Automatic Estimation of Volumetric Breast Density Using Artificial Neural Network-Based Calibration of Full-Field Digital Mammography : Feasibility on Japanese Women With and Without Breast Cancer

Background: Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating Full-Field Digital Mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. Methods: ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Results: Phantom validations reached an R2 of 0.993. Intra-patient validations ranged from R2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. Conclusions: ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer

Predicting metastasis in clinically negative axillary lymph nodes with minimum apparent diffusion coefficient value in luminal A-like breast cancer

Background We investigated the usefulness of the minimum ADC value of primary breast lesions for predicting axillary lymph node (LN) status in luminal A-like breast cancers with clinically negative nodes in comparison with the mean ADC. Methods Forty-four luminal A-like breast cancers without axillary LN metastasis at preoperative clinical evaluation, surgically resected with sentinel LN biopsy, were retrospectively studied. Mean and minimum ADC values of each lesion were measured and statistically compared between LN positive (n = 12) and LN negative (n = 32) groups. An ROC curve was drawn to determine the best cutoff value to differentiate LN status. Correlations between mean and minimum ADC values and the number of metastatic axillary LNs were investigated. Results Mean and minimum ADC values of breast lesions with positive LN were significantly lower than those with negative LN (mean 839.9 +/- 110.9 vs. 1022.2 +/- 250.0 x 10(- 6) mm(2)/s, p = 0.027, minimum 696.7 +/- 128.0 vs. 925.0 +/- 257.6 x 10(- 6) mm(2)/s, p = 0.004). The sensitivity and NPV using the best cutoff value from ROC using both mean and minimum ADC were 100%. AUC of the minimum ADC (0.784) was higher than that of the mean ADC (0.719). Statistically significant negative correlations were observed between both mean and minimum ADCs and number of positive LNs, with stronger correlation to minimum ADC than mean ADC. Conclusions The minimum ADC value of primary breast lesions predicts axillary LN metastasis in luminal A-like breast cancer with clinically negative nodes, with high sensitivity and high NPV

Strong cytoplasmic expression of NF-κB/p65 correlates with a good prognosis in patients with triple-negative breast cancer

Purpose: Recent studies have indicated that constitutive NF-κB activity could be involved in the proliferation of triple-negative breast cancer. Methods: NF-κB/p65 expression and the effects of the NF-κB inhibitor, (-)-DHMEQ were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed. Expression of NF-κB/p65, Bcl2 and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens, and predictive factors for neoadjuvant chemotherapy and prognosis were analyzed. Results: NF-κB/p65 was dominantly expressed in the cytoplasm in MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-κB/p65 expression was detected in the nuclei of a few cells in 7 tumors before neoadjuvant chemotherapy, although expression of NF-κB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. Expression levels of NF-κB/p65 were not associated with response to neoaduvant chemotherapy, although expression levels of cytoplasmic NF-κB/p65 intensity were significantly decreased in post-treatment tumor samples compared with those in pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-κB/p65 expression before neoadjuvant chemotherapy are currently disease-free. Conclusion: Our results suggest that strong cytoplasmic NF-κB/p65 expression could be a prognostic marker in triple-negative breast cancer

Genetic and environmental factors and serum hormones, and risk of estrogen receptor-positive breast cancer in pre- and postmenopausal Japanese women

Breast cancer incidence in Japanese women has more than tripled over the past two decades. We have previously shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive, HER2-negative subtype. We conducted a case-control study; ER-positive, HER2-negative breast cancer patients who were diagnosed since 2011 and women without disease were recruited. Environmental factors, serum levels of testosterone and 25-hydroxyvitamin D, and common genetic variants reported as predictors of ER-positive breast cancer or found in Asian women were evaluated between patients and controls in pre-and postmenopausal women. To identify important risk predictors, risk prediction models were created by logistic regression models. In premenopausal women, two environmental factors (history of breastfeeding, and history of benign breast disease) and four genetic variants (TOX3-rs3803662, ESR1-rs2046210, 8q24-rs13281615, and SLC4A7-rs4973768) were considered to be risk predictors, whereas three environmental factors (body mass index, history of breastfeeding, and hyperlipidemia), serum levels of testosterone and 25-hydroxyvitamin D, and two genetic variants (TOX3-rs3803662 and ESR1-rs2046210) were identified as risk predictors. Inclusion of common genetic variants and serum hormone measurements as well as environmental factors improved risk assessment models. The decline in the birthrate according to recent changes of lifestyle might be the main cause of the recent notable increase in the incidence of ER-positive breast cancer in Japanese women

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment. In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEG-unmodified MEND due to less accumulation in liver and spleen

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