Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development.

We investigated the significance of PI3K/AKT/mTOR pathway and its interactions with MAPK, JAK/STAT and Notch pathways in meningioma progression. Paraffin-embedded tissue from 108 meningioma patients was analysed for the presence of mutations in PIK3CA and AKT1. These were correlated with the expression status of components of the PI3K/AKT/mTOR pathway, including p85α and p110γ subunits of PI3K, phosphorylated (p)-AKT, p-mTOR, p-p70S6K and p-4E-BP1, as well as of p-ERK1/2, p-STAT3 and Notch-1, clinicopathological data and patient survival. A mutation in PIK3CA or AKT1 was found in around 9 % of the cases. Higher grade meningiomas displayed higher nuclear expression of p-p70S6K; higher nuclear and cytoplasmic expression of p-4E-BP1 and of Notch-1; lower cytoplasmic expression of p85αPI3K, p-p70S6K and p-ERK1/2; and lower PTEN Histo-scores (H-scores). PTEN H-score was inversely correlated with recurrence probability. In univariate survival analysis, nuclear expression of p-4E-BP1 and absence of p-ERK1/2 expression portended adverse prognosis, whereas in multivariate survival analysis, p-ERK1/2 expression emerged as an independent favourable prognostic factor. Treatment of the human meningioma cell line HBL-52 with the PI3K inhibitor LY294002 resulted in reduction of p-AKT, p-p70S6K and p-ERK1/2 protein levels. The complex interactions established between components of the PI3K/AKT/mTOR pathway, or with components of the MAPK, JAK/STAT and Notch-1 pathways, appear to be essential for facilitating and fuelling meningioma progression.

Mortality in diabetic and nondiabetic patients after amputations performed from 1996 to 2005 in a tertiary hospital population: a 3-year follow-up study.

AIMS: Diabetes is the leading cause of lower-extremity amputations worldwide. The objective of this study was to look at the survival after first amputation between subjects with and without diabetes in a sample of Greek population. METHOD: We performed a retrospective study of all nontrauma, nonneoplasm-related amputations performed in a tertiary centre during the years 1996-2005 in diabetic (n=183) and nondiabetic patients (n=75). Survival status was assessed from the first amputation until December 31, 2005. RESULTS: A total of 54.6% of amputees with diabetes and 51.6% of those without diabetes died in a mean [95% confidence interval (CI)] time of 4.3 (3.5-5.1) and 6.6 (4.6-8.6) years after the first amputation, respectively (P=.65). Diabetic patients underwent a second amputation (P=.003) and contralateral amputations (P=.02) more often in comparison with nondiabetic subjects. Predictors of all-cause mortality in the diabetic group, after adjustment for sex, were age [hazard ratio (HR) (95% CI), 1.04 (1.02-1.06); P<.001] and the level of amputation (major vs. minor) [HR, 1.55 (1.00-2.40), P=.05]. The respective values in the nondiabetic patients were HR of 1.06 (1.03-1.08; P<.001) and HR of 3.12 (1.27-7.64; P=.01). Median length of hospital stay was comparable between the two groups. CONCLUSION: Mortality rates after amputation were high in both patients with and without diabetes. Older age and a higher level of amputation were associated with poorer survival. Diabetic patients more often underwent a second amputation to the same and the contralateral limb. Additionally, mortality rates, length of hospital stay, and perioperative mortality were not different between patients with and without diabetes.