Gadobutrol in Renally Impaired Patients: Results of the GRIP Study.

OBJECTIVE: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF). MATERIALS AND METHODS: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. RESULTS: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF. CONCLUSIONS: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases

Dysregulated Gab1 signalling in triple negative breast cancer

Abstract Background Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is especially aggressive and associated with high metastasis. The aetiology of TNBC is heterogeneous and characterised by multiple different mutations that amongst others cause constitutive and dysregulated MAPK and PI3K signalling. Additionally, in more than 50% of TNBC patients, the epidermal growth factor receptor (EGFR) is overexpressed and constitutively active. The multi-site docking protein Grb2-associated binder 1 (Gab1) is a central signalling hub that connects MAPK and PI3K signalling. Methods Expression and activation of members of the Gab1/PI3K/MAPK signalling network were assessed in cells from different breast cancer subtypes. Influence of short- and long-term inhibition of EGFR, MAPK and PI3K on the activation of the Gab1/PI3K/MAPK signalling network as well as on cell viability, proliferation and migration was determined. Additionally, cellular localisation of Gab1 and Gab1 variants in naive cells and cells treated with the above-mentioned inhibitors was investigated. Results We show that, activation of the Gab1/PI3K/MAPK signalling network is heterogeneous between different breast cancer subtypes. Gab1 phosphorylation and plasma membrane recruitment of Gab1 are dysregulated in the EGFRhigh TNBC cell line MDA-MB-468. While the Gab1/MAPK/PI3K signalling network follows canonical Gab1 signalling in naive MDA-MB-468 cells, Gab1 signalling is changed in cells that acquired resistance towards MAPK and PI3K inhibition. In resistant cells, Gab1 is not located at the plasma membrane despite strong activation of PI3K and MAPK. Furthermore, Gab1 tyrosine phosphorylation is uncoupled from plasma membrane recruitment. Conclusion Our study indicates that Gab1 signalling changes fundamentally during the acquisition of resistance to pharmacological inhibitors. Given the molecular heterogeneity between breast cancer subtypes, the detailed understanding of dysregulated and aberrant signalling is an absolute necessity in order to develop personalised therapies for patients with TNBC

Gadobutrol in Renally Impaired Patients

Objective: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF). Materials and Methods: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. Results: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF. Conclusions: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases