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.

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.

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.

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.

Each year more than 180,000 new cases of breast cancer are diagnosed in women in the U.S. If cancer is detected when small and local, treatment options are less dangerous, intrusive, and costly-and more likely to lead to a cure. Yet those simple facts belie the complexity of developing and disseminating acceptable techniques for breast cancer diagnosis. Even the most exciting new technologies remain clouded with uncertainty. Mammography and Beyond provides a comprehensive and up-to-date perspective on the state of breast cancer screening and diagnosis and recommends steps for developing the most reliable breast cancer detection methods possible. This book reviews the dramatic expansion of breast cancer awareness and screening, examining the capabilities and limitations of current and emerging technologies for breast cancer detection and their effectiveness at actually reducing deaths. The committee discusses issues including national policy toward breast cancer detection, roles of public and private agencies, problems in determining the success of a technique, availability of detection methods to specific populations of women, women's experience during the detection process, cost-benefit analyses, and more. Examining current practices and specifying research and other needs, Mammography and Beyond will be an indispensable resource to policy makers, public health officials, medical practitioners, researchers, women's health advocates, and concerned women and their families.

The impact of molecular imaging on diagnostics, therapy, and follow-up in oncology is increasing steadily. Many innovative molecular imaging probes have already entered clinical practice, and there is no doubt that the future emphasis will be on multimodality imaging in which morphological, functional, and molecular imaging techniques are combined in a single clinical investigation. This handbook addresses all aspects of molecular imaging in oncology, from basic research to clinical applications. The first section is devoted to technology and probe design, and examines a variety of PET and SPECT tracers as well as multimodality probes. Preclinical studies are then discussed in detail, with particular attention to multimodality imaging. In the third section, diverse clinical applications are presented, and the book closes by looking at future challenges. This handbook will be of value to all who are interested in the revolution in diagnostic oncology that is being brought about by molecular imaging.

Breast carcinoma is a dreaded disease. The incidence of breast cancer, which appears to be increasing, is 1 in 1500 women with an annual death rate of 4,000 from this disease in the United States (1). It is a cancer which threatens its victims with mutilation as weIl as early death. Although response to therapy has not been good, improved methods for earlier and more complete diagnosis are providing hope for better results. When a woman presents herself for routine breast examination, what diagnostic procedures are indicated? If a breast mass is present, what diagnostic and therapeutic methods are employed? When the mass proves to be malignant, what then? Should biopsy and mastectomy be a combined procedure? Should a positive biopsy be followed by a complete diagnostic work-up before definitive therapy is undertaken? While some answers may seem obvious and others less obvious, common medical practices vary considerably in response to all of these situations. No easy formula exists. Each patient must be given individual consideration and her* treatment carefully planned to incorporate all the diagnostic findings. Experience to date indicates that some diagnostic and therapeutic procedures have established efficacy while others are not very helpful and still others need more evaluation before their usefulness can be . assessed fully. Traditionally, treatment of breast cancer has been surgical. Through the years poor results from surgery, along with acquisition of knowledge of the lymphatic spread of this malignancy, prompted more and more extensive surgical procedures.