Yuri R. Parisky

The Relative Importance of Genetics and Environment on Mammographic Density

Background: Although several environmental factors predict mammographic density, estimates of its heritability have been quite high. We investigated whether part of the presumed heritability might be attributed to differential sharing of modifiable risk factors in monozygotic (MZ) and dizygotic (DZ) twins. Methods: We measured percent and absolute mammographic density using mammograms from 257 MZ and 296 DZ twin pairs. The correlation of intrapair mammographic density was compared according to zygosity across strata of modifiable risk factors. Portions of variance attributable to additive genetic factors, shared environment, and individual environment were calculated using a variance component methodology in the entire set, and within twin pairs stratified by environmental trait similarity. Results: Both percent density and absolute mammographic density were more highly correlated between MZ twins than DZ twins, but the correlations varied across strata. Body mass index (BMI) and parity strongly predicted differences in mammographic density within MZ twin pairs. After adjusting for covariates, 53% of the total variance in percent density and 59% of that in absolute density seemed attributable to genetic effects, but these estimates varied greatly by stratum. For twins dissimilar on BMI (difference >2.5 kg/m2), the additive genetic component of absolute density was estimated at only 20% (±19%), and the common and individual environment at 21% (±14%) and 49%, respectively (P value for heterogeneity across BMI = 0.0001). Conclusion: Our results confirm that the genome is an important determinant of mammographic density but suggest that an unknown portion of the mammographic density effect attributed to the genome may be due to shared modifiable environmental factors. (Cancer Epidemiol Biomarkers Prev 2009;18(1):102–12)

Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: Results from a pilot study

IntroductionMammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast.MethodsWe obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD.ResultsThe adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%).ConclusionAlthough based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.

A multisite phase iii study of the safety and efficacy of a new manganese chloride-based gastrointestinal contrast agent for mri of the abdomen and pelvis

The purpose of this study was to evaluate the safety and efficacy of a manganese chloride‐based oral magnetic resonance (MR) contrast agent during a Phase III multisite clinical trial. Two hundred seventeen patients were enrolled who were already scheduled for MRI of the abdomen and/or pelvis. In this group of patients, it was postulated that the use of an oral agent would better allow discrimination of pathology from bowel. Patients with known gastrointestinal pathology including peptic ulcer disease, inflammatory bowel disease, obstruction, or perforation were excluded to minimize confounding variables that could affect the safety assessment. Of these 217 patients, 18 received up to 900 mL of placebo, and 199 patients were given up to 900 mL of a manganese chloride‐based oral contrast agent, LumenHance® (Bracco Diagnostics, Inc.). Safety was determined by comparing pre‐ and post‐dose physical examinations, vital signs, and laboratory examinations and by documenting adverse events. Efficacy was assessed by unblinded site investigators and two blinded reviewers who compared pre‐ and post‐dose T1‐ and T2‐weighted MRI scans of the abdomen and/or pelvis. In 111 (57%) of the 195 cases evaluated for efficacy by site investigators (unblinded readers), MRI after LumenHance provided additional diagnostic information. Increased information was found by two blinded readers in 52% and 51% of patients, respectively. In 44/195 cases (23%) unblinded readers felt the additional information would have changed patient diagnosis and in 50 patients (26%), it would have changed management and/or therapy. Potential changes in patient diagnosis or management/therapy were seen by the two blinded readers in 8–20% of patients. No clinically significant post‐dose laboratory changes were seen. Forty‐eight patients (24%) receiving LumenHance and four patients (22%) receiving placebo experienced one or more adverse events. Gastrointestinal tract side effects were most common, seen in 29 (15%) of LumenHance patients and in 3 (17%) of the placebo patients. LumenHance is a safe and efficacious oral gastrointestinal contrast agent for MRI of the abdomen and pelvis.J. Magn. Reson. Imaging 1999;10:15–24.

Management of complex urologic injuries.

The management of complex urologic trauma requires considerable experience and familiarity with reconstructive techniques. The goal should always be maximum preservation of normal function, with the fewest serious complications. Ideally these cases are treated by a multidisciplinary team rather than the trauma surgeon alone.

Modified Bi-Rads Scoring of Breast Imaging Findings Improves Clinical Judgment.

In contrast with the reporting requirements currently mandated under the Federal Mammography Quality Standards Act (MQSA), we propose a modification of the Breast Imaging Reporting and Data System (Bi‐Rads) in which a concluding assessment category is assigned, not to the examination as a whole, but to every potentially malignant abnormality observed. This modification improves communication between the radiologist and the attending clinician, thereby facilitating clinical judgment leading to appropriate management. In patients with breast cancer eligible for breast conserving therapy, application of this modification brings to attention the necessity for such patients to undergo pretreatment biopsies of all secondary, synchronous ipsilateral lesions scored Bi‐Rads 3‐5. All contralateral secondary lesions scored Bi‐Rads 3‐5 also require pretreatment biopsies. The application of this modification of the MSQA demonstrates the necessity to alter current recommendations (“short‐interval follow‐up”) for secondary, synchronous Bi‐Rads 3 (“probably benign”) image‐detected abnormalities prior to treatment of the index malignancy.