Uncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform.

The mammary gland is a highly vascularized tissue capable of expansion and regression during development and disease. To enable mechanistic insight into the coordinated morphogenic crosstalk between the epithelium and vasculature, we introduce a 3D microfluidic platform that juxtaposes a human mammary duct in proximity to a perfused endothelial vessel. Both compartments recapitulate stable architectural features of native tissue and the ability to undergo distinct forms of branching morphogenesis. Modeling HER2/ERBB2 amplification or activating PIK3CA(H1047R) mutation each produces ductal changes observed in invasive progression, yet with striking morphogenic and behavioral differences. Interestingly, PI3KαH1047R ducts also elicit increased permeability and structural disorganization of the endothelium, and we identify the distinct secretion of IL-6 as the paracrine cause of PI3KαH1047R-associated vascular dysfunction. These results demonstrate the functionality of a model system that facilitates the dissection of 3D morphogenic behaviors and bidirectional signaling between mammary epithelium and endothelium during homeostasis and pathogenesis.

Cross talk of vascular endothelial growth factor and neurotrophins in mammary gland development.

During the period of lactation, there is extensive growth and development of the mammary gland in order to fulfil the increased demands of milk for the growing infant. Angiogenesis plays a key role in alveolar development and facilitates optimal milk production. Vascular endothelial growth factor (VEGF) is one of the key growth factors regulating angiogenesis in mammary gland. Apart from VEGF, neurotrophins are also known to regulate angiogenesis through direct or indirect mechanisms. Few studies have demonstrated mRNA levels of neurotrophins and their receptors in mammary gland both in humans and rodents. A cross talk between VEGF and neurotrophins has been described in placental development. The enteric and central nervous system are not fully developed at birth, making it imperative to have appropriate levels of angiogenic factors and neurotrophins during postnatal period. The current review summarises studies which describe the role of neurotrophins and angiogenic factors in the mammary gland development.

Efficacy and safety of topical nitroglycerin in the prevention of mastectomy flap necrosis: a systematic review and meta-analysis.

Flap necrosis is a common complication after mastectomy, and nitroglycerin (NTG) ointment has been used successfully to treat it. However, it is not clear whether topical NTG can completely prevent the occurrence of flap necrosis after breast cancer surgery, and it is also unclear whether this treatment may cause side effects. Three randomized controlled trials (RCTs) and two retrospective cohort studies (RCSs) were included in our investigation. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We found that NTG significantly reduced the rates of mastectomy flap necrosis, full-thickness flap necrosis, and debridement as well as the rate of early complications other than flap necrosis. However, there was no significant difference in drug-related adverse reactions, explantation, superficial flap necrosis, infection, hematoma or seroma between the NTG and placebo groups.

Breast Arterial Calcification is Associated with the Progression of Coronary Atherosclerosis in Asymptomatic Women: A Preliminary Retrospective Cohort Study.

We evaluated whether breast arterial calcification (BAC) is associated with the progression of coronary atherosclerosis in asymptomatic women. This retrospective observational cohort study analysed asymptomatic women from the BBC registry. In 126 consecutive women (age, 54.5 ± 7.0 years) who underwent BAC evaluation and repeated coronary computed tomography angiography (CCTA) examinations, the coronary arterial calcification score (CACS) and segment stenosis score (SSS) were evaluated to assess the progression of coronary arterial calcification (CAC) and coronary atherosclerotic plaque (CAP). CAC and CAP progression were observed in 42 (33.3%) and 26 (20.6%) women, respectively (median interscan time, 4.3 years), and were associated with the presence of BAC and a higher BAC score at baseline. Women with BAC demonstrated higher CAC and CAP progression rates and showed higher chances for CAC and CAP progression during follow-up (p < 0.001 for both). In multivariable analyses, the BAC score remained independently associated with both CAC and CAP progression rates after adjustment for clinical risk factors (ß = 0.087, p = 0.029; and ß = 0.020, p = 0.010, respectively) and with additional adjustment for baseline CACS (ß = 0.080, p = 0.040; and ß = 0.019, p = 0.012, respectively) or SSS (ß = 0.079, p = 0.034; and ß = 0.019, p = 0.011, respectively). Thus, BAC may be related to the progression of coronary atherosclerosis and its evaluation may facilitate decision-making.

Inaudible components of the human infant cry influence haemodynamic responses in the breast region of mothers.

Distress vocalizations are fundamental for survival, and both sonic and ultrasonic components of such vocalizations are preserved phylogenetically among many mammals. On this basis, we hypothesized that ultrasonic inaudible components of the acoustic signal might play a heretofore hidden role in humans as well. By investigating the human distress vocalization (infant cry), here we show that, similar to other species, the human infant cry contains ultrasonic components that modulate haemodynamic responses in mothers, without the mother being consciously aware of those modulations. In two studies, we measured the haemodynamic activity in the breasts of mothers while they were exposed to the ultrasonic components of infant cries. Although mothers were not aware of ultrasounds, the presence of the ultrasounds in combination with the audible components increased oxygenated haemoglobin concentration in the mothers' breast region. This modulation was observed only when the body surface was exposed to the ultrasonic components. These findings provide the first evidence indicating that the ultrasonic components of the acoustic signal play a role in human mother-infant interaction.

Label-Free Imaging of Blood Vessels in Human Normal Breast and Breast Tumor Tissue Using Multiphoton Microscopy.

Blood vessels are the important components of the circulatory systems that transport blood throughout the human body and maintain the homeostasis of physiological tissues. Pathologically, blood vessels are often affected by diseases, leading to the formation of unstable, irregular, and hyperpermeable blood vessels. In the tumor microenvironment, abnormal leakage of tumor blood vessels is related to the histological grade and malignant potential of tumors and may also facilitate metastasis of cancer. Visual diagnosis of blood vessels is very important for us to understand the occurrence and development of diseases. Multiphoton microscopy (MPM) is a potential label-free diagnostic tool based on second harmonic generation (SHG) and two-photon excited fluorescence (TPEF). MPM can effectively observe the morphological changes of biological tissues at the molecular and cellular levels. In this work, we demonstrate that label-free MPM can be used to visualize the microstructure of blood vessels in human normal breast and breast tumor tissue. Moreover, MPM can monitor the changes of blood vessels in tumor microenvironment. These results show that the MPM will become a promising technique for clinicians to study the properties of the microstructure of the blood vessels.

Effect of internal mammary vessels radiation dose on outcomes of free flap breast reconstruction.

To assess the impact of internal mammary (IM) vessels radiation dose on autologous free-flap based breast reconstruction outcomes. We retrospectively evaluated the medical records of breast cancer patients who underwent mastectomy and free-flap breast reconstruction after postoperative radiation therapy (RT) to the breast/chest wall with (n = 9) or without (n = 11) electively including the IM lymph nodes. Twenty patients were included. Median age at diagnosis was 50 years (range, 33-63). The median time interval between the start of RT and reconstructive surgery was 16 months (range, 6-45). The maximal IM vessels dose was not associated with the risk of all complications (P = 0.44) or fat necrosis (P = 0.31). The mean IM vessels dose was not significant for the risk of all complications (P = 0.13) but was significant for fat necrosis (P = 0.04). A high mean IM vessels dose was related to the occurrence of fat necrosis.

Parallel vessels as a predictor of benignity in solid breast masses.

To evaluate the presence of a parallel artery and vein on color Doppler ultrasound as a predictor of benignity in solid breast masses. This prospective study included all patients with solid breast masses identified by ultrasound at our center from January 2012 through December 2015. All masses were studied with B mode and color Doppler ultrasound. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value, and their respective 95% confidence intervals for the parallel vessel sign against the histologic findings or 2 years' follow-up without changes. A total of 526 solid masses were included in the 3-year period; the parallel vessel sign was observed in 377 (71.6%). We found 74.8% (95% CI: 70.9-78.7) sensitivity, 65% (95% CI: 50.2-79.7) specificity, 96.2% (95% CI: 94.3-98.1) positive predictive value, and 17.5% (95% CI: 11.4-23.6) negative predictive value. Of the 379 masses classified as breast imaging reporting and data system (BI-RADS) 3, the parallel vessel sign was observed in 275 (72.5%); all of these were definitively benign. Of the 109 masses classified as BI-RADS 4, the parallel vessel sign was observed in 89 (80.7%); 88 (98.8%) of these were definitively benign. Of the 38 masses classified as BI-RADS 5, the parallel vessel sign was observed in 13 (34.2%); all of these were definitively malignant. The parallel artery and vein sign is a good predictor of benignity, although it must be analyzed together with other morphologic descriptors.

Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression.

We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration below normal are less likely to respond to chemotherapy. Such behavior was recently reported for neo-adjuvant chemotherapy of locally advanced breast tumors.

Effect of the chest wall on the measurement of hemoglobin concentrations by near-infrared time-resolved spectroscopy in normal breast and cancer.

BACKGROUND: Optical imaging and spectroscopy using near-infrared light have great potential in the assessment of tumor vasculature. We previously measured hemoglobin concentrations in breast cancer using a near-infrared time-resolved spectroscopy system. The purpose of the present study was to evaluate the effect of the chest wall on the measurement of hemoglobin concentrations in normal breast tissue and cancer. METHODS: We measured total hemoglobin (tHb) concentration in both cancer and contralateral normal breast using a near-infrared time-resolved spectroscopy system in 24 female patients with breast cancer. Patients were divided into two groups based on menopausal state. The skin-to-chest wall distance was determined using ultrasound images obtained with an ultrasound probe attached to the spectroscopy probe. RESULTS: The apparent tHb concentration of normal breast increased when the skin-to-chest wall distance was less than 20 mm. The tHb concentration in pre-menopausal patients was higher than that in post-menopausal patients. Although the concentration of tHb in cancer tissue was statistically higher than that in normal breast, the contralateral normal breast showed higher tHb concentration than cancer in 9 of 46 datasets. When the curves of tHb concentrations as a function of the skin-to-chest wall distance in normal breast were applied for pre- and post-menopausal patients separately, all the cancer lesions plotted above the curves. CONCLUSIONS: The skin-to-chest wall distance affected the measurement of tHb concentration of breast tissue by near-infrared time-resolved spectroscopy. The tHb concentration of breast cancer tissue was more precisely evaluated by considering the skin-to-chest wall distance.

Impacts of Maternal Nutrition on Vascularity of Nutrient Transferring Tissues during Gestation and Lactation.

As the demand for food increases with exponential growth in the world population, it is imperative that we understand how to make livestock production as efficient as possible in the face of decreasing available natural resources. Moreover, it is important that livestock are able to meet their metabolic demands and supply adequate nutrition to developing offspring both during pregnancy and lactation. Specific nutrient supplementation programs that are designed to offset deficiencies, enhance efficiency, and improve nutrient supply during pregnancy can alter tissue vascular responses, fetal growth, and postnatal offspring outcomes. This review outlines how vascularity in nutrient transferring tissues, namely the maternal gastrointestinal tract, the utero-placental tissue, and the mammary gland, respond to differing nutritional planes and other specific nutrient supplementation regimes.

Prevalence of coronary artery disease evaluated by coronary CT angiography in women with mammographically detected breast arterial calcifications.

