Herein we demonstrate the construction of the first reported fluorescence animal tomographer for molecular investigations of cancer-associated expression patterns. Using inversion techniques that account for the diffuse nature of photon propagation in tissue and near infrared fluorescent molecular beacons we were able to obtain three-dimensional in-vivo images of cathepsin B expression of orthopic gliomas. We demonstrate that fluorescent probes, activated by carcinogenesis, can be detected with high positional accuracy and high sensitivity in deep tissues, that molecular specificities of different beacons towards enzymes can be resolved, and that tomography of beacon activation is linearly related to enzyme concentration. The tomographic imaging method offers a range of new capabilities for studying biological function using fluorescent chemical sensors, for identifying molecular expression patterns via multispectral imaging and for continuously monitoring drug therapies. It is envisaged that molecular sensing will significantly improve the detection capacity of early cancer since malignancy identification is based on the molecular signals responsible for carcinogenesis and not on structural or functional tissue changes inflicted by well-formed cancers that are currently targeted by traditional medical imaging techniques.

Optical imaging has enjoyed a large following in cancer in general and breast cancer in particular (i.e., diffuse optical imaging, DOI and diffuse optical tomography, DOT). Optical imaging biomarkers emerge from modeling specific near-infrared (NIR) absorption signatures that are sensitive indicators of important molecular concentration and disposition. We have developed Diffuse Optical Spectroscopic Imaging (DOSI) by increasing spectral information content for the purpose of increasing access to molecular targets and states. Malignancy-specific optical imaging biomarkers may be important because the above-mentioned changes in tumor hemoglobin, water and lipids are a necessary but not a sufficient condition to classify therapeutic response. We note that for all therapeutic imaging assessments (i.e., mammography, ultrasound, MRI, PET) that the same case is true for their respective contrast mechanisms. By a novel spectral analysis method, we have discovered the presence of absorption signatures that are unique to malignant lesions. A reproducible absorption spectrum (Specific Tumor Component, STC) with several distinct spectral features emerges when compared with the normal absorption spectra (the flat line near zero) measured from the normal tissue of these subjects plus an additional 21 patients without any evidence of malignancy. These data demonstrate the existence of a spectral signature that acts as an optical biomarker for malignancy. We are not aware of any other such biomarker that combines high specificity with ease of application in the imaging field. This DOSI-measured malignancy-specific biomarker STC provides an ideal non-invasive surrogate biomarker for breast lesion detection and differentiation. Although STC offers both spectroscopic and quantitative information for breast malignancy, this method relies on complicated data analysis and lacks of standardization. Thus, it is still far from a clinical reality. In order to carry out a quantitative assessment of its potential in becoming a standardized clinical detection modality for tumor detection/prediction/prognosis, the longitudinal temporal stability of signatures must be evaluated and the detection limit must be set. The overall clinical goal is to evaluate the possibilities for STC detection method to become a future clinical practice. Building the linkage between pre-existing detection modalities (pathological biomarkers, DCE-MRI) and novel spectral signature detection is essential. The medical interpretation of the findings from conventional tools will shed light on the understanding and further employment of STC biomarker. Similarly, STC detection with a high diagnosis sensitivity and specificity could be very well an adjunct method for traditional modalities.

Written by an authority involved in the field since its nascent stages, Diffuse Optical Tomography: Principles and Applications is a long-awaited profile of a revolutionary imaging method. Diffuse Optical Tomography (DOT) provides spatial distributions of intrinsic tissue optical properties or molecular contrast agents through model-based reconstruction algorithms using NIR measurements along or near the boundary of tissue. Despite the practical value of DOT, many engineers from electrical or applied mathematics backgrounds do not have a sufficient understanding of its vast clinical applications and portability value, or its uncommon advantages as a tool for obtaining functional, cellular, and molecular parameters. A collection of the author’s research and experience, this book fuses historical perspective and experiential anecdotes with fundamental principles and vital technical information needed to successfully apply this technology—particularly in medical imaging. This reference finally outlines how to use DOT to create experimental image systems and adapt the results of laboratory studies for use in clinical applications including: Early-stage detection of breast tumors and prostate cancer "Real-time" functional brain imaging Joint imaging to treat progressive diseases such as arthritis Monitoring of tumor response New contrast mechanisms and multimodality methods This book covers almost every aspect of DOT—including reconstruction algorithms based on nonlinear iterative Newton methods, instrumentation and calibration methods in both continuous-wave and frequency domains, and important issues of imaging contrast and spatial resolution. It also addresses phantom experiments and the development of various image-enhancing schemes, and it describes reconstruction methods based on contrast agents and fluorescence DOT. Offering a concise description of the particular problems involved in optical tomography, this reference illustrates DOT’s fundamental foundations and the principle of image reconstruction. It thoroughly explores computational methods, forward mathematical models, and inverse strategies, clearly illustrating solutions to key equations.

In November 1999, the Institute of Medicine, in consultation with the Commission on Life Sciences, the Commission on Physical Sciences, Mathematics, and Applications, and the Board on Science, Technology and Economic Policy launched a one year study on technologies for early detection of breast cancer. The committee was asked to examine technologies under development for early breast cancer detection, and to scrutinize the process of medical technology development, adoption, and dissemination. The committee is gathering information on these topics for its report in a number of ways, including two public workshops that bring in outside expertise. The first workshop on "Developing Technologies for Early Breast Cancer Detection" was held in Washington DC in February 2000. The content of the presentations at the workshop is summarized here. A second workshop, which will focus on the process of technology development and adoption, will be held in Washington, DC on June 19-20. A formal report on these topics, including conclusions and recommendations, will be prepared by the committee upon completion of the one-year study.

New near-infrared (NIR) diffuse optical tomography (DOT) approaches were developed to detect, locate, and image small targets embedded in highly scattering turbid media. The first approach, referred to as time reversal optical tomography (TROT), is based on time reversal (TR) imaging and multiple signal classification (MUSIC). The second approach uses decomposition methods of non-negative matrix factorization (NMF) and principal component analysis (PCA) commonly used in blind source separation (BSS) problems, and compare the outcomes with that of optical imaging using independent component analysis (OPTICA). The goal is to develop a safe, affordable, noninvasive imaging modality for detection and characterization of breast tumors in early growth stages when those are more amenable to treatment. The efficacy of the approaches was tested using simulated data, and experiments involving model media and absorptive, scattering, and fluorescent targets, as well as, "realistic human breast model" composed of ex vivo breast tissues with embedded tumors. The experimental arrangements realized continuous wave (CW) multi-source probing of samples and multi-detector acquisition of diffusely transmitted signal in rectangular slab geometry. A data matrix was generated using the perturbation in the transmitted light intensity distribution due to the presence of absorptive or scattering targets. For fluorescent targets the data matrix was generated using the diffusely transmitted fluorescence signal distribution from the targets. The data matrix was analyzed using different approaches to detect and characterize the targets. The salient features of the approaches include ability to: (a) detect small targets; (b) provide three-dimensional location of the targets with high accuracy (~within a millimeter or 2); and (c) assess optical strength of the targets. The approaches are less computation intensive and consequently are faster than other inverse image reconstruction methods that attempt to reconstruct the optical properties of every voxel of the sample volume. The location of a target was estimated to be the weighted center of the optical property of the target. Consequently, the locations of small targets were better specified than those of the extended targets. It was more difficult to retrieve the size and shape of a target. The fluorescent measurements seemed to provide better accuracy than the transillumination measurements. In the case of ex vivo detection of tumors embedded in human breast tissue, measurements using multiple wavelengths provided more robust results, and helped suppress artifacts (false positives) than that from single wavelength measurements. The ability to detect and locate small targets, speedier reconstruction, combined with fluorophore-specific multi-wavelength probing has the potential to make these approaches suitable for breast cancer detection and diagnosis.

In this thesis, we apply sensor-based tools for investigating breast tissue characteristics to identify anomalies, including cancer. The non-invasive technologies utilized are based on the Electrical Impedance Spectroscopy (EIS) and Diffuse Optical Imaging (DOI). As the accuracy of Clinical Breast Examination (CBE) depends on the physician's experience, these technologies enhance the diagnostic capabilities by providing additional information. We tested twenty patients utilizing these technologies, in a clinical trial, with around 100% success rate in identifying the location of cancerous tumors.The correlation between healthy and cancerous tissue electrical properties is defined by extracting the electrical features of tissues based on Cole-Cole model. Also, by processing the raw data of the DOI-probe, we have been able to create the cross-sectional optical images of the breast in different wavelengths from 690nm to 850nm. This study suggests that EIS and DOI are useful technologies for early detection of breast cancers.