Faculty Bibliography

Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of alpha-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.

Patients with stage IB melanoma have a 10% risk of melanoma-specific mortality within five years. The current prognostic paradigm, however, is insufficient to predict which of these patients are most likely to recur. Additional prognostic characteristics of stage IB melanoma are needed to identify this patient subset who are at highest risk of recurrence, and may benefit from closer follow-up. We evaluated a prospective cohort of stage IB patients (n = 655) treated at NYU Langone Medical Center. In a research subset (n = 149) composed of patients with recurrent (n = 63) and nonrecurrent (n = 86) disease matched for age, sex, thickness, ulceration and mitoses, primary tumors were independently reviewed for digitally calculated area, manually calculated area (depth x width), width, and conformation (contiguous versus noncontiguous) using computer-assisted histopathological analysis (Aperio, Vista, CA USA). We tested the association between histologic variables and recurrence-free survival (RFS) using Cox univariate analysis. Increasing digital area (HR 1.08, P < 0.01), tumor width (HR 1.17, P = 0.01), and non-contiguous conformation (HR 0.57, P = 0.05) were independently prognostic of RFS. Linear regression analysis showed a significant correlation between the manual and digital area (estimate 0.64, P < 0.01), which became even stronger when restricted to patients with contiguous tumors (estimate 0.75, P < 0.01), suggesting manually calculated tumor area may also provide useful prognostic information for providers without access to similar software. Computer-assisted measurement of cross-sectional tumor area, width, and contiguity may help risk-stratification in stage IB patients. Independent validation of these primary tumor characteristic is needed to fully comprehend their prognostic role in stage IB melanoma

Patients with thick (>4 mm) primary melanomas have highly variable outcomes. Current staging criteria for these patients are based primarily on the presence of nodal disease, which often serves as the basis for adjuvant trial eligibility. Identification of novel biomarkers could help identify patients who may benefit from promising, new adjuvant therapies or, alternatively, spare patients with good prognoses the cost and potential toxicity of these drugs. We examined patients with thick primary melanoma to determine whether proliferation markers (mitotic index and Ki- 67) and other clinicopatholgical features were associated with survival. We studied 171 patients with thick primary melanomas; median thickness was 6.0 mm (median follow-up, 3.0 years). In clinically node-negative patients, Ki-67 expression was an independent predictor of worse RFS (HR 2.19, P = 0.024) and OS (HR 2.49, P = 0.028). In a separate model, moderate (>1 to <5 per mm²) and many (>5 per mm²) mitoses were each significantly associated with RFS (HR = 9.97, P = 0.035 and HR = 11.93, P = 0.025, respectively); and OS (HR = 12.79, P = 0.033 and HR = 18.68, P = 0.017, respectively). In the same model, natural log-transformed tumor thickness was also significantly associated with worse OS (HR 2.37, P = 0.009). In sum, we identified cell proliferation markers Ki-67 and mitotic index as independent predictors of survival in clinically nodenegative patients with thick primary melanoma. Greater tumor thickness was also an independent predictor of survival in this cohort. With further investigation, these measures may improve risk-stratification for patients with thick primary melanoma

Purpose To identify MR imaging features of melanoma brain metastases (MBM) that correlate with genetic profile of melanoma and patient survival. Materials and methods Patients with newly diagnosed melanoma metastases were identified from institutional database A retrospective review of brain MRI was performed focusing on lesion number, size, T1-, T2- and diffusion-weighted signal characteristics, hemorrhage, necrosis, enhancement pattern and edema. Genomic (BRAF status), treatment and survival data was collected. Results 98 patients were included in final analysis. A strong correlation was found between size of the largest lesion and the percent of lesions with T1-weighted hyperintense signal (R = 0.49), percent of lesions with size >1 cm (0.55), and the lesions that are clearly hemorrhagic (0.43). The analyzed imaging parameters were found to be independent of BRAF mutation status. The median survival of subjects with single lesion (9.1 months) was significantly higher than the median survival of subjects with more than 1 lesion (4.9 months) (p = 0.002). Patients with 2-18 lesions had significantly longer survival (5.6 months) than with >18 lesions (2 months) (p < 0.001). Other imaging parameters such as lesion size, T1-weighted hyperintensity, number of lesions with edema and hemorrhage were not found to be significantly related to survival. BRAF inhibitor treatment was found to be the most significant prognostic factor (p = 0.002) among patients with multiple lesions. Conclusion There is a statistically significant correlation between number of brain metastases and survival. In patients with multiple lesions, BRAF inhibitor treatment was the most significant prognostic factor.

BACKGROUND: Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts. METHODS: We queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as 65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis. RESULTS: We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas. CONCLUSIONS: Older age at time of melanoma diagnosis is associated with shorter MSS, however age's association with clinicopathologic features is dependent upon specific characteristics of the study population. TIL as a read-out of the host immune response may have greater prognostic impact in patients older than age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly.