Association of TGF-ß2 levels in breast milk with severity of breast biopsy diagnosis.

PURPOSE: TGF-ß plays a dual role in breast carcinogenesis, acting at early stages as tumor-suppressors and later as tumor-promoters. TGF-ß isoforms are expressed in breast tissues and secreted in milk, suggesting that analysis of levels in milk might be informative for breast cancer risk. Accordingly, we assessed TGF-ß2 levels in milk from women who had undergone a breast biopsy and related the concentrations to diagnosis. METHODS: Milk donated by women who had undergone or were scheduled for a breast biopsy was shipped on ice for processing and testing. Breast cancer risk factors were obtained through a self-administered questionnaire, and biopsy diagnoses were extracted from pathology reports. TGF-ß2 levels in milk, assessed as absolute levels and in relation to total protein, were analyzed in bilateral samples donated by 182 women. Linear regression was used to estimate relationships of log-transformed TGF-ß2 levels and TGF-ß2/ total protein ratios to biopsy category. RESULTS: Milk TGF-ß2 levels from biopsied and non-biopsied breasts within women were highly correlated (r (2) = 0.77). Higher mean TGF-ß2 milk levels (based on average of bilateral samples) were marginally associated with more severe breast pathological diagnosis, after adjusting for duration of nursing current child (adjusted p trend = 0.07). CONCLUSIONS: Our exploratory analysis suggests a borderline significant association between higher mean TGF-ß2 levels in breast milk and more severe pathologic diagnoses. Further analysis of TGF-ß signaling in milk may increase understanding of postpartum remodeling and advance efforts to analyze milk as a means of assessing risk of breast pathology.

Prospective trial evaluating electrical impedance scanning of thyroid nodules before thyroidectomy: final results.

BACKGROUND: Electrical impedance scanning (EIS) identifies tissue impedance changes associated with malignancy. Methods to distinguish benign from malignant thyroid nodules, particularly in patients with indeterminate cytology are lacking. PURPOSE: To determine the diagnostic accuracy of EIS in the preoperative evaluation of thyroid nodules. PATIENTS AND METHODS: From September 2002 to December 2006, 216 patients underwent thyroid fine needle aspiration (FNA) and EIS prethyroidectomy in this prospective cohort study. EIS, either positive or negative for malignancy, was correlated with final histopathology. A focal bright spot over a thyroid nodule correlating with increased conductivity and/or capacitance >25% baseline sternocleidomastoid muscle impedance defined positive EIS. Study endpoints were EIS accuracy, sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV). This study has been registered in the National Institutes of Health's public trials registry at ClinicalTrials.gov. The registration number is NCT00571077. RESULTS: EIS correctly diagnosed 96 of 110 patients with malignant and 75 of 106 patients with benign dominant thyroid nodules: Sn = 87%, Sp = 71%, PPV = 76%, NPV = 84%: overall EIS accuracy = 79%. Pretest cancer probability of 51% (110 of 216) increased to 76% (96 of 127) post-EIS, and preoperative use of EIS would result in a significant reduction (71%, 75 of 106) in number of operations performed for benign nodules. EIS performance was similar for 109 patients with indeterminate FNA: Sn = 83%, Sp = 67%, PPV = 61%, NPV = 87%, accuracy = 73%. Pretest probability of cancer increased from 39% (42 of 109) to 61% (35 of 57) post-EIS. The use of EIS would result in a significant reduction (67%, 45 of 67) in the number of purely diagnostic thyroidectomy for indeterminate FNA. CONCLUSION: EIS shows promise in differentiating thyroid nodules. Further EIS hardware and software optimization is warranted to improve upon the already favorable negative predictive value in indeterminate thyroid nodules.

Electrical impedance scanning for the early detection of breast cancer in young women: preliminary results of a multicenter prospective clinical trial.

