Incidence and risk factors of peripheral arterial occlusive disease in a prospective cohort of 700 adult elderly men followed for 5 years.

OBJECTIVE: This study was designed to assess the incidence of peripheral arterial occlusive disease (PAOD) in a population-based cohort of men aged 55-74 years and to establish a predictive function based on risk factors for the disease. METHODS: This was a prospective study of 699 men representative of an urban population. Cardiovascular risk factors, history of cardiovascular events, and ankle-brachial index (ABI) at baseline and at 5 years were measured. PAOD was defined as a confirmed ABI <0.9. RESULTS: A total of 468 (67%) subjects could be evaluated at 5 years. In the remaining 233 subjects, 94 had PAOD at baseline, 66 died during the study, and 73 were lost to follow-up. At the end of the 5-year study period, 56 (12%) subjects developed PAOD (21.4% ABI <0.6, 78.6% ABI between 0.61 and 0.9). Independent predictors for PAOD were age older than 70 years at baseline (odds ratio [OR] 2.5, P = 0.004), smoking history more than 40 pack-year (OR = 2.27, P = 0.007), history of cerebrovascular disease (OR = 3.49, P = 0.02), and symptomatic coronary disease (OR = 3.36, P = 0.004). The 5-year incidence of PAOD was 22.4% for subjects older than 70 years, 21.5% for heavy smokers, 29.4% for those with previous cerebrovascular events, and 25% for subjects with ischemic heart disease. The risk for PAOD in subjects without risk factors was 6%. CONCLUSIONS: Twelve percent of adult men aged between aged 55 and 74 years developed PAOD during a follow-up of 5 years. Besides subjects with history of cardiovascular disease, men older than aged 70 years and heavy smokers constituted a high-risk group for PAOD and, therefore, the object of directed efforts of primary prevention.

Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma.

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including MK2206, RAD001, BEZ235, MLN0128, and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 × 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK-targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 downregulated and dephosphorylated the cell-cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. In vivo data on tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as a radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients. Mol Cancer Ther; 17(2); 347-54. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."