Breast-Lesion Characterization using Textural Features of Quantitative Ultrasound Parametric Maps

© 2017 The Author(s). This study evaluated, for the first time, the efficacy of quantitative ultrasound (QUS) spectral parametric maps in conjunction with texture-analysis techniques to differentiate non-invasively benign versus malignant breast lesions. Ultrasound B-mode images and radiofrequency data were acquired from 78 patients with suspicious breast lesions. QUS spectral-analysis techniques were performed on radiofrequency data to generate parametric maps of mid-band fit, spectral slope, spectral intercept, spacing among scatterers, average scatterer diameter, and average acoustic concentration. Texture-analysis techniques were applied to determine imaging biomarkers consisting of mean, contrast, correlation, energy and homogeneity features of parametric maps. These biomarkers were utilized to classify benign versus malignant lesions with leave-one-patient-out cross-validation. Results were compared to histopathology findings from biopsy specimens and radiology reports on MR images to evaluate the accuracy of technique. Among the biomarkers investigated, one mean-value parameter and 14 textural features demonstrated statistically significant differences (p < 0.05) between the two lesion types. A hybrid biomarker developed using a stepwise feature selection method could classify the legions with a sensitivity of 96%, a specificity of 84%, and an AUC of 0.97. Findings from this study pave the way towards adapting novel QUS-based frameworks for breast cancer screening and rapid diagnosis in clinic

Cross-imaging system comparison of backscatter coefficient estimates from a tissue-mimicking material

A key step toward implementing quantitative ultrasound techniques in a clinical setting is demonstrating that parameters such as the ultrasonic backscatter coefficient (BSC) can be accurately estimated independent of the clinical imaging system used. In previous studies, agreement in BSC estimates for well characterized phantoms was demonstrated across different laboratory systems. The goal of this study was to compare the BSC estimates of a tissue mimicking sample measured using four clinical scanners, each providing RF echo data in the 1-15 MHz frequency range. The sample was previously described and characterized with single-element transducer systems. Using a reference phantom for analysis, excellent quantitative agreement was observed across the four array-based imaging systems for BSC estimates. Additionally, the estimates from data acquired with the clinical systems agreed with theoretical predictions and with estimates from laboratory measurements using single-element transducers

Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound

<p>Abstract</p> <p>Background</p> <p>Genetically engineered mouse models of mammary gland cancer enable the <it>in vivo </it>study of molecular mechanisms and signaling during development and cancer pathophysiology. However, traditional whole mount and histological imaging modalities are only applicable to non-viable tissue.</p> <p>Methods</p> <p>We evaluated three techniques that can be quickly applied to living tissue for imaging normal and cancerous mammary gland: reflectance confocal microscopy, green fluorescent protein imaging, and ultrasound imaging.</p> <p>Results</p> <p>In the current study, reflectance confocal imaging offered the highest resolution and was used to optically section mammary ductal structures in the whole mammary gland. Glands remained viable in mammary gland whole organ culture when 1% acetic acid was used as a contrast agent. Our application of using green fluorescent protein expressing transgenic mice in our study allowed for whole mammary gland ductal structures imaging and enabled straightforward serial imaging of mammary gland ducts in whole organ culture to visualize the growth and differentiation process. Ultrasound imaging showed the lowest resolution. However, ultrasound was able to detect mammary preneoplastic lesions 0.2 mm in size and was used to follow cancer growth with serial imaging in living mice.</p> <p>Conclusion</p> <p>In conclusion, each technique enabled serial imaging of living mammary tissue and visualization of growth and development, quickly and with minimal tissue preparation. The use of the higher resolution reflectance confocal and green fluorescent protein imaging techniques and lower resolution ultrasound were complementary.</p

