Wavelength Optimization for Quantitative Spectral Imaging of Breast Tumor Margins

A wavelength selection method that combines an inverse Monte Carlo model of reflectance and a genetic algorithm for global optimization was developed for the application of spectral imaging of breast tumor margins. The selection of wavelengths impacts system design in cost, size, and accuracy of tissue quantitation. The minimum number of wavelengths required for the accurate quantitation of tissue optical properties is 8, with diminishing gains for additional wavelengths. The resulting wavelength choices for the specific probe geometry used for the breast tumor margin spectral imaging application were tested in an independent pathology-confirmed ex vivo breast tissue data set and in tissue-mimicking phantoms. In breast tissue, the optical endpoints (hemoglobin, β-carotene, and scattering) that provide the contrast between normal and malignant tissue specimens are extracted with the optimized 8-wavelength set with <9% error compared to the full spectrum (450–600 nm). A multi-absorber liquid phantom study was also performed to show the improved extraction accuracy with optimization and without optimization. This technique for selecting wavelengths can be used for designing spectral imaging systems for other clinical applications.     

Quantitative Segmentation of Fluorescence Microscopy Images of Heterogeneous Tissue: Application to the Detection of Residual Disease in Tumor Margins

Purpose

To develop a robust tool for quantitative in situ pathology that allows visualization of heterogeneous tissue morphology and segmentation and quantification of image features.

Materials and Methods

Tissue excised from a genetically engineered mouse model of sarcoma was imaged using a subcellular resolution microendoscope after topical application of a fluorescent anatomical contrast agent: acriflavine. An algorithm based on sparse component analysis (SCA) and the circle transform (CT) was developed for image segmentation and quantification of distinct tissue types. The accuracy of our approach was quantified through simulations of tumor and muscle images. Specifically, tumor, muscle, and tumor+muscle tissue images were simulated because these tissue types were most commonly observed in sarcoma margins. Simulations were based on tissue characteristics observed in pathology slides. The potential clinical utility of our approach was evaluated by imaging excised margins and the tumor bed in a cohort of mice after surgical resection of sarcoma.

Results

Simulation experiments revealed that SCA+CT achieved the lowest errors for larger nuclear sizes and for higher contrast ratios (nuclei intensity/background intensity). For imaging of tumor margins, SCA+CT effectively isolated nuclei from tumor, muscle, adipose, and tumor+muscle tissue types. Differences in density were correctly identified with SCA+CT in a cohort of ex vivo and in vivo images, thus illustrating the diagnostic potential of our approach.

Conclusion

The combination of a subcellular-resolution microendoscope, acriflavine staining, and SCA+CT can be used to accurately isolate nuclei and quantify their density in anatomical images of heterogeneous tissue.     

A Quantitative Diffuse Reflectance Imaging (QDRI) System for Comprehensive Surveillance of the Morphological Landscape in Breast Tumor Margins

In an ongoing effort to address the clear clinical unmet needs surrounding breast conserving surgery (BCS), our group has developed a next-generation multiplexed optical-fiber-based tool to assess breast tumor margin status during initial surgeries. Specifically detailed in this work is the performance and clinical validation of a research-grade intra-operative tool for margin assessment based on diffuse optical spectroscopy. Previous work published by our group has illustrated the proof-of-concept generations of this device; here we incorporate a highly optimized quantitative diffuse reflectance imaging (QDRI) system utilizing a wide-field (imaging area = 17cm²) 49-channel multiplexed fiber optic probe, a custom raster-scanning imaging platform, a custom dual-channel white LED source, and an astronomy grade imaging CCD and spectrograph. The system signal to noise ratio (SNR) was found to be greater than 40dB for all channels. Optical property estimation error was found to be less than 10%, on average, over a wide range of absorption (μ_a = 0–8.9cm^-1) and scattering (μ_s’ = 7.0–9.7cm^-1) coefficients. Very low inter-channel and CCD crosstalk was observed (2% max) when used on turbid media (including breast tissue). A raster-scanning mechanism was developed to achieve sub-pixel resolution and was found to be optimally performed at an upsample factor of 8, affording 0.75mm spatially resolved diffuse reflectance images (λ = 450–600nm) of an entire margin (area = 17cm²) in 13.8 minutes (1.23cm²/min). Moreover, controlled pressure application at the probe-tissue interface afforded by the imaging platform reduces repeated scan variability, providing <1% variation across repeated scans of clinical specimens. We demonstrate the clinical utility of this device through a pilot 20-patient study of high-resolution optical parameter maps of the ratio of the β-carotene concentration to the reduced scattering coefficient. An empirical cumulative distribution function (eCDF) analysis is used to reduce optical property maps to quantitative distributions representing the morphological landscape of breast tumor margins. The optimizations presented in this work provide an avenue to rapidly survey large tissue areas on intra-operative time scales with improved sensitivity to regions of focal disease that may otherwise be overlooked.     

