HER-2/neu expression as a predictor of response to neoadjuvant docetaxel in patients with operable breast carcinoma

BACKGROUND: The use of biologic markers to predict response to neoadjuvant chemotherapy may permit tailoring regimens to achieve maximal tumor response. Taxanes have demonstrated excellent activity in breast carcinoma; however, tumor-specific factors that predict clinical response have not been characterized thoroughly. METHODS: The authors performed a historic review evaluating the association of tumor prognostic factors and response to neoadjuvant cyclophosphamide and doxorubicin (AC) with or without docetaxel (D) (AC vs. AC+D) in 121 women who previously were enrolled in a Phase III, randomized, clinical trial. Using pretreatment biopsy materials, immunohistochemical studies were performed for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, p53, and Ki-67. Outcome variables were pathologic complete response (pCR) and positive clinical response (cPOS), which was defined as a >/= 50% regression in clinical tumor size prior to surgery. RESULTS: In a multivariate analysis that controlled for tumor size and lymph node status, improved cPOS rates were observed with the addition of docetaxel in women with HER-2/neu-negative tumors (81% vs. 51%; P < 0.05), yielding an adjusted odds ratio of 3.5 (95% confidence interval, 1.2-13.0) in favor of docetaxel. Women who had HER-2/neu-negative tumors appeared to have a lower response rate with AC alone compared with women who had HER-2/neu-positive tumors (51% vs. 75%; P = 0.06), but response rates were matched when docetaxel was added (81% vs. 78%; P = 0.99). ER, PR, p53, and Ki-67 results were not associated significantly with response rates. CONCLUSIONS: HER-2/neu status may predict improved clinical response rates from the addition of docetaxel to anthracycline-based neoadjuvant chemotherapy. Docetaxel may "rescue" the response in women who have HER-2/neu-negative tumors to match that observed in women who have HER-2/neu-positive tumors treated with AC alone.     

Bailout use of platelet glycoprotein IIb-IIIa inhibition during coronary stent implantation: observations from the ESPRIT trial

Glycoprotein (GP) IIb/IIIa inhibitors are often used as a rescue or bailout therapy to manage complications arising during percutaneous coronary intervention, rather than as prophylactic treatment. We sought to identify the characteristics and outcomes of patients requiring bailout treatment. The ESPRIT trial randomized 2,064 patients to receive eptifibatide or placebo starting immediately before percutaneous coronary intervention (PCI). Bailout therapy was used in 77 patients: 43 (4.2%) randomized to placebo and 34 (3.3%) to eptifibatide (p = 0.3). Bailout therapy for thrombosis was used more often in the placebo group (2.1% versus 1.0%; p = 0.03). Multivariable predictors of bailout included a greater than or equal to 90% stenosis, or visible thrombus on the baseline angiogram, and no aspirin pre-treatment before PCI. However, overall the model predicted bailout poorly (c-index = 0.64). The need for bailout cannot be reliably predicted using baseline characteristics. Patients experiencing complications have poor clinical outcomes despite bailout use of GP IIb/IIIa inhibitors.     

The impact of the accident at the Three Mile Island on the behavior and well-being of nuclear workers: Part II: job tension, psychophysiological symptoms, and indices of distress.

TMI workers experienced much greater job tension and lower occupational self-esteem (supervisors only). At the time of the accident, TMI workers reported experiencing more periods of anger, extreme worry and extreme upset, and more psychophysiological symptoms. Six months after the accident, some persistence of these feelings and symptoms was evident. Demoralization was greater primarily among TMI non-supervisory workers. The impact of the accident was not greater among TMI workers living closer to the plant. Presence of a preschool child at home enhanced the impact of the accident, but primarily among TMI supervisors.     

Observations on the ultrastructure of human urothelium: The response of normal bladder of elderly subjects to hyperthermia

Summary An electron microscopic study of normal bladder urothelium of elderly subjects treated by hyperthermic perfusions has shown that the tissue responds, sooner or later, in every instance by desquamation. There is no evidence of cell death prior to desquamation although various organelles undergo structural alterations. Mitochondria are especially prone to suffer varying degrees of damage. A short heat shock has revealed differences in the initial response of the thick and thin regions of bladder urothelium known to occur in elderly subjects. After a long, fractionated treatment, regeneration is evident within 3 daysof the end of treatment, and follow-up biopsies have revealed a hyperplastic urothelium within 10 to 12 weeks. The constituent cells show signs of cytodifferentiation at this time but it remains unknown when an ultrastructurally normal urothelium with characteristic cell layers will be restored. The various treatments in this study suggest that the stem cells in the epithelium are unaffected by the levels of hyperthermia employed and that their unimpaired proliferative capacity ensures regeneration of the urothelium.     

Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated upregulation of p27

Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 microM) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 microM) or geranylgeranyl pyrophosphate (5 microM) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H2O2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H2O2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.     

Reducing the global burden of hazardous alcohol use: a comparative cost-effectiveness analysis

OBJECTIVE: Intervention strategies are available for reducing the high global burden of hazardous alcohol use as a risk factor for disease, but little is known about their potential costs and effects at a population level. This study set out to estimate these costs and effects. METHOD: Analyses were carried out for 12 epidemiological World Health Organization subregions of the world. A population model was used to estimate the impact of evidence-based personal and nonpersonal interventions--including brief physician advice, taxation, roadside random breath testing, restricted sales access and advertising bans. Costs were measured in international dollars (I$); population-level intervention effects were gauged in terms of disability-adjusted life years (DALYs) averted. Average and incremental cost-effectiveness ratios (CERs) were computed. RESULTS: The most costly interventions to implement are brief advice in primary care and roadside breath testing of drivers. In populations with a high prevalence of heavy drinkers (more than 5%, such as Europe and North America), the most effective and cost-effective intervention was taxation (more than 500 DALYs averted per 1 million population; CER < I$500 per DALY averted). In populations with a lower prevalence of heavy drinking, however, taxation is estimated to be less cost effective overall than other, more targeted strategies, such as brief physician advice, roadside breath testing and advertising bans. CONCLUSIONS: The most efficient public health response to the burden of alcohol use depends on the prevalence of hazardous alcohol use, which is related to overall per capita consumption. Population-wide measures, such as taxation, are expected to represent the most cost-effective response in populations with moderate or high levels of drinking, whereas more targeted strategies are indicated in populations with lower rates of hazardous alcohol use.