Citations

Evidence has emerged that the clinical benefit of tamoxifen is related to the functional status of the hepatic metabolizing enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6 is the key enzyme responsible for the generation of the potent tamoxifen metabolite, endoxifen. Multiple studies have examined the relationship of CYP2D6 status to breast cancer outcomes in tamoxifen-treated women; the majority of studies demonstrated that women with impaired CYP2D6 metabolism have lower endoxifen concentrations and a greater risk of breast cancer recurrence. As a result, practitioners must be aware that some of the most commonly prescribed medications coadministered with tamoxifen interfere with CYP2D6 function, thereby reducing endoxifen concentrations and potentially increasing the risk of breast cancer recurrence. After reviewing the published data regarding tamoxifen metabolism and the evidence relating CYP2D6 status to breast cancer outcomes in tamoxifen-treated patients, we are providing a guide for the use of medications that inhibit CYP2D6 in patients administered tamoxifen.

ABSTRACT The laboratory diagnosis of syphilis is based primarily upon serologic findings. Historically, serologic testing for syphilis has relied on assays such as rapid plasma reagin, fluorescent treponemal antibody absorption, Treponema pallidum particle agglutination (TP-PA), and more recently, enzyme immunoassay (EIA). In this study, we evaluated the performance of a novel multiplex flow immunoassay (BioPlex 2200 Syphilis; Bio-Rad Laboratories, Hercules, CA) for the detection of antitreponemal IgG- and IgM-class antibodies. Serum specimens ( n = 1,008) submitted for routine treponema-specific antibody testing by syphilis IgM and IgG EIA (Trep-Chek; Phoenix-Biotech, Mississauga, Ontario, Canada) were also analyzed by the BioPlex Syphilis multiplex assay. Specimens showing discordant results were repeat tested, with further discrepancies being arbitrated by TP-PA. Compared directly to the results of EIA, the BioPlex IgG assay demonstrated 98.7% (77/78) sensitivity and 99.4% (916/930) specificity. Compared to the Trep-Chek IgM EIA, the BioPlex IgM assay showed 80% (4/5) sensitivity and 97.9% (652/666) specificity. These results indicate that the BioPlex Syphilis multiplex assay shows similar serological agreement with EIA while allowing for a fully automated random-access platform that provides faster (1.7 h for 100 samples versus 4.5 h by EIA) and higher-throughput (800 samples per 9 h versus 200 samples by EIA) analysis of the syphilis serologic response.

As medical providers seek new ways to control costs, online visits have begun to receive serious consideration. The purpose of this study was to compare the odds of being a cost outlier during a 6-month period after either an online visit or a standard drop-in visit in a conventional medical office setting. Medical records of primary care patients (both adults and children) seen in a large group practice in Minnesota in 2008 were analyzed for this study. Two groups of patients were studied: those who had an online visit ( N = 390) and a comparison group who had regular office care for same-day, acute visits ( N = 376). Case types were classified as either complex or common, with common being defined as treatment for pinkeye, sore throat, viral illness, bronchitis, or cough. Outliers were defined as patients for whom standard costs exceeded the 75 th percentile during a 6-month period after the index visit. Multiple logistic regression analysis was used to adjust for differences between groups. The percentage of online visitors who were cost outliers was 21.2 (versus 28.5 in the standard visit group). Median standard costs were $161 for online visits and $219 for same-day acute visits. The adjusted odds of being a cost outlier was lower for the online visit group than for the standard visit group (odds ratio [OR] 0.52, 95% confidence interval [95% CI] 0.35–0.77) after adjusting for number of visits in the previous 6 months, age, sex, and case type. Outpatient visits in the previous 6 months were positively related to outlier status (OR 1.23, 95% CI 1.17–1.29). Online visits appeared to reduce medical costs for patients during a 6-month period after the visit. ( Population Health Management 2010;13:59–63)

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 −75 ), ARMS2 ( P < 10 −59 ), C2/CFB ( P < 10 −20 ), C3 ( P < 10 −9 ), and CFI ( P < 10 −6 ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 −11 ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 −7 ; CETP , P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 −3 ) and ABCA1 ( P = 5.6 × 10 −4 ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Abstract Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of anastrozole and anastrozole metabolites. There were large interindividual variations in plasma anastrozole and anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58–45.2 and 0.635–97.0 pg/mL, respectively). E1 conjugates after anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50–2,990 pg/mL). Two patients seemed to extensively metabolize anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to “individualize” therapy with this drug. Cancer Res; 70(8); 3278–86. ©2010 AACR.

Rapid calculations of the intensity are required for models of the radiation force generated by linear ultrasound phased arrays. To determine the computation times and numerical errors produced by two medical ultrasound simulation packages, namely, FIELD II and FOCUS, comparisons of the calculated pressures and intensities are performed using a simulated Vermon L5 phased array probe with 128 active elements. In these simulations, the array generates a fixed focus 25 mm from the array for a 5-MHz excitation, and the pressure field is computed on a 133 × 133 × 261 rectilinear grid that is centered at the focus. Half wavelength sampling is employed in all three directions. In FIELD II, this calculation takes approximately 4 h on a 64-bit laptop running Linux, and in FOCUS, the same calculation takes less than 4 min on the same computer. The numerical errors are also much smaller with FOCUS. Details of the simulation approaches employed for this transducer model will be presented, including selection of FIELD II and FOCUS simulation parameters and calculations of the reference pressure field for error evaluations. The impact of numerical errors on shear wave calculations will also be discussed.

Vibro-acoustography is an ultrasound-based imaging modality that maps the acoustic response of an object induced by acoustic radiation force. The method employs two ultrasound beams with frequencies separated by a small difference, typically in the kilohertz range. Using a 1.75D array transducer, which has multiple rows of elements, offers an advantage over linear array transducers because it allows for focusing in the elevation direction. We have performed simulations of different arrangements for the apertures assigned to the two ultrasound frequencies and evaluated resolution and sidelobe levels for different arrangements. However, the large size of the elements produces grating lobes in the transmitted fields. We will describe metrics for evaluating grating lobe levels compared to the main lobe of the transmitted field as a quantitative approach to optimize aperture design. We present experimental measurements of the transmitted field and compare with simulation results. Finally, we present imaging results from phantom experiments. This beamforming study is directed toward improving vibro-acoustography image formation using a General Electric Vivid 7 scanner for breast and thyroid imaging. [Mayo Clinic and two of the authors have potential financial interest related to devices or technology referenced above. Work supported by NIH Grant No. R21CA121579 and AIUM Award No. AIUM-EER#1.]