Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.

Abstract Background: The study goal was to test the ability of a miniature flexible RF sensor (Dune Medical Devices), designed to be mounted on the surface of surgical tools, in measuring and mapping the various breast tissue types in terms of electrical properties. This study was part of the first stage in developing a measuring device for use during biopsy procedures. Methods: One hundred and two (102) patients undergoing lumpectomy, open biopsy or mastectomy in 3 medical centers between January and October 2012 were enrolled in this study. The device was applied to numerous sites of freshly excised specimens. Measurement sites were accurately marked, to ensure registration between device measurement and histology analysis. The dielectric properties of the various tissue types were derived from matching between measurements and histology. The correlation between device readings and tissue type, as well as the ability of the device to differentiate between malignant and non-malignant sites, was assessed. Results: A total of 4322 measurements from 102 patients were analyzed. The dielectric properties of 10 tissue types in the low RF frequency (4-30MHz) range were measured, showing distinct differences between the various types. The correlation between the RF measurements, as quantified by a score variable, and the tissue types, is demonstrated, with a correlation coefficient of 0.90 (95% CI: 0.89 - 0.91). Differentiation ability between tissue types is also demonstrated using ROC curve analysis, with AUG of 0.96 (95% CI: 0.95 - 0.97), and sensitivity and specificity of 90.2% (95% CI: 84 - 95) and 90.9% (95% CI: 90 - 92), respectively, at feature sizes at or above 0.8 mm in diameter. Conclusions: First results from a radio-frequency near-field spectroscopy miniature flexible sensor evaluate the dielectric properties of various breast tissue types. The results also show promise in differentiating between various breast tissue types, and specifically for differentiation between cancer and normal tissues. The sensor's dimensions (radius of ∼1mm) and flexible design enable use in lumpectomy procedures (for margin assessment) as well as in minimally invasive devices and breast biopsy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-03-02.

Background and Objectives: In two-thirds of breast cancer patients undergoing reoperation no residual tumor will be found. A scoring system for selection of patients who might benefit from relumpectomy is proposed.Methods: This study is based on 293 patients with invasive breast cancer undergoing reoperation due to margins of < 2 mm. Eighteen parameters were evaluated by univariate and multivariate stepwise logistic regression.Results: Univariate analysis identified nine parameters associated with a residual invasive tumor: surgical margins; lobular histological type; grade 3; multifocality; positive lymph modes; non-fine needle localization (FNL) versus FNL lumpectomy; vascular/lymphatic invasion; age < 50 years; and tumor size >= 3 cm. Multivariate stepwise logistic regression study identified six out of nine parameters associated with a higher probability of finding a residual invasive tumor: margins < 1 mm, multifocality, tumor size >= 3 cm, positive lymph nodes, age < 50 years, and lumpectomy without previous FNL. Odds of these factors were used for scoring.Conclusions: For patients with surgical margins < 2 mm and a score of < 4, the probability of finding a residual invasive tumor is 0%, while the probability of finding a microfocus of < 2 mm of invasive carcinoma is 3.2% and of finding residual DCIS is up to 10%. J. Surg. Oncol. 2012; 105: 376-380. (C) 2011 Wiley Periodicals, Inc.

Background. Margin status in breast lumpectomy procedures is a prognostic factor for local recurrence and the need to obtain clear margins is often a cause for repeated surgical procedures. A recently developed device for real-time intraoperative margin assessment (Margin Probe; Dune Medical Devices, Caesarea, Israel), was clinically tested. The work presented here looks at the diagnostic performance of the device.Methods. The device was applied to freshly excised lumpectomy and mastectomy specimens at specific tissue measurement sites. These measurement sites were accurately marked, cut out, and sent for histopathologic analysis. Device readings (positive or negative) were compared with histology findings (namely malignant, containing any microscopically detected tumor, or nonmalignant) on a per measurement site basis. The sensitivity and specificity of the device was computed for the full dataset and for additional relevant subgroups.Results. A total of 869 tissue measurement sites were obtained from 76 patients, 753 were analyzed, of which 165 were cancerous and 588 were nonmalignant. Device performance on relatively homogeneous sites was: sensitivity 1.00 (95% CI: 0.85-1), specificity 0.87 (95% CI: 0.83-0.90). Performance for the full dataset was: sensitivity 0.70 (95% CI: 0.63-0.77), specificity 0.70 (95% CI: 0.67-0.74). Device sensitivity was estimated to change from 56% to 97% as the cancer feature size increased from 0.7 mm to 6.6 mm. Detection rate of samples containing pure DCIS clusters was not different from rates of samples containing IDC.Conclusions. The device has high sensitivity and specificity in distinguishing between normal and cancer tissue even down to small cancer features. (C) 2010 Elsevier Inc. All rights reserved.

HOX genes are developmental genes that determine anterior-posterior embryonic pattern and govern the process of differentiation. Inappropriate expression of HOX genes has been implicated in developmental abnormalities and hematopoietic malignancies. In addition, HOX genes silencing by DNA methylation has been reported in cancers and related to disease aggressiveness and outcome. On the other hand, accumulating evidence suggests that epigenetic changes at HOX genes are linked to normal development and differentiation. To better understand the relationship between HOXA methylation and cancer, we analyzed the methylation pattern of HOXA genes in human primary breast and colon carcinomas, normal tissues, and normal white blood cells. Genome-wide methylation arrays of breast cancers and white blood cells demonstrated similar methylation patterns. Quantitative methylation analysis of seven representative HOXA genes revealed various levels of methylation in both normal tissues and cancers. Analysis of epithelial-enriched normal breast tissue and stroma indicated that the stroma was the major origin of HOXA methylation. Furthermore, in selected dense breast cancers, minimal increase in methylation of several HOXA genes did not correlate with the predominance of malignant epithelial cells in these tumors. Our results suggest that methylation of the HOXA cluster may be a normal developmental and cell type specific process rather than a cancer specific mechanism.

The possible association between ovulation-inducing drugs and breast cancer development has been debated. Our aim was to evaluate the incidence of breast cancer in a cohort of women exposed to in vitro fertilization (IVF).

BACKGROUND:One of the major clinical problems in breast cancer detection is the relatively high incidence of occult lymph node metastases undetectable by standard procedures. Since the ascertainment of breast cancer stage determines the following treatment, such a "hypo-diagnosis" leads to inadequate therapy, and hence is detrimental for the outcome and survival of the patients. The purpose of our study was to investigate functional metabolic characteristics of living cells derived from metastatic and tumor-free lymph nodes of breast cancer (BC) patients.METHODS:Our methodology is based on the ability of living cells to hydrolyze fluorescein diacetate (FDA) by intracellular esterases and on the association of FDA hydrolysis rates with a specific cell status, both in physiological and pathological conditions.RESULTS:The present study demonstrates a significant difference in the ability to utilize FDA by lymph node cells derived from metastatic and tumor-free lymph nodes in general average, as well as in the metastatic and tumor-free lymph nodes of individual patients. Cells from metastatic lymph nodes had a higher capacity for FDA hydrolysis, and increased this activity after additional activation by autologous tumor tissue (tt). The association between increased FDA hydrolysis rate and activated T lymphocytes and antigen-presenting cells (APC) was shown.CONCLUSION:The results of the present study may contribute to predicting the risk of involvement of seemingly "tumor-free" axillary lymph nodes in occult metastatic processes, and to reducing false-negative results of axillary examination.

Background This randomized, double-arm trial was designed to study the benefit of a novel device (MarginProbe, Dune Medical Devices, Caesarea, Israel) in intraoperative margin assessment for breast-conserving surgery (BCS) and the associated reduction in reoperations. Methods In the device group, the probe was applied to the lumpectomy specimen and additional tissue was excised according to device readings. Study arms were compared by reoperation rates and by correct surgical reaction confirmed by histology. Results Three hundred patients were enrolled. Device use was associated with improved correct surgical reaction, defined as additional re-excision in all histologically detected positive margins, with tumor within 1 mm of inked margin. The repeat lumpectomy rate was significantly reduced by 56% in the device arm: 5.6% versus 12.7% in the control arm. There were no differences in excised tissue volume or cosmetic outcome. Conclusions Intraoperative use of the MarginProbe for positive margin detection is safe and effective in BCS and decreases the rate of repeat operations.

The development of distant metastases is the major cause of death in breast cancer (BC). In many BC cases, metastases are present in patients with no metastasis-positive lymph nodes (LN). Hence, there is a need to improve prognosis by a better prediction of the nodal status and tumor spread. The current study is designed to develop and utilize new functional characteristics of the cells and microenvironment of BC-draining LN, which may help to improve the estimation of LN metastatic involvement. Innovative devices and methodologies were developed for collecting, transferring, and analyzing LN at an individual-cell resolution. Using these devices, a suspension of living cells were prepared from the LN and processed for various assays, including immunophenotypic analysis, activation status, and invasion activity. The functional profile of tumor-activated LN cells showed an increase in the intracellular enzymatic reaction rate, accompanied by a homogeneous distribution of transferrin receptor as well as by a significant increase in matrix metalloproteinase proteolytic activity. Moreover, the proportion of cells exhibiting such a profile was significantly higher in tumor-containing LN than in tumor-free LN. Thus, the live and postfixation features of LN cells and their microenvironment, correlated with the functional status of the LN, may serve to improve their predictive value in breast cancer examination.