Biomarkers of Residual Disease,Disseminated Tumor Cells,and Metastases in the MMTV-PyMT Breast Cancer Model

Cancer metastases arise in part from disseminated tumor cells originating from the primary tumor and from residual disease persisting after therapy. The identification of biomarkers on micro-metastases, disseminated tumors, and residual disease may yield novel tools for early detection and treatment of these disease states prior to their development into metastases and recurrent tumors. Here we describe the molecular profiling of disseminated tumor cells in lungs, lung metastases, and residual tumor cells in the MMTV-PyMT breast cancer model. MMTV-PyMT mice were bred with actin-GFP mice, and focal hyperplastic lesions from pubertal MMTV-PyMT;actin-GFP mice were orthotopically transplanted into FVB/n mice to track single tumor foci. Tumor-bearing mice were treated with TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), and residual and relapsed tumor cells were sorted and profiled by mRNA microarray analysis. Data analysis revealed enrichment of the Jak/Stat pathway, Notch pathway, and epigenetic regulators in residual tumors. Stat1 was significantly up-regulated in a DNA-damage-resistant population of residual tumor cells, and a pre-existing Stat1 sub-population was identified in untreated tumors. Tumor cells from adenomas, carcinomas, lung disseminated tumor cells, and lung metastases were also sorted from MMTV-PyMT transplant mice and profiled by mRNA microarray. Whereas disseminated tumors cells appeared similar to carcinoma cells at the mRNA level, lung metastases were genotypically very different from disseminated cells and primary tumors. Lung metastases were enriched for a number of chromatin-modifying genes and stem cell-associated genes. Histone analysis of H3K4 and H3K9 suggested that lung metastases had been reprogrammed during malignant progression. These data identify novel biomarkers of residual tumor cells and disseminated tumor cells and implicate pathways that may mediate metastasis formation and tumor relapse after therapy.     

基于谱域光学相干层析系统中光谱涨落的指纹获取

指纹因其特异性和稳定性等特点而被称为"证据之首",在案件侦破中起着极其重要的作用。多种物理学、化学和光学技术都可以用于获取现场遗留的指纹,然而这些方法存在一些缺点,如会对指纹造成破坏、潜在的毒副作用、在现场留有痕迹等。利用谱域光学相干层析(spectral domain optical coherence tomography,简记为SD-OCT)技术进行指纹探测具有非接触、对指纹无损伤和高灵敏度的优势,利用OCT系统的相位敏感性我们可以在低对比条件下再现遗留在物体表面的指纹,但处理结果受指纹所在表面高低起伏影响,使得指纹信息对比度降低,难以被分离和提取。本文提出了一种基于干涉光谱涨落的指纹获取方法,只需对OCT系统得到的干涉光谱的涨落进行处理分析,即可得到遗留在物体表面的指纹图案,不需进行相位和表面轮廓高度的求取,算法简单、处理速度快,处理结果不受样品表面高低起伏的影响。实验结果表明,在起伏表面上,使用该方法也能较好地显现遗留在物体表面的指纹图案。     

Liquid-Solid Phase-Inversion PLGA Implant for the Treatment of Residual Tumor Tissue after HIFU Ablation