To assess the correlation between breast arterial calcifications (BAC) on digital mammography and the extent of coronary artery disease (CAD) diagnosed with dual source coronary computed tomography angiography (CTA) in a population of women both symptomatic and asymptomatic for coronary artery disease. 100 consecutive women (aged 34 - 86 years) who underwent both coronary CTA and digital mammography were included in the study. Health records were reviewed to determine the presence of cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and smoking. Digital mammograms were reviewed for the presence and degree of BAC, graded in terms of severity and extent. Coronary CTAs were reviewed for CAD, graded based on the extent of calcified and non-calcified plaque, and the degree of major vessel stenosis. A four point grading scale was used for both coronary CTA and mammography. The overall prevalence of positive BAC and CAD in the studied population were 12% and 29%, respectively. Ten of the 12 patients with moderate or advanced BAC on mammography demonstrated moderate to severe CAD as determined by coronary CTA. For all women, the positive predictive value of BAC for CAD was 0.83 and the negative predictive value was 0.78. The presence of BAC on mammography appears to correlate with CAD as determined by coronary CTA (Spearman's rank correlation coefficient = 0.48, p<.000001). Using logistic regression, the inclusion of BAC as a feature in CAD predication significantly increased classification results (p=0.04).

Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.

Antiangiogenic therapy is commonly used in the clinic, but its beneficial effects are short-lived, leading to tumor relapse within months. Here, we found that the efficacy of angiogenic inhibitors targeting the VEGF/VEGFR pathway was dependent on induction of the angiostatic and immune-stimulatory chemokine CXCL14 in mouse models of pancreatic neuroendocrine and mammary tumors. In response, tumors reinitiated angiogenesis and immune suppression by activating PI3K signaling in all CD11b+ cells, rendering tumors nonresponsive to VEGF/VEGFR inhibition. Adaptive resistance was also associated with an increase in Gr1+CD11b+ cells, but targeting Gr1+ cells was not sufficient to further sensitize angiogenic blockade because tumor-associated macrophages (TAMs) would compensate for the lack of such cells and vice versa, leading to an oscillating pattern of distinct immune-cell populations. However, PI3K inhibition in CD11b+ myeloid cells generated an enduring angiostatic and immune-stimulatory environment in which antiangiogenic therapy remained efficient.

Regulation of blood vessels by prolactin and vasoinhibins.

Prolactin (PRL) stimulates the growth of new blood vessels (angiogenesis) either directly through actions on endothelial cells or indirectly by upregulating proangiogenic factors like vascular endothelial growth factor (VEGF). Moreover, PRL acquires antiangiogenic properties after undergoing proteolytic cleavage to vasoinhibins, a family of PRL fragments (including 16 kDa PRL) with potent antiangiogenic, vasoconstrictive, and antivasopermeability effects. In view of the opposing actions of PRL and vasoinhibins, the regulation of the proteases responsible for specific PRL cleavage represents an efficient mechanism for controlling blood vessel growth and function. This review briefly describes the vascular actions of PRL and vasoinhibins, and addresses how their interplay could help drive biological effects of PRL in the context of health and disease.

Near-infrared optical imaging of cancer vascular remodeling after antiangiogenic therapy.

BACKGROUND: Near-infrared diffuse optical imaging (DOSI) has been recently accepted as a method to assess tumor vascularity and oxygenation by measuring tissue hemoglobin (Hb) concentration. It is expected that DOSI could be used to monitor changes in vascularity after antiangiogenic therapy. METHODS: A patient with advanced breast cancer was treated with single-agent bevacizumab followed by addition of weekly paclitaxel to it. DOSI was performed in the tumor-bearing breast and contralateral normal breast at baseline, 3, 6, 12, 24 h, and then daily for 1 week. Images of a tumor-to-normal ratio of tHb (rtHb) were constructed for identifying a tumor lesion. RESULTS: Serial images of rtHb showed a tumor lesion which corresponded to a hot spot. The level of rtHb rapidly decreased within several hours after administration of single-agent bevacizumab and then persisted at low levels during treatment. From day 2, the value of rtHb gradually increased and peaked on day 5. CONCLUSION: This trend may be explained considering sequential images of rtHb indicating the inhibition of angiogenesis due to antiangiogenic therapy. We conducted a clinical study using single-agent bevacizumab followed by neoadjuvant chemotherapy in primary breast cancer patients to understand vascular remodeling after antiangiogenic agent at very early time points using DOSI.