PURPOSE: To evaluate the feasibility and patient satisfaction with electrical impedance scanning (EIS) for early detection of breast cancer in young women. METHODS: Women undergoing screening clinical breast examination, imaging, or biopsy were eligible for EIS examination with T-Scan 2000ED (Mirabel Medical Systems, Austin, TX). Multiple logistic regression analysis evaluated the association between clinical variables and EIS performance. Patients completed a screening EIS satisfaction questionnaire (1 = least satisfied to 5 = most satisfied). RESULTS: Twenty-nine cancers were identified among 1,103 women. Sixty-six percent (19 of 29) of cancers were nonpalpable and 55% (16 of 29) were in women age < or = 50 years. EIS sensitivity and specificity in women younger than 40 years was 50% and 90%, respectively. Exogenous estrogen use (P < .001) and menopausal status (P = .007) correlated significantly with EIS performance. False-positive rates were increased in postmenopausal women and those taking exogenous hormones. No correlation was evident between EIS performance and family history, prior breast cancer, breast density, or palpability. EIS-positive women younger than age 40 were 4.5 times more likely to have breast carcinoma than were women randomly selected from the general population. Patients were highly satisfied with the comfort, speed, and reporting of EIS screening (mean score, 4.8). CONCLUSION: EIS seems promising for early detection of breast cancer, and identification of young women at increased risk for having the disease at time of screening. Positive EIS-associated breast cancer risk compares favorably with relative risks of conditions commonly used to justify early breast cancer screening. Patients are satisfied with a screening paradigm involving breast EIS.

Novel EIS postprocessing algorithm for breast cancer diagnosis.

A new postprocessing algorithm was developed for the diagnosis of breast cancer using electrical impedance scanning. This algorithm automatically recognizes bright focal spots in the conductivity map of the breast. Moreover, this algorithm discriminates between malignant and benign/normal tissues using two main predictors: phase at 5 kHz and crossover frequency, the frequency at which the imaginary part of the admittance is at its maximum. The thresholds for these predictors were adjusted using a learning group consisting of 83 carcinomas and 378 benign cases. In addition, the algorithm was verified on an independent test group including 87 carcinomas, 153 benign cases and 356 asymptomatic cases. Biopsy was used as gold standard for determining pathology in the symptomatic cases. A sensitivity of 84% and a specificity of 52% were obtained for the test group.

Breast electrical impedance and estrogen use in postmenopausal women.

OBJECTIVES: To examine the potential for using electrical impedance measurements on the breast as an indicator of estrogen activity in breast tissue. METHODS: Eighty-six postmenopausal women were examined with TS2000, a device that measures electrical capacitance and conductance on the breast. Seventy women had undergone natural menopause (NM) and 16 had had a hysterectomy/ovarectomy. Twenty-one women were using estrogen replacement therapy (ERT). Each woman had electrical impedance measured over several frequencies on the nipple sector of both breasts. We analyzed capacitance and conductance at 200 and 1100 Hz and the slopes and intercepts of regression lines relating capacitance and conductance to the natural log of frequency. RESULTS: Type of menopause (natural or induced) was not statistically related to any measured variable. The number of years since the start of menopause was statistically related to all measured variables. Overall, levels of capacitance and conductance decreased as the number of years since the start of menopause increased. Women who used ERT had a statistically higher level of nipple conductance at 200 Hz than did women who did not use ERT. CONCLUSIONS: The pattern of electrical measurements on the nipple (and in particular conductance at 200 Hz) is correlated with the pattern of estrogen changes after menopause. These data indicate that electrical measurements might be a useful, non-invasive assay of estrogen activity in breast tissue.

Increased promoter methylation in exfoliated breast epithelial cells in women with a previous breast biopsy.

