Citations

BackgroundA substantial body of evidence collected from epidemiologic, correlative, and experimental studies strongly associates atherosclerotic vascular disease (AVD) with Alzheimer's disease (AD). Depending on the precise interrelationship between AVD and AD, systematic application of interventions used to maintain vascular health and function as a component of standard AD therapy offers the prospect of mitigating the presently inexorable course of dementia. To assess this hypothesis, it is vital to rigorously establish the measures of AVD that are most strongly associated with an AD diagnosis.MethodsA precise neuropathological diagnosis was established for all subjects, using a battery of genetic, clinical, and histological methods. The severity of atherosclerosis in the circle of Willis was quantified by direct digitized measurement of arterial occlusion in postmortem specimens and was compared between AD and nondemented control groups by calculating a corresponding index of occlusion.ResultsAtherosclerotic occlusion of the circle of Willis arteries was more extensive in the AD group than in the nondemented control group. Statistically significant differences were also observed between control and AD groups with regard to Braak stage, total plaque score, total neurofibrillary tangle score, total white matter rarefaction score, brain weight, Mini‐Mental State Examination scores, and apolipoprotein E allelic frequencies.ConclusionsOur results, combined with a consideration of the multifaceted effects of impaired cerebral circulation, suggest an immediate need for prospective clinical trials to assess the efficacy of AD prevention using antiatherosclerotic agents.

Abstract In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Abstract Background. Breast density assessed from mammography is a strong predictor of breast cancer risk, but the strength of the association may vary with adiposity. To examine effect modification by adiposity, we combined data from four case-control studies on breast density that represented an ethnically diverse population with a wide variation in level of adiposity as measured by body mass index (BMI, kg/m2). Methods. We combined data from four case-control studies representing different locations: California, Hawaii and Minnesota in the United States, and Gifu in Japan. All studies included incident breast cancer cases diagnosed between 1994 and 2002 and matched controls representing the underlying case population. One mammographic image per subject was selected, specifically the mammogram at diagnosis for the studies from California, Minnesota, and Japan and the closest prediagnostic mammogram for Hawaii. Percent density was measured by one reader, who was blinded to case status, using a computer-assisted method. Self-reported anthropometric measures were used to classify women as normal, overweight, and obese according to ethnic-specific BMI cut points (<23, 23-27.4, and ≥27.5 for Asian women and <25, 25-29.9, and ≥30 for other ethnic groups). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) and to evaluate interactions using the likelihood ratio while adjusting for potential confounders, including age and ethnicity. Heterogeneity across studies was marginally significant as assessed by examining density-by-study interaction (P = 0.09) and, therefore, we also adjusted for study-site. Results. The study included 1,699 cases and 2,422 controls of diverse ethnicity: 45% Caucasian, 40% Asian, 9% African-American, and 7% Other. Of these women, we classified 34% as overweight and19% as obese. Age-adjusted mean percent density was significantly greater for cases than for controls: 31.7% versus 28.9%, respectively (P < 0.001). BMI was inversely associated with breast density; the estimated age-adjusted mean percent density was 36.5%, 26.8%, and 19.3% for normal, overweight, and obese, respectively (Ptrend < 0.001). The overall OR for a 10% higher percent density was 1.15 (95% CI: 1.05, 1.18) with higher estimates in overweight (OR: 1.19, 95% CI: 1.09, 1.29) and obese (OR: 1.25, 95% CI: 1.11, 1.41) than normal BMI (OR: 1.11, 95% CI: 1.05, 1.18). The effect modification by BMI was statistically significant (Pinteraction = 0.01). Conclusions. Our findings confirm that the elevated risk of breast cancer associated with breast density differs by level of adiposity, with a higher risk for overweight and obese than normal BMI. Further research is needed to understand the underlying biological reasons for these noted differences in association by adiposity. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B25.

Background— Patients with diabetes mellitus have accelerated progression of heart failure and often have impaired cardiac sympathetic innervation. The present study examines the implications for heart failure progression of cardiac sympathetic denervation, assessed by I-123 metaiodobenzylguanidine imaging, in diabetic compared with nondiabetic subjects. Methods and Results— We evaluated 343 diabetic and 618 nondiabetic subjects with New York Heart Association class II or III heart failure and a left ventricular ejection fraction ≤35% over a median follow-up of 17 months. A multivariable Cox proportional hazards model was used to examine the influence of clinical variables, b-type natriuretic peptide, plasma norepinephrine, left ventricular ejection fraction, and I-123 metaiodobenzylguanidine imaging parameters on time to a heart failure event. The late heart-to-mediastinum (H/M) ratio and the interaction term of diabetes mellitus with the prospectively selected late H/M ratio <1.6 were independent predictors of heart failure progression, providing incremental prognostic information beyond that available from all other variables. In diabetic subjects, late H/M ratio <1.6 was associated with a 2.99-fold greater 2-year rate of heart failure progression (33.5%) than late H/M ratio ≥1.6 (11.2% event rate). Conclusions— The combination of diabetes mellitus and I-123 metaiodobenzylguanidine H/M ratio is an independent predictor of heart failure progression, confirming the high risk of diabetic subjects with impaired cardiac sympathetic nerve function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00126438 and NCT00126425.

