Faculty Bibliography

PURPOSE: To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria. EXPERIMENTAL DESIGN: Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria. RESULTS: We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into 'better' and 'worse' prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma. CONCLUSIONS: MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models. Clin Cancer Res; 16(5); 1577-86

ABSTRACT: BACKGROUND: Increased levels of cryptic collagen epitope HU177 in the sera of melanoma patients have been shown to be associated with thicker primary melanomas and with the nodular histologic subtype. In this study, we investigate the association between HU177 shedding in the sera and clinical outcome in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Serum samples from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (mean age=58, mean thickness=2.09 mm, stage I=136, stage II=41, stage III=32, median follow-up=54.9 months) were analyzed for HU177 concentration using a validated ELISA assay. HU177 serum levels at the time of diagnosis were used to divide the study cohort into two groups: low and high HU177. DFS and OS were estimated by Kaplan-Meier survival analysis, and the log-rank test was used to compare DFS and OS between the two HU177 groups. Multivariate Cox proportional hazards regression models were employed to examine the independent effect of HU177 category on DFS and OS. RESULTS: HU177 sera concentrations ranged from 0-139.8 ng/ml (mean and median of 6.2 ng/ml and 3.7 ng/ml, respectively). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. Higher HU177 serum level was associated with an increased rate of melanoma recurrence (p=0.04) and with increasing mortality (p=0.01). The association with overall survival remained statistically significant after controlling for thickness and histologic subtype in a multivariate model (p=0.035). CONCLUSIONS: Increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis. Further studies are warranted to determine the clinical utility of HU177 in risk stratification compared to the current standard of care

BACKGROUND: Teaching and assessing the Accreditation Council for Graduate Medical Education (ACGME) competencies of Professionalism and Communication have proven to be a challenge for surgical residency training programs. This study used innovative pedagogic approaches and tools in teaching these two competencies. The purpose of this study was to determine whether the learners actually are assimilating and using the concepts and values communicated through this curriculum. METHODS: A six-station Objective Structured Clinical Examination (OSCE) was designed using standardized patients to create varying Professionalism and Communication scenarios. The surgical resident learners were evaluated using these OSCEs as a baseline. The faculty then facilitated a specially designed curriculum consisting of six interactive sessions focusing on information gathering, rapport building, patient education, delivering bad news, responding to emotion, and interdisciplinary respect. At the conclusion of this curriculum, the surgical resident learners took the same six-station OSCE to determine if their professionalism and communication skills had improved. RESULTS: The surgical resident learners were rated by the standardized patients according to a strict task checklist of criteria at both the precurricular and postcurricular OSCEs. Improvement in the competencies of Professionalism and Communication did achieve statistical significance (P = .029 and P = .011, respectively). CONCLUSIONS: This study suggests that the Communication and Professionalism ACGME competencies can be taught to surgical resident learners through a carefully crafted curriculum. Furthermore, these newly learned competencies can affect surgical resident interactions with their patients positively

Background: Most skin cancer-related deaths are due to malignant melanoma. Risk assessment criteria for melanoma currently include skin phenotype, family and sun exposure history, factors that are subject to observer and recall bias. Genetic markers of susceptibility have been identified in association studies; however little progress has been made in developing them to improve screening and identification of individuals at risk of melanoma. Tyrosinase (TYR), a known susceptibility gene and a determinant of skin pigmentation, was thus investigated further to characterize its association with melanoma susceptibility and to identify markers which can be used in a risk assessment model. Methods: The cohort consisted of 326 individuals diagnosed with melanoma and 400 control subjects. TYR was interrogated using fifteen tag single nucleotide polymorphisms (SNPs) spanning the gene and statistical association tests performed. Additionally, ancestry informative markers were utilized to correct for population genetic sub-structure. Haplotype analysis was performed to determine if specific regions of the gene contributed more significantly to susceptibility. Coding regions of the gene are currently being sequenced and identified variants will be tested for impact on enzymatic function. Results: Of the 15 SNPs, 8 were associated with melanoma; 4 with decreased risk (Odds ratios 0.41-0.71) and 4 with increased risk (Odds ratios 1.43-1.96). SNPs localized to 2 regions of the gene (spanning exon 1 to intron 2 and intron 3 to 4) with markers of increased as well as decreased susceptibility present in both areas. With the exception of one coding region variant, SNPs were localized to introns. Conclusions: SNPs localized to TYR may serve as useful biomarkers for determining susceptibility to melanoma. We are currently sequencing the gene in our population in order to identify additional and potentially more potent markers of melanoma susceptibility. Coding region variants are being characterized for their effect on protein stability and enzyme activity such that functional active variants (most likely to affect susceptibility to melanoma) can be identified and assessed for their utility in melanoma risk assessment

Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging