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Treatment with 131I-MIBG has mainly hematologic toxicity, which can be abrogated with bone marrow rescue. The high response rate in refractory disease suggests that this agent may be useful in combination with myeloablative chemotherapy and autologous stem-cell rescue to improve outcome in advanced neuroblastoma.

A better understanding of tumor metastasis requires development of animal models that authentically reproduce the metastatic process. By modifying an existing mouse model of breast cancer, we discovered that macrophage-stimulating protein promoted breast tumor growth and metastasis to several organs. A special feature of our findings was the occurrence of osteolytic bone metastases, which are prominent in human breast cancer. To explore the clinical relevance of our model, we examined expression levels of three genes involved in activation of the MSP signaling pathway (MSP, MT-SP1, and MST1R) in human breast tumors. We found that overexpression of MSP, MT-SP1, and MST1R was a strong independent indicator of both metastasis and death in human breast cancer patients and significantly increased the accuracy of an existing gene expression signature for poor prognosis. These data suggest that signaling initiated by MSP is an important contributor to metastasis of breast cancer and introduce an independent biomarker for assessing the prognosis of humans with breast cancer.bone metastasis ͉ Ron ͉ tumor ͉ inflammation ͉ prognostic factor B reast cancer often results in metastasis to many organs, including lymph nodes, bone, lungs, brain, and liver. The most frequent site of breast cancer metastasis is the bone, which occurs in Ϸ80% of patients with advanced disease (1). To better understand metastasis of breast cancer, models are needed in which metastases spontaneously occur from tumors arising in the orthotopic site. Such models have been described, although they use immortalized cell lines and usually require immunodeficient hosts. We describe here the modification of a mouse model of breast cancer in which tumors originate from primary breast epithelial cells, and metastasis occurs from an orthotopic tumor in immunocompetent animals. This experimental system allows us to efficiently examine the effect of individual genes or combinations of genes on tumor behavior. In this study, we examined the role of macrophage-stimulating protein (MSP) in breast tumor growth and metastasis.MSP was originally identified as a serum protein that elicited macrophage chemotaxis and activation (2, 3). MSP is secreted as an inactive single-chain precursor (pro-MSP), which becomes active after proteolytic cleavage to yield a disufide-linked heterodimer. The protease that activates pro-MSP was isolated from the extracellular membranes of macrophages (4) and has recently been identified as membrane-type serine protease-1 (MT-SP1, also known as matripase), which is expressed on macrophages and several types of epithelial cells, including breast cells (5).The biological effects of MSP are not restricted to macrophages. In particular, MSP can promote migration of various epithelial cell lines (6, 7), and the receptor for MSP, macrophage-stimulating-1 receptor (MST1R, also known as Ron), can induce an epithelialto-mesenchymal transition in immortalized canine kidney cells in vitro (8). Evidence is accumulating that the MSP/MST1R pathway is inv...

The need to study dynamic biologic processes in intact smallanimal models of disease has stimulated the development of highresolution nuclear imaging methods. These methods are capable of clarifying molecular interactions important in the onset and progression of disease, assessing the biologic relevance of drug candidates and potential imaging agents, and monitoring therapeutic effectiveness of pharmaceuticals serially within a single-model system. Single-photon-emitting radionuclides have many advantages in these applications, and SPECT can provide 3-dimensional spatial distributions of g-(and x-) ray-emitting radionuclide imaging agents or therapeutics. Furthermore, combining SPECT with CT in a SPECT/CT system can assist in defining the anatomic context of biochemical processes and improve the quantitative accuracy of the SPECT data. Over the past decade, dedicated small-animal SPECT and SPECT/CT systems have been developed in academia and industry. Although significant progress in this arena has been realized through system development and biologic application, further innovation continues to address challenges in camera sensitivity, spatial resolution, and image reconstruction and quantification. The innumerable applications of small-animal SPECT and SPECT/CT in drug development, cardiology, neurology, and oncology are stimulating further investment in education, research, and development of these dedicated small-animal imaging modalities. Rapi dly evolving knowledge of molecular biology has stimulated exploration of novel therapies targeting specific points in molecular pathways associated with cardiac disease, neurologic disorders, cancer, and many other pathologic processes. However, identifying the role of a molecule in a disease process modeled in vitro does not necessarily translate to an understanding of its interactions with other molecular processes in vivo. On the other hand, few of all disease processes can be fully studied in human patients because of logistical and ethical concerns. Small-animal models represent a critical bridge between discoveries at the molecular level and implementation of clinically relevant diagnostics or therapeutics. Emphasis is ever increasing that these models accurately recapitulate both the disease itself and the environment in which the key molecular processes take place. For example, xenograft mouse models of cancer are simple to develop but are not considered particularly useful in understanding molecular interactions involved in carcinogenesis. More sophisticated approaches, such as transgenic models using oncogene activation or tumor suppressor inactivation, have evolved to the point at which cancers may be induced in a spatially and temporally defined manner using deletion of specified genetic sequences with Cre recombinase (1,2). Sophisticated infrastructures have been developed to manage data related to small-animal models of disease and provide greater access to various mouse models for all investigators, exemplified by the Mouse Models of Human Cancer Cons...