Background: Historical outcomes in anaplastic thyroid carcinoma (ATC) are poor, with a median survival of only 5 months and <20% of patients surviving 1 year from diagnosis. We hypothesized that survival in newly diagnosed patients with stages IVA and IVB locoregionally confined ATC might be improved by utilizing an aggressive therapeutic approach, prioritizing both the eradication of disease in the neck and preemptive treatment of occult metastatic disease. Methods: Between January 1, 2003, and December 31, 2007, 25 new ATC patients were evaluated at our institution. Of these 25 patients, 10 (40%) had metastatic disease at diagnosis and therefore underwent palliative treatment, whereas 5 (20%) had regionally confined disease and desired treatment at their local medical facilities. The remaining 10 consecutive patients (40%) had regionally confined ATC and elected aggressive therapy combining individualized surgery (where feasible), intensity-modulated radiation therapy (IMRT), and radiosensitizing + adjuvant chemotherapy intending four cycles of docetaxel + doxorubicin. Outcomes were assessed on an intention to treat basis. Results: There were no deaths from therapy, but hospitalization was required in two patients (20%) because of treatment-related adverse events. Five patients (50%) are alive and cancer-free, all having been followed >32 months (range: 32–89 months; median: 44 months) with a median overall Kaplan–Meier survival of 60 months. Overall survival at 1 and 2 years was 70% and 60%, respectively, compared to <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation at our and other institutions. Conclusions: Although based upon a small series of consecutively treated patients, an aggressive approach combining IMRT and radiosensitizing plus adjuvant chemotherapy appears to improve outcomes, including survival in stages IVA and IVB regionally confined ATC, but remains of uncertain benefit in patients with stage IVC (metastatic) disease. Also uncertain is the optimal chemotherapy regimen to use in conjunction with IMRT. Further multicenter randomized trials are required to define optimal therapy in this rare but deadly cancer.

ABSTRACT Introduction Sexual health is an integral part of overall health. Sexual dysfunction can have a major impact on quality of life and psychosocial and emotional well-being. Aim To provide evidence-based, expert-opinion consensus guidelines for clinical management of sexual dysfunction in men. Methods An international consultation collaborating with major urologic and sexual medicine societies convened in Paris, July 2009. More than 190 multidisciplinary experts from 33 countries were assembled into 25 consultation committees. Committee members established scope and objectives for each chapter. Following an exhaustive review of available data and publications, committees developed evidence-based guidelines in each area. Main Outcome Measures New algorithms and guidelines for assessment and treatment of sexual dysfunctions were developed based on work of previous consultations and evidence from scientific literature published from 2003 to 2009. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of medical literature, and cultural and ethical considerations. Results Algorithms, recommendations, and guidelines for sexual dysfunction in men are presented. These guidelines were developed in an evidence-based, patient-centered, multidisciplinary manner. It was felt that all sexual dysfunctions should be evaluated and managed following a uniform strategy, thus the International Consultation of Sexual Medicine (ICSM-5) developed a stepwise diagnostic and treatment algorithm for sexual dysfunction. The main goal of ICSM-5 is to unmask the underlying etiology and/or indicate appropriate treatment options according to men’s and women’s individual needs (patient-centered medicine) using the best available data from population-based research (evidence-based medicine). Specific evaluation, treatment guidelines, and algorithms were developed for every sexual dysfunction in men, including erectile dysfunction; disorders of libido, orgasm, and ejaculation; Peyronie’s disease; and priapism. Conclusions Sexual dysfunction in men represents a group of common medical conditions that need to be managed from a multidisciplinary perspective.

AbstractTwo prior studies suggest genetic counselors self‐disclose primarily because patients ask them to do so (Peters et al., 2004; Thomas et al., 2006). However, scant research has investigated effects of counselor disclosure on genetic counseling processes and outcomes. In this study, 151 students (98 undergraduates, 53 graduates) completed one of three surveys describing a hypothetical genetic counseling session in which a patient at risk for FAP was considering whether to pursue testing or surveillance procedures. Dialogue was identical in all surveys, except for a final response to the question: “What would you do if you were me?” The counselor either revealed what she would do (Personal Disclosure), what other patients have done (Professional Disclosure), or deflected the question (No Disclosure). Imagining themselves as the patient, participants wrote a response to the counselor and indicated their perceptions of her. Participants rated thenon‐disclosingcounselor significantly lower in social attractiveness than either disclosing counselor, and less satisfying than theprofessional disclosingcounselor. Analysis of written responses yielded four themes: Made Decision, Sought Information, Expressed Thoughts/Feelings, and No Decision. Practice implications and research recommendations are provided.