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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA029605-32
Application #
8544985
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
32
Fiscal Year
2013
Total Cost
$773,536
Indirect Cost
$428,342
Name
John Wayne Cancer Institute
Department
Type
DUNS #
556074458
City
Santa Monica
State
CA
Country
United States
Zip Code
90404
Wang, Jinhua; Huang, Sharon K; Marzese, Diego M et al. (2015) Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J Invest Dermatol 135:532-41
Lessard, Laurent; Liu, Michelle; Marzese, Diego M et al. (2015) The CASC15 Long Intergenic Noncoding RNA Locus Is Involved in Melanoma Progression and Phenotype Switching. J Invest Dermatol 135:2464-74
Wang, Jinhua; Hua, Wei; Huang, Sharon K et al. (2015) RASSF8 regulates progression of cutaneous melanoma through nuclear factor-κb. Oncotarget 6:30165-77
Deutsch, Gary B; Kirchoff, Daniel D; Faries, Mark B (2015) Metastasectomy for stage IV melanoma. Surg Oncol Clin N Am 24:279-98
Faries, Mark B (2015) From the guest editor: The sentinel node: evolution of the revolution. Introduction. Cancer J 21:1-2
Marzese, Diego M; Hoon, Dave Sb (2015) Emerging technologies for studying DNA methylation for the molecular diagnosis of cancer. Expert Rev Mol Diagn 15:647-64
Faries, M B; Cochran, A J; Elashoff, R M et al. (2015) Multicenter Selective Lymphadenectomy Trial-I confirms the central role of sentinel node biopsy in contemporary melanoma management: response to 'No survival benefit for patients with melanoma undergoing sentinel lymph node biopsy: critical appraisal of t Br J Dermatol 172:571-3
Marzese, Diego M; Liu, Michelle; Huynh, Jamie L et al. (2015) Brain metastasis is predetermined in early stages of cutaneous melanoma by CD44v6 expression through epigenetic regulation of the spliceosome. Pigment Cell Melanoma Res 28:82-93
Ono, Shigeshi; Oyama, Takashi; Lam, Stella et al. (2015) A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients. Oncotarget 6:7053-64
Cochran, Alistair J; Huang, Rong-Rong; Su, Albert et al. (2015) Is sentinel node susceptibility to metastases related to nodal immune modulation? Cancer J 21:39-46

Showing the most recent 10 out of 248 publications