BackgroundHIFU has been shown to be a more suitable alternative for the treatment of primary solid tumors and metastatic diseases than other focal heat ablation techniques due to its noninvasive and extracorporeal nature. However, similar to other focal heat ablation techniques, HIFU is still in need of refinements due to tumor recurrence.MethodsIn this work, we investigated the effectiveness of an adjunct treatment regimen using doxorubicin (DOX)-loaded, injectable, in situ-forming, and phase-inverting PLGA as the second line of defense after HIFU ablation to destroy detrimental residual tumors and to prevent tumor recurrence. All of the statistical analyses were performed using the Statistical Package for the Social Sciences 18.0(SPSS, Inc., Chicago, IL, USA), and p< 0.05 was considered statistically significant. All of the results are presented as the means ± STDEV (standard deviation). For multiple comparisons, ANOVA (differences in tumor volumes, growth rates, apoptosis, proliferation indexes, and Bcl-2 and Bax protein levels) was used when the data were normally distributed with homogenous variance, and rank sum tests were used otherwise. Once significant differences were detected, Student-t tests were used for comparisons between two groups.ResultsOur results revealed that DOX diffused beyond the ablated tissue regions and entered tumor cells that were not affected by the HIFU ablation. Our results also show that HIFU in concert with DOX-loaded PLGA led to a significantly higher rate of tumor cell apoptosis and a lower rate of tumor cell proliferation in the areas beyond the HIFU-ablated tissues and consequently caused significant tumor volume shrinkage (tumor volumes:0.26±0.1,1.09±0.76, and 1.42±0.9cm³ for treatment, sham, and no treatment control, respectively).ConclusionsFrom these results, we concluded that the intralesional injection of DOX-loaded PLGA after HIFU ablation is significantly more effective than HIFU alone for the treatment of solid tumors.     

Ultrasound Guided Optoacoustic Tomography in Assessment of Tumor Margins for Lumpectomies

PURPOSE: To determine the accuracy of a handheld ultrasound-guided optoacoustic tomography (US-OT) probe developed for human deep-tissue imaging in ex vivo assessment of tumor margins postlumpectomy. METHODS: A custom-built two-dimensional (2D) US-OT–handheld probe was used to scan 15 lumpectomy breast specimens. Optoacoustic signals acquired at multiple wavelengths between 700 and 1100 nm were reconstructed using model linear algorithm, followed by spectral unmixing for lipid and deoxyhemoglobin (Hb). Distribution maps of lipid and Hb on the anterior, posterior, superior, inferior, medial, and lateral margins of the specimens were inspected for margin involvement, and results were correlated with histopathologic findings. The agreement in tumor margin assessment between US-OT and histopathology was determined using the Bland–Altman plot. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of margin assessment using US-OT were calculated. RESULTS: Ninety margins (6 × 15 specimens) were assessed. The US-OT probe resolved blood vessels and lipid up to a depth of 6 mm. Negative and positive margins were discriminated by marked differences in the distribution patterns of lipid and Hb. US-OT assessments were concordant with histopathologic findings in 87 of 89 margins assessed (one margin was uninterpretable and excluded), with diagnostic accuracy of 97.9% (kappa = 0.79). The sensitivity, specificity, PPV, and NPV were 100% (4/4), 97.6% (83/85), 66.7% (4/6), and 100% (83/83), respectively. CONCLUSION: US-OT was capable of providing distribution maps of lipid and Hb in lumpectomy specimens that predicted tumor margins with high sensitivity and specificity, making it a potential tool for intraoperative tumor margin assessment.     

Detection of Human Papillomavirus DNA in Patients with Breast Tumor in China

The presence of HPV in breast tissue and the potential causal association between human papillomavirus (HPV) and breast cancer (BC) remains controversial. The aim of the present study was to compare the HPV prevalence in BC tissues, adjacent normal breast tissues and breast benign disease tissues and to investigate the possible association between HPV and breast tumor development in Chinese women. Paraffin-embedded specimens from 187 pairs of BCs including tumor and normal breast tissue adjacent to tumors and 92 breast benign lesions between June 2009 and July 2014 were investigated by nested polymerase chain reaction (PCR) and type-specific PCR, respectively. With strictly quality control, HPV positive infection was detected in three BC tissues. No HPV positive infection was detected in all normal breast tissue adjacent to tumors and benign breast tissues. Through our detailed analysis, rare HPV infection in this study suggests that HPV might not be associated with BC progression.     

乳腺肿瘤组织标本库与数据库的建立及信息化管理

目的:随着基础和临床研究的深入开展,拥有完整基因信息的组织标本成为了肿瘤研究工作的基础.建立电子信息化管理的乳腺肿瘤组织标本库和数据库,为临床和科研收集、保存和管理标本资源.方法:标准化收集手术切除的乳腺肿瘤组织、正常腺体组织,以及患者血液标本,预处理后保存于-80℃冰箱中.每3个月从标本库中随机抽取5例标本,提取标本的总RNA,琼脂糖凝胶电泳验证总RNA质量;运用免疫组织化学法(Immunohistochemistry,IHC)检测标本中人表皮生长因子-2(Human epidermal growth factor receptor,HER-2 or c-erbB-2)和Ki67的表达,并与术后免疫组化结果进行比较.同时利用Epidata软件管理乳腺肿瘤组织标本库.结果:收集恶性肿瘤507例,良性肿瘤212例,血液标本9347份,并建立了一套高效的信息化管理系统.总RNA电泳结果显示28 S和18S亚基条带清晰明亮,5S条带很弱,表明标本中的RNA质量较高,无降解.免疫组化结果显示标本中的HER-2和Ki67的表达与术后免疫组化结果情况吻合,存储的标本质量良好.结论:建立的实验标本收集、储存流程是有效可行的,收集的标本质量是可靠的,管理方法是高效实用的,为乳腺肿瘤基础和临床研究提供质量可靠的标本来源,可为乳腺肿瘤研究提供良好的服务平台.     

Values of MMP-2 and MMP-9 in Tumor Tissue of Basal-Like Breast Cancer Patients

Gelatinase A (MMP-2) and gelatinase B (MMP-9) are proteolytic enzymes involved in process of tumor invasion, and they are considered as possible tumor markers in breast cancer patients. In this study, we measured activity of latent and active form of MMP-2 and MMP-9 in tumor and adjacent tissue of 60 breast cancer patients by SDS-PAGE zymography. The activity of both form of gelatinases significantly increased with each advancing clinical stage of disease. ProMMP-9 and aMMP-9 activity in tumor tissue shows a positive association with tumor size. Patients with lymph node involvement have higher proMMP-2, aMMP-2 and aMMP-9 activity than node negative patients. Steroid receptor-negative tumors had enhanced aMMP-2 and aMMP-9 activity. Patients with basal-like cancers had higher proMMP-2 tumor activity and aMMP-2 adjacent tissue activity compared to patients with luminal A tumors. Patients with negative hormone receptors are associated with increased activity of both form of gelatinases in adjacent tissue. Reported increased activity of MMP-2 in tumor and adjacent tissue of basal-like tumors implicates that MMP-2 might have a role in aggressive biology of basal-like cancers. Additional investigations regarding molecular pathways in adjacent tissue could give better insight into aggressive nature of basal-like carcinomas.     

肿瘤标志物联合检测在乳腺癌早期诊断中的应用

目的：探讨肿瘤标志物癌胚抗原（CEA）、糖链抗原19-9（CA19-9）、糖链抗原15-3（CA15-3）联合检测在乳腺癌早期诊断中的应用价值。方法：检测87例乳腺癌患者,55例乳腺良性肿瘤患者和35例健康人血清中CEA、CA19-9、CA153等肿瘤标志物的水平及3种标志物不同组合对乳腺癌的阳性检出率。结果：乳腺癌患者3种肿瘤标志物显著高于正常对照组及乳腺良性肿瘤组（P〈0.01）。3项标志物不同组合对不同分期乳腺癌检出的敏感性均高于单项标志物。其中CEA＋CA199＋CA153组合的检出敏感性较其他组合均高,特别是对早期患者检出率明显提高。结论：CEA＋CA199＋CA153联合检测能提高乳腺癌的早期诊断率。     

肿瘤标志物联合检测在乳腺癌早期诊断中的应用

目的:探讨肿瘤标志物癌胚抗原(CEA)、糖链抗原19-9(CA19-9)、糖链抗原15-3(CA15-3)联合检测在乳腺癌早期诊断中的应用价值。方法:检测87例乳腺癌患者,55例乳腺良性肿瘤患者和35例健康人血清中CEA、CA19-9、CA153等肿瘤标志物的水平及3种标志物不同组合对乳腺癌的阳性检出率。结果:乳腺癌患者3种肿瘤标志物显著高于正常对照组及乳腺良性肿瘤组(P<0.01)。3项标志物不同组合对不同分期乳腺癌检出的敏感性均高于单项标志物。其中CEA+CA199+CA153组合的检出敏感性较其他组合均高,特别是对早期患者检出率明显提高。结论:CEA+CA199+CA153联合检测能提高乳腺癌的早期诊断率。     

