Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometroid and serous papillary endometrial cancer cell lines

Endometrial cancer is the most widespread gynecological cancer in Western countries and constitutes a major public health issue. The role of the insulin-like growth factor (IGF) system in endometrial biology as well as in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged in recent years as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to specifically abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR downstream signaling pathways. The aim of the present study was to investigate the potential anti-proliferative activities of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines. Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated (ECC-1, Ishikawa, USPC-1, USPC-2), whereas it abolished AKT and ERK phosphorylation in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a significant decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor. In summary, our results suggest that specific IGF-IR inhibition by NVP-AEW541 is a promising therapeutic tool in endometrial cancer

Utility of Geriatric Assessment in the Projection of Early Mortality Following Hip Fracture in the Elderly Patients

Hip fractures result in significant morbidity and mortality in elders. Indicators of frailty are associated with poor outcomes. Commonly used frailty tools rely on motor skills that cannot be performed by this population. We determined the association between the Charlson Comorbidity Score (CCS), intraoperative hypotension (IOH), and a geriatric medicine consult index (GCI) with short-term mortality in hip fracture patients. A retrospective cohort study was conducted at a single institution over a 2-year period. Patients aged 65 years and older who sustained a hip fracture following a low-energy mechanism were identified using billing records and our orthopedic fracture registry. Medical records were reviewed to collect demographic data, fracture classification and operative records, calculation of CCS, intraoperative details including hypotension, and assessments recorded in the geriatric consult notes. The GCI was calculated using 30 dichotomous variables contained within the geriatric consult note. The index, ranging from 0 to 1, included markers for physical and cognitive function, as well as medications. A higher GCI score indicated more markers for frailty. One hundred eight patients met inclusion criteria. Sixty-four (59%) were females and the average age was 77.3 years. Thirty-five (32%) patients sustained femoral neck fractures, and 73 (68%) patients sustained inter-/pertrochanteric hip fractures. The 30-day mortality was 6%; the 90-day mortality was 13%. The mean GCI was 0.30 in the 30-day survivor group as compared to 0.52 in those who died. The mean GCI was 0.28 in patients who were alive at 90 days as compared to 0.46 in those who died. In contrast, the CCS and IOH were not associated with 30- or 90-day mortality. In our older hip fracture patients, an index calculated from information routinely obtained in the geriatric consult evaluation was associated with 30- and 90-day mortality, whereas the CCS and measures of IOH were not