Project I will continue to support MSLT-I and MSLT-II by providing expert consultation and close quality assurance services. Using data from these trials, we will evaluate pathological aspects of the techniques of lymphatic mapping and sentinel node (SN) biopsy, investigate the cellular and molecular basis of SN susceptibility to metastases and the cellular and molecular mechanisms that underlie that susceptibility. Specifically Project I personnel, working with Core B will confirm and categorise the primary melanomas and SN of all patients entering MSLT-II. Patient demographic characteristics for MSLT-I and MSLT4I and characteristics of their primary melanomas, singly and combined into algorithms, will be be evaluated for capacity to predict tumor-positive SN (histologically and/or molecularly-positive SN (Project II), extranodal recurrence and death from melanoma (with Project III).We will also assess the impact of extent of SN sampling on frequency of positive SN, nodal (false-negative SN) and extranodal recurrences and death from melanoma). We will also investigate the capacity of characteristics of SN tumor and SN immune reactivity to predict melanoma in non-SN, subsequent extranodal metastases and death from mealanoma. These studies wil include analysis of the amount and distribution of SN tumor, biological characteristics of the cells of SN metastases, alterations in the density, dendriticity and maturity immunophenotype of paracortical dendritic cells, subtyping of T lymphocytes and assessment of the nodal vasculature. These studies will be closely correlated with the outcome-predictive potential of nodes that are molecularly positive, but histologically negative (Project II). In addition, we will evaluate the basis of molecular-positivity in face of histological negativity, by exhaustively evaluating tissue blocks from such patients by histology and immunohistology. We will continue to investigate the cellular and molecular basis of SN immunedownregulation and susceptibility to metastases by assessing the constitution of immune competent cell populations in tumor-positive and tumor-negative SN and in the tissues adjacent to autologous primary melanomas by immunohistology and quanitative morphometry. The molecular basis of relationships between primary melanomas and immunologically active cells associated with them and tumor-positive and -negative SN will depend on cytokine and chemokine profiling of primaries and their associated cells by immunohistology and RT in situ PCR.
Quality assurance is critical for acceptance of MSLT-II outcome data, more accurate prediction of SN status, extranodal recurrence and death from melanoma and better individualized treatment. Understanding optimal SN sampling for histology and the biology and significance of ?molecularly? positive SN will determine optimal laboratory evaluation of SN. Knowledge of the cellular and molecular mechanisms underpinning SN susceptibility to metastases may lead to novel therapies.
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|Marzese, Diego M; Scolyer, Richard A; Huynh, Jamie L et al. (2014) Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis. Hum Mol Genet 23:226-38|
|Morton, Donald L; Thompson, John F; Cochran, Alistair J et al. (2014) Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370:599-609|
|Marzese, Diego M; Hirose, Hajime; Hoon, Dave S B (2013) Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn 13:827-44|
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