皮肤肿瘤早期筛查的快速无创电阻抗检测方法

目的 随着环境问题和臭氧层空洞化的加剧,皮肤肿瘤的患病率也大幅增加,但是皮肤肿瘤前期隐蔽性高、症状不明显,导致大部分病例都是在中晚期发现的。因此,本文基于生物阻抗谱(bioimpedance spectroscopy,BIS)技术,提出一种皮肤肿瘤早期筛查的快速无创电阻抗检测方法。方法 首先,建立四层皮肤模型,采用数值分析方法研究角质层对BIS测量的阻碍作用。其次,使用去除角质层的皮肤模型研究混有不同半径和浸润深度的皮肤肿瘤组织电学特性。最后,使用凝胶处理后的猪皮组织实验验证肿瘤浸润深度(h)的影响。结果 角质层仿真结果表明,去除角质层的皮肤对激励信号的响应更明显。皮肤肿瘤模型仿真表明,当肿瘤半径(R_tumor)及h>1.5 mm时能够区分肿瘤组织与正常组织。同时根据实验结果中正常组织与肿瘤组织虚部弛豫阻抗(Z_imag-relax)定义了组织病变度(ε_worse,为肿瘤组织虚部阻抗相对于正常组织虚部阻抗变化的百分比),并绘制了肿瘤组织浸润深度(Depth)与Z_imag-relax的拟合曲线。当...     

三维微波热声成像系统及早期乳腺肿瘤检测研究

本文讨论了正常乳房组织与肿瘤组织的微波吸收差异,从理论上证明了利用微波热声成像技术检测乳腺肿瘤的可能性;建立了一套三维热声扫描系统,并利用此系统对模拟肿瘤和真实离体肿瘤进行成像实验。实验结果表明,三维微波热声成像系统能对乳腺肿瘤高分辨率高对比度成像,有希望应用于早期乳腺肿瘤检测。     

基于相关检测的多通道近红外光组织光学测量系统

研制了一套基于相关检测技术的三波长多通道近红外光信号采集系统。采用相敏检波模块CD505R有效提高信噪比。Delphi开发的上位机程序通过串口方式与单片机通信。使用光纤传递光源及探测信号,使系统具有更大的灵活性,适用于多种组织光学特性测量方式。模型实验的结果证明该系统准确可靠,前臂阻断实验表明系统对不同深度组织血氧状况具有较好的测量能力。     

The Association between Breast Tissue Optical Content and Mammographic Density in Pre- and Post-Menopausal Women

Mammographic density (MD), associated with higher water and lower fat content in the breast, is strongly related to breast cancer risk. Optical attenuation spectroscopy (OS) is a non-imaging method of evaluating breast tissue composition by red and near-infrared light transmitted through the breast that, unlike mammography, does not involve radiation. OS provides information on wavelength dependent light scattering of tissue and on absorption by water, lipid, oxy-, deoxy-hemoglobin. We propose that OS could be an alternative marker of breast cancer risk and that OS breast tissue measures will be associated with MD. In the present analysis, we developed an algorithm to estimate breast tissue composition and light scattering parameters using a spectrally constrained global fitting procedure employing a diffuse light transport model. OS measurements were obtained from 202 pre- and post-menopausal women with normal mammograms. Percent density (PD) and dense area (DA) were measured using Cumulus. The association between OS tissue composition and PD and DA was analyzed using linear regression adjusted for body mass index. Among pre-menopausal women, lipid content was significantly inversely associated with square root transformed PD (β = -0.05, p = 0.0002) and DA (β = -0.05, p = 0.019); water content was significantly positively associated with PD (β = 0.06, p = 0.008). Tissue oxygen saturation was marginally inversely associated with PD (β = -0.03, p = 0.057) but significantly inversely associated with DA (β = -0.10, p = 0.002). Among post-menopausal women lipid and water content were significantly associated (negatively and positively, respectively) with PD (β_lipid = -0.08, β_water = 0.14, both p<0.0001) and DA (β_lipid = -0.10, p<0.0001; β_water = 0.11, p = 0.001). The association between OS breast content and PD and DA is consistent with more proliferation in dense tissue of younger women, greater lipid content in low density tissue and higher water content in high density tissue. OS may be useful for assessing physiologic tissue differences related to breast cancer risk, particularly when mammography is not feasible or easily accessible.     