Three-dimensional quantitative computed tomographic (QCT) studies of the lumbar spine were extended with finite element analysis (FEA) to include bone distribution in assessment of vertebral body strength. Fifty-nine FEA models were created from data from 43 patients, 28 with no evidence of osteoporosis and 15 with previous vertebral fractures. Simulated loads were applied to the vertebral models to estimate vertebral strength. Yield strength in the models from patients with osteoporosis was 0.22-1.05 MPa (average, 0.57 MPa +/- 0.26 [mean +/- standard deviation]), compared with 0.80-2.79 MPa (1.46 +/- 0.52, P less than .001) in patients with normal bone. Yield strength of vertebrae in patients with osteoporosis uniformly fell below approximately 1.0 MPa, with minimal overlap between patients with osteoporosis and those with normal bone compared with the overlap in bone mineral content and trabecular mineral density. Reproducibility of the FEA technique was 12.1% in a subgroup of patients with normal bone. A constant relationship between cortical and trabecular contributions was observed in patients with osteoporosis but not in control patients.

Calculations of radiation dose are important in assessing the medical and biological implications of ionizing radiation in medical imaging techniques such as SPECT and PET. In contrast, radiation dose estimates of SPECT and PET imaging of small animals are not very well established. For that reason we have estimated the whole-body radiation dose to mice and rats for isotopes such as 18F, 99mTc, 201Tl, (111)In, 123I, and 125I that are used commonly for small animal imaging. We have approximated mouse and rat bodies with uniform soft tissue equivalent ellipsoids. The mouse and rat sized ellipsoids had a mass of 30 g and 300 g, respectively, and a ratio of the principal axes of 1:1:4 and 0.7:1:4. The absorbed fractions for various photon energies have been calculated using the Monte Carlo software package MCNP. Using these values, we then calculated MIRD S-values for two geometries that model the distribution of activity in the animal body: (a) a central point source and (b) a homogeneously distributed source, and compared these values against S-value calculations for small ellipsoids tabulated in MIRD Pamphlet 8 to validate our results. Finally we calculated the radiation dose taking into account the biological half-life of the radiopharmaceuticals and the amount of activity administered. Our calculations produced S-values between 1.06 x 10(-13) Gy/Bq s and 2.77 x 10(-13) Gy/Bq s for SPECT agents, and 15.0 x 10(-13) Gy/Bq s for the PET agent 18F, assuming mouse sized ellipsoids with uniform source distribution. The S-values for a central point source in an ellipsoid are about 10% higher than the values obtained for the uniform source distribution. Furthermore, the S-values for mouse sized ellipsoids are approximately 10 times higher than for the rat sized ellipsoids reflecting the difference in mass. We reviewed published data to obtain administered radioactivity and residence times for small animal imaging. From these values and our computed S-values we estimated that the whole body dose in small animals ranges between 6 cGy and 90 cGy for mice and between about 1 cGy and 27 cGy for rats. The whole body dose in small animal imaging can be very high in comparison to the lethal dose to mice (LD50/30 approximately 7 Gy). For this reason the dose in small animal imaging should be monitored carefully and the administered activity should be kept to a minimum. These results also underscore the need of further development of instrumentation that improves detection efficiency and reduces radiation dose in small animal imaging.

SPECT/CT has emerged over the past decade as a means of correlating anatomical information from CT with functional information from SPECT. The integration of SPECT and CT in a single imaging device facilitates anatomical localization of the radiopharmaceutical to differentiate physiological uptake from that associated with disease and patient-specific attenuation correction to improve the visual quality and quantitative accuracy of the SPECT image. The first clinically available SPECT/CT systems performed emission-transmission imaging using a dual-headed SPECT camera and a low-power x-ray CT sub-system. Newer SPECT/CT systems are available with high-power CT sub-systems suitable for detailed anatomical diagnosis, including CT coronary angiography and coronary calcification that can be correlated with myocardial perfusion measurements. The high-performance CT capabilities also offer the potential to improve compensation of partial volume errors for more accurate quantitation of radionuclide measurement of myocardial blood flow and other physiological processes and for radiation dosimetry for radionuclide therapy. In addition, new SPECT technologies are being developed that significantly improve the detection efficiency and spatial resolution for radionuclide imaging of small organs including the heart, brain, and breast, and therefore may provide new capabilities for SPECT/CT imaging in these important clinical applications.

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