Accurately identifying women at increased risk of developing breast cancer will provide greater opportunity for early detection and prevention. DNA promoter methylation is a promising biomarker for assessing breast cancer risk. Breast milk contains large numbers of exfoliated epithelial cells that are ideal for methylation analyses. Exfoliated epithelial cells were isolated from the milk obtained from each breast of 134 women with a history of a non-proliferative benign breast biopsy (Biopsy Group). Promoter methylation of three tumor suppressor genes, RASSF1, SFRP1 and GSTP1, was assessed by pyrosequencing of bisulfite-modified DNA. Methylation scores from the milk of the 134 women in the Biopsy Group were compared to scores from 102 women for whom a breast biopsy was not a recruitment requirement (Reference Group). Mean methylation scores for RASSF1 and GSTP1 were significantly higher in the Biopsy than in the Reference Group. For all three genes the percentage of outlier scores was greater in the Biopsy than in the Reference Group but reached statistical significance only for GSTP1. A comparison between the biopsied and non-biopsied breasts of the Biopsy Group revealed higher mean methylation and a greater number of outlier scores in the biopsied breast for both SFRP1 and RASSF1, but not for GSTP1. This is the first evidence of CpG island methylation in tumor suppressor genes of women who may be at increased risk of developing breast cancer based on having had a prior breast biopsy.

Breast cancer screening compliance among young women in a free access healthcare system.

BACKGROUND AND OBJECTIVES: To examine mammographic screening compliance among young military healthcare beneficiaries and to examine factors related to one time and recent mammographic compliance. METHODS: Medical records were reviewed for 1,073 subjects (age 41-47) recording dates of the two most recent screening mammograms. Examined outcomes were: whether the woman ever had mammography and, if so, whether she had a mammogram within 400 days. Examined predictors were: ethnicity, age, Gail Model risk score, family history, whether the woman knew a young woman with breast cancer, and importance attributed to breast cancer screening. RESULTS: 90.4% of women studied had at least one mammogram. 71.1% underwent screening within 400 days. Rates of ever having mammography were higher for women with family history of breast cancer and Asian, Pacific Islander, Black or Hispanic women. No measured covariate correlated with having mammography within 400 days. CONCLUSIONS: One time screening participation was high in this select group of women for whom cost and access barriers were removed, but was lower with regard to having a recent mammogram. Correlates of ever having and recent mammography are not synonymous.

Electrical impedance scanning as a new breast cancer risk stratification tool for young women.

BACKGROUND: Electrical impedance scanning (EIS) measures changes in breast tissue associated with breast cancer (Br-Ca) development. The T-Scan(tm2000 (ED is designed to use EIS to identify women ages 30-39 with elevated risk of breast cancer (i.e., T-Scan+ women). AIM: To estimate the relative probability of breast cancer in a T-Scan+ woman compared to a randomly selected young woman. METHODS: A prospective, two-cohort trial was conducted in pre-menopausal women. The Specificity (S(p))-Cohort evaluated T-Scan specificity in 1,751 asymptomatic women ages 30-39. The Sensitivity)S(n))-Cohort evaluated T-Scan sensitivity in 390 women ages 45-30 scheduled for biopsy. Specificity, sensitivity, and conservative estimate of disease prevalence were used to calculate relative probability. RESULTS: In the S(p)-Cohort, 93 of 1,751 women were T-Scan+ (S(p) = 94.7%; 95% CI: 93.7-95.7%). In the S(n)-Cohort, 23 of 87 biopsy-proven cancers were T-Scan+ (S(n) = 26.4%; 95% CI: 17.4-35.4%). Given S(p) = 94.7%, S(n) = 26.4% and prevalence of 1.5 cancers/1,000 women (ages 30-39), the relative probability of a T-Scan+ woman having Br-Ca is 4.95: (95% CI: 3.16-7.14). CONCLUSION: EIS can identify a subset of young women with a relative probability of breast cancer almost five times greater than in the population of young women at-large. T-Scan+ women have a sufficiently high risk of Br-Ca to warrant further surveillance or imaging.

The dynamic of the t-haplotype in wild populations of the house mouse Mus musculus domesticus in Israel.

The t-haplotype, a variant of the proximal part of the mouse chromosome 17, is composed of at least four inversions and is inherited as a single genetic unit. The haplotype causes embryonic mortality or male sterility when homozygous. Genes within the complex are responsible for distortion of Mendelian transmission ratio in males. Thus, the t-haplotype in heterozygous males is transferred to over 95% of the progeny. We examined the dynamic and behavior of the t-haplotype in wild populations of the house mouse in Israel. The Israeli populations show high frequency (15%-20%) of both partial and complete t-carrying mice, supporting the suggestion that the t-complex evolved in the M. domesticus line in the Israeli region. In one population that had the highest frequency of t-carrying individuals, we compared the level of gene diversity between t-carrying and normal mice in the marker's loci: H-2 locus of the major histocompatibility complex (MHC) on the t-haplotype of chromosome 17, three microsatellites on other chromosomes, and the mitochondrial D-loop. Genetic variability was high in all tested loci in both t and (+) mice. All t mice carried the same chromosome and showed the same H-2 haplotype. While t-carrying mice showed significant H-2 heterozygotes access, (+) mice expressed significant H-2 heterozygote deficiency. There were no differences in the level of gene diversity between t and (+) mice in the other loci. Heterozygosity level at the MHC may be an additional factor in the selective forces balancing the t-haplotype polymorphism.

Satisfaction with breast cancer screening and future screening participation.

BACKGROUND: To measure satisfaction with an investigational breast cancer risk screening technique [electrical impedance scanning (EIS)] and to investigate the relationship between satisfaction and willingness to return for follow-up examination one year later. MATERIAL/METHODS: 2727 women volunteers (age 18-45 years, military healthcare beneficiaries) underwent an EIS exam [reported as "negative" (average risk) or "positive" (high risk)]; then they filled out a questionnaire assessing satisfaction with the procedure. One year later, women were invited for follow-up screening. RESULTS: Satisfaction score was significantly related to EIS exam result (higher for women with negative exams), importance assigned to breast cancer screening, and family history of breast cancer. However, satisfaction was not related to scheduling a visit the following year for a follow-up examination. The only satisfaction component predicting return was satisfaction with exam reporting for participants with positive exam results. Return was related positively to age and race/ethnicity; older women and Hispanic women were more likely, while African American women were less likely, to return for follow-up. CONCLUSIONS: Factors affecting breast cancer screening participation among younger women are diverse and complex. Further study and delineation of such factors is necessary to understand how best to tailor breast cancer education programs in young women.

Electrical impedance scanning of thyroid nodules before thyroid surgery: a prospective study.

BACKGROUND: Electrical impedance scanning (EIS) is a novel imaging technique based on differential electrical conductivity and capacitance of malignant and normal human tissues. The aim of this study was to evaluate the accuracy of EIS in the detection of thyroid malignancies. METHODS: Patients with thyroid nodules scheduled for thyroid surgery were eligible for the study. Enrolled patients underwent EIS with a T-Scan 2000ED. Nodule location, size, and type (cystic vs. solid) measured by ultrasound, cytology results, thyroid conductivity, and capacitance calculated by EIS were recorded. EIS results were interpreted as positive or negative for malignancy and compared with final histopathology results. Study end points included EIS accuracy, sensitivity, specificity, negative and positive predictive values, and false-positive and false-negative rates. RESULTS: Sixty-four patients were enrolled onto the study, and all underwent either lobectomy-isthmusectomy (20%) or total thyroidectomy (80%). The mean tumor diameter was 2.64 +/- 14.8 mm. Thyroid cancers were identified by histology in 30 patients (46.9%). There were 11 false-positive and four false-negative cases. The overall diagnostic accuracy of EIS was 76.6% (49 of 64 correct diagnoses). The sensitivity and specificity of EIS were 86.7% (26 of 30 true positive) and 67.6% (23 of 34 true negative), respectively. The corresponding positive and negative predictive values were 70.3% and 85.2%. CONCLUSIONS: EIS is a potentially useful imaging modality for differentiating thyroid neoplasms. If these results are confirmed in large-scale trials, EIS may be an important part of the evaluation of thyroid nodules.