Sampling Considerations for Disease Surveillance in Wildlife Populations

Abstract Disease surveillance in wildlife populations involves detecting the presence of a disease, characterizing its prevalence and spread, and subsequent monitoring. A probability sample of animals selected from the population and corresponding estimators of disease prevalence and detection provide estimates with quantifiable statistical properties, but this approach is rarely used. Although wildlife scientists often assume probability sampling and random disease distributions to calculate sample sizes, convenience samples (i.e., samples of readily available animals) are typically used, and disease distributions are rarely random. We demonstrate how landscape-based simulation can be used to explore properties of estimators from convenience samples in relation to probability samples. We used simulation methods to model what is known about the habitat preferences of the wildlife population, the disease distribution, and the potential biases of the convenience-sample approach. Using chronic wasting disease in free-ranging deer (Odocoileus virginianus) as a simple illustration, we show that using probability sample designs with appropriate estimators provides unbiased surveillance parameter estimates but that the selection bias and coverage errors associated with convenience samples can lead to biased and misleading results. We also suggest practical alternatives to convenience samples that mix probability and convenience sampling. For example, a sample of land areas can be selected using a probability design that oversamples areas with larger animal populations, followed by harvesting of individual animals within sampled areas using a convenience sampling method.     

血清多肿瘤标志物蛋白芯片检测在乳腺癌诊断中的价值

目的:探讨血清多肿瘤标志物蛋白芯片检测系统在乳腺癌诊断中的临床价值。方法:临床确诊的乳腺癌患者307例为乳腺癌组,非乳腺癌的其他恶性肿瘤患者495例为对照组。应用多肿瘤标志物蛋白芯片检测系统检测12种肿瘤标志物水平,评价血清肿瘤标志物的在乳腺癌组与对照组之间的差异。结果:CA153,CEA,Free-PSA这三项指标为诊断乳腺癌的独立相关因素(P<0.05),比较三项指标ROC曲线下面积可见,CA153对于鉴别乳腺癌准确性更高,其敏感性、特异性分别为78.92和56.14,女性乳腺癌患者Free-PSA可见明显升高,对乳腺癌有特殊提示意义,手术前后标志物CA199、CA242、Ferrin、CA125水平差异有统计学意义。结论:在临床常用的肿瘤标记物中,CA153,CEA,Free_PSA水平的升高与乳腺癌发生独立相关,其中CA153具有更高的诊断准确性,Free_PSA水平升高对乳腺癌的诊断有特别提示意义。     

Breast Tissue Composition and Its Dependence on Demographic Risk Factors for Breast Cancer: Non-Invasive Assessment by Time Domain Diffuse Optical Spectroscopy

Background

Breast tissue composition is recognized as a strong and independent risk factor for breast cancer. It is a heritable feature, but is also significantly affected by several other elements (e.g., age, menopause). Nowadays it is quantified by mammographic density, thus requiring the use of ionizing radiation. Optical techniques are absolutely non-invasive and have already proved effective in the investigation of biological tissues, as they are sensitive to tissue composition and structure.

Methods

Time domain diffuse optical spectroscopy was performed at 7 wavelengths (635-1060 nm) on 200 subjects to derive their breast tissue composition (in terms of water, lipid and collagen content), blood parameters (total hemoglobin content and oxygen saturation level), and information on the microscopic structure (scattering amplitude and power). The dependence of all optically-derived parameters on age, menopausal status, body mass index, and use of oral contraceptives, and the correlation with mammographic density were investigated.

Results

Younger age, premenopausal status, lower body mass index values, and use of oral contraceptives all correspond to significantly higher water, collagen and total hemoglobin content, and lower lipid content (always p < 0.05 and often p < 10^-4), while oxygen saturation level and scattering parameters show significant dependence only on some conditions. Even when age-adjusted groups of subjects are compared, several optically derived parameters (and in particular always collagen and total hemoglobin content) remain significantly different.

Conclusions

Time domain diffuse optical spectroscopy can probe non-invasively breast tissue composition and physiologic blood parameters, and provide information on tissue structure. The measurement is suitable for in vivo studies and monitoring of changes in breast tissue (e.g., with age, lifestyle, chemotherapy, etc.) and to gain insight into related processes, like the origin of cancer risk associated with breast density.