Soft tissue viscoelastic properties: measurements, models and interpretation

The quantification of mechanical properties of soft tissues has been of great interest for more than two decades because they have the potential of being used as biomarkers for disease diagnosis. Indentation techniques, the most recognized techniques for characterizing mechanical properties, are widely used for basic science investigations in research labs. The use of elastography techniques coupled with imaging technologies has been growing rapidly in recent years, which is promising for clinical applications. Each technique produces different mechanical behaviors due to the interaction of the stimuli and the structure of the tissue. An appropriate model will parameterize these behaviors to reflect the corresponding tissue microscopic features with high fidelity. The objective of this thesis is to identify combinations of techniques and models that will yield mechanical parameters with diagnostic interpretations about tissue microenvironment. Three techniques for characterizing tissue viscoelastic properties were developed and validated, each offers strengths in a large variety of applications. Indentation based techniques measure low-frequency force-displacement curves under different loading profiles. Ultrasound-based techniques and optical based techniques measure the dispersion behaviors of the propagating wave velocities at mid-to-high frequency ranges. When a material is linear, isotropic, and contains only elastic components, the “intrinsic” elastic modulus of the material can be obtained independently of the technique used when corrections are properly made to eliminate the bias from boundary effects. If the material includes time-dependent components, models must be included in the analysis to provide parametric estimates. Classical models for viscoelastic solids such as the Kelvin-Voigt model do not fully represent mechanical measurements in tissues because they are not material continua. Tissue properties are determined in part by fluid movement in the open- and closed-cell compartments found within a viscoelastic collagen matrix that is actively maintained by the embedded cells to meet programmed needs. These biphasic (solid/fluid) media exhibit multifaceted deformation responses that are particularly difficult to model using a concise feature set. The Kelvin-Voigt fractional derivative (KVFD) model introduced in this study represents the measurement data of a broad range in both time and frequency domain with a small number of parameters, and it yields stable estimates for many types of phantoms and tissues. It is superior to the integer derivative models for the materials and techniques we used in this study. Moreover, the KVFD model provides a three-dimensional feature space of mechanical properties that properly characterizes the composition and structure of a material. This was validated through measurements on gelatin-cream emulsion samples exhibiting viscoelastic behavior, as well as ex vivo liver tissue samples. For the elastic property, KVFD parameter E_0 mainly represents the elasticity of the solid matrix and is approximately equal to the shear modulus no matter which technique is used. For the viscous property, when combined with different measurement techniques, KVFD model parameter α and τ represent different tissue components. The combination of these techniques and the KVFD model have the potential to be able to distinguish between healthy and pathological tissues described by the histological features

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Spectral Ultrasound Characterization of Tissues and Tissue Engineered Constructs.

Even though ultrasound imaging is widely used in clinical diagnosis and image-guided interventions, the field is far behind other areas of clinical quantitative image analysis, such as MRI, CT and X-ray mammography. In this thesis, non-destructive and non-invasive ultrasound characterization techniques were developed to study the tissue micro-structural details using high frequency spectral ultrasound imaging (SUSI). The techniques were explored in in-vitro conditions of acellular and cellular tissue engineered constructs and then on ex-vivo tissues for their characterization. SUSI was used to assess the amount of hydroxyl-apatite (HA) mineral, differentiate HA mineral types and study their distribution in acellular tissue engineered constructs. The process of mineral deposition from surrounding mineralizing media onto simple collagen constructs was also studied and characterized with SUSI. 3D morphological changes of the constructs with MC3t3 cells was monitored and characterized for the developmental changes such as net cell proliferation/apoptosis and cell differentiation process through mineral production by the early osteoblastic MC3t3-cell constructs in-situ. A novel method was introduced using SUSI to estimate the amount of mineral secreted by the differentiated osteoblast cells in a non-destructive method. Then, SUSI was investigated in ex-vivo cardiac tissues to monitor and characterize the cellular changes during high-intensity focused ultrasound ablation with high-frame-rate and high-resolution ultrasound imaging. The mechanistic hypotheses behind the improvement in lesion detection were investigated and best identification methods to assess lesion formation and transient gas body activities were proposed to provide a method for visualizing spatiotemporal evolution of lesion and gas–body activity and for predicting macroscopic cavity formation upon its implementation as a real-time monitoring technique with feedback control system for HIFU treatment of atrial fibrillation to improve the ablation process. Even though the results from the developed techniques show great promise in in-vitro and ex-vivo settings, additional work needs to be carried out to demonstrate the applicability of the techniques in in-vivo.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/99788/1/msreddy_1.pd

Investigating the Role of Bptf in Immunoediting in Breast Cancer and Melanoma

In this study, we explore the effects of NURF depletion on the growth of tumors in immune-competent mice. NURF depletion in tumors results in reduced tumor growth in immune-competent mice, suggesting enhanced anti-tumor immunity. Analysis of the tumor microenvironment by flow cytometry revealed a significantly elevated CD8 and progressively elevated activated CD8 phenotype in Bptf KD tumors, possibly contributing to the increase in cell death and decrease in tumor weight observed. Examination of antigen presentation was evaluated using the OT-1 and Pmel-17 models, though no significant difference in cytotoxicity was observed as measured by LDH and/or IFNγ assays. This indicates possible novel antigen presentation mechanisms in tumor cells, and not increased presentation of existing antigens, contributes to the decreased tumor weight observed in Bptf KD tumors