Citations

Background— Although older patients frequently undergo percutaneous coronary interventions (PCI), frailty, comorbidity, and quality of life are seldom part of risk prediction approaches. We assessed their incremental prognostic value over and above the risk factors in the Mayo Clinic risk score. Methods and Results— Patients ≥65 years who underwent PCI were assessed for frailty (Fried criteria), comorbidity (Charlson index), and quality of life [SF-36]. Of the 628 discharged [median follow-up of 35.0 months (interquartile range, 22.7 to 42.9)], 78 died and 72 had a myocardial infarction (MI). Three-year mortality was 28% for frail patients, 6% for nonfrail patients. The respective 3-year rates of death or MI were 41% and 17%. After adjustment, frailty [hazard ratio (HR), 4.19 [95% confidence interval (CI), 1.85, 9.51], physical component score of the SF-36 (HR, 1.59; 95% CI, 1.24 to 2.02), and comorbidity, (HR, 1.10; 95% CI, 1.05, 1.16) were associated with mortality. Frailty was associated with mortality/MI (HR, 2.61, 1.52, 4.50). Models with conventional Mayo Clinic risk score had C-statistics of 0.628, 0.573 for mortality and mortality/MI, respectively. Adding frailty, quality of life, and comorbidity, the C-statistic was (0.675, 0.694, 0.671) for mortality and (0.607, 0.587, 0.576) for mortality/MI, respectively. Including frailty, comorbidities and SF-36, conferred a discernible improvement to predict death and death/MI (integrated discrimination improvement, 0.027 and 0.016, and net reclassification improvement of 43% and 18%, respectively). Conclusions— After PCI, frailty, comorbidity and poor quality of life are prevalent and are associated with adverse long-term outcomes. Their inclusion improves the discriminatory ability of the Mayo Clinic risk score derived from the routine cardiovascular risk factors.

Discoveries over the past decade suggest that castration-resistant prostate cancer (CRPC) is sensitive, but not resistant to, further manipulation of the androgen–androgen receptor (AR) axis. Several new therapies that target this axis have demonstrated clinical activity. In this article, preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed. Reviews of scientific and clinical development are divided into those occurring prereceptor (androgen production and conversion) and at the level of the receptor (AR aberrations and therapies targeting AR directly). Intracrine androgen production and AR amplification, among others, are among the principal aberrancies driving CRPC growth. Phase III data with abiraterone acetate and phase II data with MDV-3100, along with other similar therapies, confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease. Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way. The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling, even in the castrate state.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Abstract Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients. Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells. Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells. Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801–11. ©2011 AACR.

Background: Cortical spreading depression (CSD) is a wave of depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex. CSD is believed to be the underlying mechanism of aura in migraine; however, whether CSD can elicit pain associated with migraine headache is unclear. Methods: Awake, freely moving rats were monitored for both CSD events and behavioral responses resulting from dural-cortical pinprick and/or KCl injection to the occipital cortex. Results: We observed tactile allodynia of the face and hindpaws, as well as enhanced Fos expression within the trigeminal nucleus caudalis (TNC) following CSD induced by KCl injection into the cortex, but not by pinprick. Application of KCl onto the dura elicited cutaneous allodynia and increased Fos staining in the TNC but did not elicit CSD events. Conclusions: These data suggest that sustained activation of trigeminal afferents that may be required to establish cutaneous allodynia may not occur following CSD events in normal animals.