; Lymphedema (LE) is a disabling, disfiguring disease that results in limb swelling, pain, increased incidence of infections, skin fibrosis, and depression. LE may be hereditary (primary) or acquired (secondary), with most cases of secondary LE in the developed world resulting from cancer treatment. Not everyone who survives cancer surgery, chemotherapy, and radiation treatment develops LE-40% of breast cancer, 10-20% of reproductive tract cancer, and 75% of head and neck cancer survivors experience swelling, starting anytime during or after treatment. The cause of secondary LE after cancer treatment is completely unknown. There is a critical unmet need to be able to determine who will develop LE after cancer treatment, because early LE diagnosis and treatment can often reverse swelling and prevent long-term morbidities such as skin fibrosis and cellulitis. Additionally, identifying causative or correlative immune parameters may suggest therapeutic intervention strategies to arrest LE development. Despite recent reports implying a role for inflammation in LE in animal studies, no studies to date have compared the status of systemic host immunity in cancer survivors who develop LE and those who do not. Given these findings, we hypothesize that near-infrared fluorescence imaging (NIRFLI) will allow visualization of the earliest changes in lymphatic architecture and function as LE develops, and these changes can be correlated to alterations in toll-like receptor (TLR) activity in peripheral blood immune cells that can drive production of the inflammatory cytokines TNF-?, IL-1, and IL-6 to slow lymph pumping and allow LE development. This hypothesis will be addressed in the experiments of the following Specific Aims: (1) to examine if NIRFLI can detect the earliest LE-related changes to lymphatic vessel anatomy and function in advanced breast cancer patients, (2) to determine if changes in plasma cytokine levels and peripheral blood mononuclear cell (PBMC) and granulocyte function associate with development of lymphedema, and (3) to assess if changes to lymphatic vessel anatomy and function correlate to the appearance of plasma and immune cell markers of autoimmunity. This work is a prospective Phase I study to evaluate the efficacy of NIRFLI in detecting the earliest changes in lymphatic vessel architecture and pumping as LE develops, correlated to peripheral blood immune status. The information gleaned from this study could help to predict susceptibility to development of LE, ensure early treatment and perhaps prevention, and guide selection of potential therapeutics.
These exploratory studies are relevant and important to public health for two reasons. First, they may provide the first visual description of changes in lymphatic architecture and function during the development of lymphedema following radiation and axillary lymph node dissection treatment in humans. Secondly, the work can define the systemic inflammatory immune changes occurring during and after radiation treatment, providing potential therapeutic targets for lymphedema.
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