Clinicopathological and prognostic impact of imaging of breast cancer angiogenesis and hypoxia using diffuse optical spectroscopy.

Near-infrared diffuse optical spectroscopy (DOS) imaging can non-invasively measure tumor hemoglobin concentration using high contrast to normal tissue, thus providing vascularity and oxygenation status. We assessed the clinical usefulness of DOS imaging in primary breast cancer. In all, 118 women with a histologically confirmed diagnosis of primary malignant tumor were enrolled. All participants underwent testing using time-resolved DOS before treatment initiation. Visual assessment of DOS imaging for detecting tumors was carried out by two readers blinded to the clinical data. Relative total hemoglobin (rtHb) and oxygen saturation (stO2 ) of the tumors was compared with clinicopathological variables and 10-year prognosis was calculated. Sensitivity for detecting a tumor based on the rtHb breast map was 62.7% (74/118). The sensitivity depended on T stage: 100% (7/7) for T3, 78.9% (45/57) for T2, 44.7% (17/38) for T1, and 31.3% (5/16) for Tis . Tumors showed unique features of higher rtHb with a wider range of stO2 than normal breast tissue, depending on histological type. There was a significant correlation of rtHb with tumor size, lymphatic vascular invasion, and histological grade, and of stO2 with age and tumor size. Neither rtHb nor stO2 correlated with intrinsic biomarkers such as estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2; rtHb inversely correlated with 10-year relapse-free survival and overall survival, with statistical significance. Diffuse optical spectroscopy imaging has limited utility for the early detection of breast cancer; nonetheless, the findings suggest that the degree of tumor angiogenesis and hypoxia may be associated with tumor aggressiveness and poor prognosis.

Blood flow characteristics of the human lactating breast.

BACKGROUND: Despite the increased metabolic activity of the lactating breast, no studies have been carried out to determine mammary blood flow (MBF) parameters or the relationship between MBF and milk production in women. The aim of this study was to measure the MBF in the internal mammary artery (IMA) and lateral thoracic artery (LTA) of lactating women and determine if these were related to milk production. METHODS: Blood flow in the IMA and LTA was measured with color Doppler ultrasound in 55 lactating women. Twenty-four-hour milk production was determined with the test-weigh method. RESULTS: IMA contributed the greater proportion of blood flow to the lactating breast (70%). MBF was highly variable between women but consistent between the left (126 L/24 h; interquartile range, 76-169) and right (110 L/24 h) breasts. No relationship between MBF and milk production was demonstrated. For 3 women, MBF was markedly reduced in 1 breast that was synthesizing almost no milk compared to the other that was producing a normal volume of milk. DISCUSSION: Although no relationship between MBF and milk production was found, the substantial reduction in blood flow in the breasts of lactating women producing almost no milk suggests a threshold below which milk production is compromised. CONCLUSION: Doppler ultrasound did not demonstrate a relationship between MBF and milk production in lactating women. Further investigation is required to fully understand the role of blood flow in milk synthesis.

[Pathomorphosis of the mammary gland tissue during radical interventions using high-frequency electrosurgical welding].

High-frequency electric welding of a live soft tissues (HFEW LST) is applied widely in all surgical specialties. Its application in surgery of mammary gland cancer constitutes a perspective trend. The impact of HFEW LST and monopolar electrocoagulation on tissues while performing radical operations in patients-women for mammary gland cancer was studied up. Basing on analysis of pathomorphological investigations data, the possibility and perspective of the welding technologies application, while performing radical operations on mammary glands, were established.