 2007 to 2011, metabolic toxicities were retrospectively collected in patients treated with an mTORi (everolimus, temsirolimus) for a metastatic renal cell carcinoma (mRCC) in a single institution. Patients were eligible if they have received an mTORi for at least 28 days. Changes in the following parameters were analyzed: lymphocytes, serum creatinine, glycemia, serum phosphate, liver transaminases, cholesterol, and triglycerides. The efficacy was assessed by progression-free survival (PFS) and tumor response. RESULTS: Data were collected from seventy-five patients (everolimus = 44 patients; temsirolimus = 31 patients). Six patients exhibited a partial response, 42 a stable disease and 15 had a progressive disease (12 missing). After a median follow-up of 12.8 months, the median PFS was 6.7 months (95% confidence interval: 4.0-9.1 months). Patients with CB had a statistically more severe absolute increase of glycemia and absolute decrease in phosphatemia (p = 0.002 and p = 0.02 respectively). The Progression Free Survival was significantly higher with the onset rate of hypophosphatemia (p = 0.03) and hyperglycemia (p = 0.001) and lower with the onset rate of lymphopenia (p = 0.004). CONCLUSIONS: Hyperglycemia, hypophosphatemia and lymphopenia, were significantly associated with tumor response and/or PFS. Those events, as well as their onset rate, should be prospectively monitored as predictors of response to mTORi.

Prominent beta-5 gene expression in the cardiovascular system and in the cartilaginous primordiae of the skeleton during mouse development.

The alpha v beta (alpha(v)beta5) heterodimer has been implicated in many biological functions, including angiogenesis. We report the beta5 gene expression pattern in embryonic and foetal mouse tissues as determined by Northern blotting and in situ hybridization. During the earliest stages, beta5 mRNA is widespread in the mesoderm. During later developmental stages, it remains mostly confined to tissues of mesodermal origin, although probable inductive effects trigger shifts of beta5 gene expression from some mesenchymatous to epithelial structures. This was observed in the teeth, skin, kidneys, and gut. Of physiological importance is the beta5 labeling in the developing cardiovascular and respiratory systems and cartilages. Furthermore, early beta5 gene expression was observed within the intra- and extraembryonic sites of hematopoiesis. This suggests a major role for beta5 in the hematopoietic and angiogenic stem cells and thus in the development of the vascular system. Later, the beta5 gene was expressed in endothelial cells of the vessels developing both by angiogenesis and vasculogenesis in the lung, heart, and kidneys. Moreover, the beta5 hybridization signal was detected in developing cartilages but not in ossified or ossifying bones. beta5-Integrin is a key integrin involved in angiogenesis, vasculogenesis, hematopoiesis, and bone formation.