Background: This trial was designed to study performance of a novel handheld probe (Dune Medical Devices, Caesarea, Israel) in intraoperative detection of positive margins and its potential benefit toward minimizing the positive margin rate.Methods: The probe was intraoperatively applied to 57 lumpectomy specimens. Surgeons were blinded to device output, and surgical decisions were not affected by probe data. Probe readings were compared with histological analysis per margin and per patient.Results: Nineteen of 22 (86%) pathology-positive patients were intraoperatively detected with device use. Per-margin sensitivity was .71, and specificity was .68, maintained within a range of positive margin definitions (0-.4 cm).Conclusions: The device is an effective tool for intraoperative detection of positive margins with the potential for significant positive margin rate reduction. (c) 2007 Excerpta Medica Inc. All rights reserved.

The characteristics, menstrual risk factors and surgical therapy of 187 consecutive patients more than 70 years of age (mean: 75.9) were investigated and compared with those of 609 patients less than 70 years of age (mean: 53.9). There was no difference in stage, size, state of axillary nodes, grade, histological types, Ki-67, vascular invasion, estrogen receptor rate, and HER-2/neu (+) rate. Positive progesterone receptor rate was higher in older patients (54.7% vs. 63.1%). Tumors were larger ( p = 0.01 ) and their stage higher ( p = 0.014 ) in patients more than 80 years of age. All menstrual risk factors were similar in the two groups. Positive familial history was more frequent in patients <60 years. Significantly more young patients used hormone replacement therapy (HRT) (21.8 vs. 8.6%). Older patients underwent less breast-conserving surgery (36.1 vs. 55.1%), and less axillary lymph node dissection (ALND) (69.7 vs. 84.9%). We conclude that breast cancer characteristics and menstrual risk factors are similar in the two age groups.

Breast cancer patients are reported to have a higher rate of second primary malignancies. We retrospectively reviewed the coexistence of breast and gastrointestinal (GI) tumors in the same patients and the characteristics of the tumors. The charts of all patients more than 35 years of age who were diagnosed with breast cancer and hospitalized for various reasons between 1985 and 2003 were reviewed and those who also had a diagnosis of GI malignancy were then selected. Age and tumor characteristics were evaluated. Out of all the patients, 2,650 had a diagnosis of breast cancer, while 40 (1.5%) also had GI malignancies. Among a comparable group of 70,784 consecutive female patients without breast cancer, 1,292 patients (1.8%) had a diagnosis of GI malignancy. The location of GI tumors in patients with both tumors was as follows: stomach, 6 (15%); right colon, 8 (20%); left colon, 7 (17.5%); sigma, 9 (22.5%); and rectum, 10 (25%). Seventeen of the patients (51.5%) had Dukes C and D tumors, 14 (42.5%) Dukes B, and 2 (6%) Dukes A or in situ. The stage of the others was not identified. The mean age at diagnosis of breast cancer was 68.5 years (range 48-88 years). In 23 (57.5%), GI cancer was diagnosed after breast cancer, in 7 (17.5%) it was diagnosed within 3 months of diagnosing breast cancer, and in 8 (20%) it was diagnosed prior to the diagnosis of breast cancer. Five patients suffered from an additional primary cancer: three endometrial, one lung, one esophageal, and one patient had two additional tumors in the endometrium and thyroid. We conclude that the rate of GI malignancies in breast cancer patients is slightly lower than in comparable patients without breast cancer. GI malignancies tend to be diagnosed later and are found more often in the distal colon.

Breast carcinoma in men is rare and comprises approximately 1% of all breast cancer cases. In contrast to the increase in the detection rate of ductal carcinoma in situ (DCIS) in women resulting from the wide use of screening mammography programs, the rate of male DCIS is still small and represents approximately 5% of all male breast cancers. Considerable debate exists concerning the nature of this entity, including the clinical course, pathologic findings, treatment, and prognosis. In this review, the relevant literature dealing with male DCIS is summarized in an attempt to more precisely define the features of this disease.