Citations

Abstract Purpose: Molecular characterization of Philadelphia chromosome–negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor β TKs, and is active against cells carrying the mutant KIT-D816V gene. Experimental Design: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph− myeloid disorders, including SM (n = 33; 28 KIT-D816V positive). Results: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. Conclusion: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.

Abstract Aim: To examine the use of complementary and alternative medicine (CAM) by women with varying levels of familial and perceived risk of breast cancer with the goal of preventing breast cancer. Methods: Cross-sectional data on CAM use were collected on 2,198 women (mean age, 63 years) personally unaffected by breast cancer in the Minnesota Breast Cancer Family Study. CAM use was compared across women at high, moderate, or average risk based on family history, as well as across categories of perceived risk of breast cancer. CAM use was also examined in relation to screening and general health behaviors, worry about breast cancer, and optimism. Results: Half (49.5%) of the women reported using at least one CAM modality with the intent of preventing breast cancer. Univariate analyses indicated that greater overall CAM use was related to greater perceived risk (P = 0.018), more general health behaviors (P < 0.0001), more breast cancer screening behaviors (P = 0.0002), greater optimism (P = 0.0002), and higher educational attainment (P < 0.0001). Multivariate analysis revealed that general health behaviors (P < 0.0001), education (P = 0.0027), and optimism (P = 0.037) were significant predictors of CAM use when in the same model with perceived risk and breast cancer screening behaviors. Conclusions: Many women use CAM with the goal of preventing breast cancer. General health-promoting behaviors, education, and optimism predict CAM use. Evidence-based guidance is needed for the public and health care providers on the potential and limitations of specific CAM approaches to affect cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1527–34)

Objective: Mother-daughter communication may be a potential pathway between family history and cancer prevention behavior. We examined the degree to which mothers reported providing advice on breast cancer prevention to their daughters, the content of such advice, and correlates of providing such advice. Methods: Data were collected via a mailed questionnaire to 1773 women from 355 families in the Minnesota Breast Cancer Family Study. Women were asked whether or not they had provided advice to their daughters on what they should do to prevent breast cancer. An additional open-ended question asked them to describe the types of advice they had provided. Results: Nine hundred seventy-six (55%) of the women reported providing breast cancer prevention advice to their daughters. The most frequent types of advice were to have a mammogram (51%), perform breast self-examination (BSE) (39%), have a clinical breast examination (CBE) (30%), and maintain a healthy lifestyle (21%). From multivariate logistic regression, older age ( p < 0.001), having a personal history of breast cancer ( p < 0.001), higher degree of breast cancer worry/concern ( p < 0.001), engaging in a higher number of health-promoting behaviors ( p < 0.001), and ever performing a BSE ( p = 0.04) were factors independently associated with the provision of advice. Analyses accounting for sample nonindependence did not change our results. Conclusions: Breast cancer prevention behaviors were associated with providing advice. By better understanding the pathways through which breast cancer family history is associated with screening mammography and other prevention behaviors, researchers can develop more effective, tailored prevention interventions at the family level.

Background— Outflow tract ventricular tachycardia originating above the semilunar valves has been reported in a small number of studies. Discrete potentials in the great arteries (above the semilunar valves) have been rarely described in patients undergoing electrophysiology evaluation and radiofrequency ablation for ventricular arrhythmias. The mechanisms of these discrete potentials in the great arteries and the utility of such potentials in guiding radiofrequency ablation are unknown. Methods and Results— Twelve patients with outflow tract ventricular arrhythmia originating above the semilunar valves with discrete arterial potentials were studied. The clinical characteristics, properties of the arterial potentials, electrophysiological evaluation and ablation, and short- and long-term outcomes were reviewed. Of the twelve patients, 8 (67%) were women. The patients’ average age was 41�14 years. The average ejection fraction was 0.52�0.16 (range: 0.16 to 0.75). Contact mapping in the great artery demonstrated discrete near-field electrograms that were separate from far-field ventricular electrograms in all patients (8 above the pulmonary valve and in 4 the aortic valve). One or more of the following electrophysiological characteristics, supportive of an arrhythmogenic substrate, were observed in 10 of 12 patients: (1) A fixed or reproducibly variable pattern of discrete potential–ventricular arrhythmia relationship was present at baseline or during pacing; (2) the discrete potential–ventricular electrogram relationship during sinus rhythm was the reverse of that during the ventricular arrhythmia; (3) during sustained ventricular tachycardia, spontaneous variation of the ventricular (V-V) cycle length was preceded by a similar variation of arterial spike potential–spike potential cycle length; and (4) ablation guided by the discrete arterial potential successfully eliminated the clinical arrhythmia. Ablation was successful in these patients. In the remaining 2 patients, the potentials were believed to be bystanders. Over 10�4 months (range: 5 to 32 months) of follow-up, there have been no recurrences of the premature ventricular complex or ventricular arrhythmia. Conclusions— Discrete potentials are present in the great arteries of a select group of patients with outflow tract ventricular tachycardia originating above the semilunar valves. When an arrhythmogenic relationship can be demonstrated, discrete potentials are useful in guiding ablation within the great vessels, despite significant anatomic complexity.

Abstract The estrogen receptors (ER) α and β are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGFβ-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ERβ, but not ERα. We have identified the regulatory elements utilized by ERβ and have demonstrated that ERβ recruits steroid receptor coactivator (SRC)1 and SRC2 to this regulatory region. Additionally, deletion of the ERβ-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ERβ is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ERβ. Overall, these data demonstrate that the estrogen induction of TIEG is ERβ specific and that the AF1 domain of ERβ confers this specificity. Finally, a novel and important role for ERβ’s AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.