The primary tumor is the primary source of metastasis in a human melanoma/SCID model. Implications for the direct autocrine and paracrine epigenetic regulation of the metastasis process.

Although previous autopsy and experimental studies had indicated that metastases can metastasize, the question of whether metastases from metastases increasingly contribute to the overall metastatic burden is crucial to the basic question of whether the metastatic process is more directly regulated by genetic or by epigenetic mechanisms. The highly metastatic human C8161 melanoma was transfected with either pSV2neo or pSV2hygro and clones of neo-C8161 and hyg-C8161 were injected intravenously and subcutaneously in SCID mice. In combination experiments, both the timing and size of inoculum of tumor cells were titrated to ensure that the hematogenously injected cells disseminated almost exclusively to the lungs and that the overall pulmonary burden was equal to the primary tumor. In s.c. injection experiments, no spontaneous metastases ever developed when the primary tumor was extirpated before it had grown to more then 0.5 cm in diameter. When the primary tumor approached 1 cm in diameter, widely-disseminated metastases developed within lungs, liver subcutaneous sites and other internal viscera. In the combination-injection experiments, while large numbers of both hematogenously and spontaneously metastatic clones were recovered from the lungs, a vast excess of only the latter clones was recovered from extrapulmonary sites. Both hematogenously and spontaneously metastatic pulmonary clones recovered showed similar levels of Matrigel invasion and collagenases by substrate gel electrophoresis, but significantly decreased levels when compared to the cell line. Primary tumor clones, in contrast, demonstrated increased invasion and increased collagenases. Our findings argue for the importance of paracrine (orthotopic) and autocrine (size) epigenetic mechanisms in the regulation of metastasis.

Physicochemical and immunological basis of silicone pathophysiology.

Silicones, model biomaterials with almost ubiquitous applications, are the focus of a contentious debate. In this review, we will consider both established physicochemical phenomena and immunological phenomena; and then consider the human clinical phenomena that relate directly to them. We will explore the two competing theories of the biological activity of silicones, and we will discuss the weaknesses in the various arguments that silicone is inert. We conclude that from a pathophysiological perspective, silicones should be expected to be bioactive materials and that the physicochemical and immunological data at the experimental level are compelling.

Silicone breast implant pathology. Clinical data and immunologic consequences.

Silicone breast prostheses are medical devices, implanted subcutaneously or subpectorally, that are designed to replace or augment the volume occupied by breast glandular tissue. They are generally effective in creating tissue mounds, and their apparent medical benefit is primarily psychological. Recent data on immunologic phenomena associated with silicone exposure suggest to us that silicone breast implants may interact with native tissue in a way that is analogous to implantable vaccinating devices. Background information, clinical findings, and possible immunologic consequences are presented.

Immunology of silicone breast implants.

Understanding the immunology of silicone breast implants, at present, consists of reconciling an increasingly large body of data with an older, established, but otherwise unsubstantiated theory. Despite the variety of silicone breast implants, there are nevertheless certain phenomena that occur with all silicone gel-filled devices. Recent clinical findings suggest that in some patients, silicone will act as an adjuvant on native macromolecules and render them immunogenic. The purpose of this review is to highlight biophysical and clinical phenomena that warrant further investigation.