Summary In this study, we investigated the mechanism(s) of altered expression of protooncogene SKP2 in metastatic melanoma and its clinical relevance in patients with metastatic melanoma. The genomic status of SKP2 was assessed in cell lines by sequencing, single nucleotide polymorphism array, and genomic PCR. Copy number status was then evaluated for concordance with SKP2 mRNA and protein expression. SKP2 protein was further evaluated by immunohistochemistry in 93 human metastatic tissues. No mutations were identified in SKP2. Increased copy number at the SKP2 locus was observed in 6/14 (43%) metastatic cell lines and in 9/22 (41%) human metastatic tissues which was associated with overexpression of SKP2 protein. Overexpression of SKP2 protein in human tissues was associated with worse survival in a multivariate model controlling for the site of metastasis. Copy number gain is a major contributing mechanism of SKP2 overexpression in metastatic melanoma. Results may have implications for the development of therapeutics that target SKP2.

Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24–3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care.

Introduction: Contrast-induced nephropathy (CIN), defined as an increase in serum creatinine (SCr) greater than 25% or ≥0.5 mg/dL within 3 days of intravenous (IV) contrast administration in the absence of an alternative cause, is the third most common cause of new acute renal failure in hospitalized patients. It is known to increase in-hospital mortality up to 27%. The purpose of this study was to investigate the rate of outpatient follow up and the occurrence of CIN in patients who presented to the emergency department (ED) and were discharged home after computed tomography (CT) of the abdomen and pelvis (AP) with IV contrast.Methods: We conducted a single center retrospective review of charts for patients who required CT of AP with IV contrast and who were discharged home. Patients' clinical data included the presence of diabetes mellitus, hypertension, chronic kidney disease (CKD) and congestive heart failure (CHF).Results: Five hundred and thirty six patients underwent CT of AP with IV contrast in 2011 and were discharged home. Diabetes mellitus was documented in 96 patients (18%). Hypertension was present in 141 patients (26.3%), and 82 patients (15.3%) were on angiotensin-converting-enzyme inhibitors (ACEI). Five patients (0.9%) had documented CHF and all of them were taking furosemide. Seventy patients (13%) had a baseline SCr >1.2 mg/dL. One hundred fifty patients (28%) followed up in one of the clinics or the ED within one week after discharge, but only 40 patients (7.5%) had laboratory workup. Out of 40 patients who followed up within 1 week after discharge, 9 patients (22.5%) developed CIN. One hundred ninety patients (35.4%) followed up in one of the clinics or the ED after 7 days and within 1 month after discharge, but only 71 patients (13.2%) had laboratory workup completed. Out of 71 patients who followed up within 1 month, 11 patients (15%) developed CIN. The overall incidence of CIN was 15.3% (17 out of 111 patients).Conclusion: There was a poor outpatient follow up after CT of AP with IV contrast and biochemically CIN appears to be present in some patients. Unlike previous reports that CKD is the major risk factor for CIN, our results demonstrated that risk factors such as advanced age, DM and hypertension seem to predispose patients to CIN rather than abnormal baseline SCr. [West J Emerg Med. 2014;15(3):276–281.]

Background: Although the current median survival time of stage-IV melanoma patients is less than 12 months, there is a subset of patients who experience long-term survival. Due to poor response rates to standard cytotoxic agents in metastatic melanoma, patients are encouraged to participate in clinical trials, the overall impact of which has not been studied, however. The aim of our study was to identify the factors associated with long-term survival and to determine the impact of clinical trial enrollment on patient outcome. Methods: We studied stage-IV melanoma patients prospectively enrolled at New York University Medical Center from 2002–2008. Associations between clinicopathologic variables and overall post-stage-IV survival were examined. Kaplan-Meier survival analysis was used to identify univariate predictors of post-stage-IV survival and the independent effect of these variables was assessed in a multivariate Cox proportional hazards regression model. The associations between clinicopathologic variables and long-term survival status (≧2 vs. <2 years) were examined by χ² analysis and the independent effect of these variables on the latter was assessed in a multivariate logistic regression model. Results: Site of metastasis, treatment (systemic vs. localized) and pretreatment lactate dehydrogenase (LDH) level independently correlated with post-stage-IV survival. Participation in clinical trials and normal LDH levels were associated with a long-term survival of ≧2 years. Conclusion: Our data suggest that enrollment in clinical trials independently correlates with prolonged survival after a diagnosis of stage IV melanoma.

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Introduction Early-stage, localized melanoma is well treatable by surgical resection yielding 5-year survival rates of 98%. Patients with advanced melanoma, however, have progressively worse 5-year survival rates of 62% and 16% in those with regional lymph node involvement and distal metastasis, respectively. Understanding molecular events that occur early in melanoma development may inform clinical decision-making and uncover novel therapeutic targets. Experimental Procedures We analyzed microRNA (miR) expression levels by Exiqon LNA arrays of RNA isolated from formalin-fixed paraffin embedded primary melanomas (n=92). We compared miR expression levels between primary tumors that did and did not metastasize (2.5-year minimum follow-up) to derive a predictive signature. Further, we used this analysis and a comparison between thick (&gt;2mM) and thin (&lt;2mM) lesions to identify candidate miRs most closely associated with a metastatic phenotype. We selected 40 candidate miRs from these analyses based on strength of significance and expression level for screening in a fluorescence-based in vitro invasion assay to test their functional relevance in a characteristic metastasis assay. Active candidates were further characterized in invasion assays across a larger panel of melanoma cell lines as well as by proliferation assays to distinguish between proliferative and invasive effects. Results The expression of 26 miRs was significantly altered (t-tests, FDR&lt;.01) in primary tumors that metastasized vs. those that did not. We built a logistic regression model using these 26 miRs to test their ability to classify tumors (metastatic vs. non-metastatic), and selected 6 significant miRs (p-values&lt;0.04) as a signature that has robust predictive power with an AUC of 93% of the ROC curve. We are currently validating our results in a second, large cohort of primary melanomas (n=114). Further analysis revealed that 197 miRs were significantly (p&lt;.01) altered in thick v. thin lesions. Moreover, of the 40 candidates selected from these analyses for invasion assay screening, we identified 5 miRs (miR-215, miR-374b*, miR-382, miR-516b, and miR-7) that robustly inhibit in vitro invasion in a panel of 5 melanoma cell lines, supporting the functional relevance of the miR profiling. Of those, miR-215, miR-382, and miR-516b over-expression yields cell-type specific growth inhibition, while miR-7 and miR-374b* impact invasion only. miR target identification is ongoing. Conclusions MicroRNA expression alterations occur at early stages of melanoma development. This study furthers our understanding of the molecular defects that occur during melanomagenesis and how they may impact the progression from a treatable primary tumor to an invasive and ultimately metastatic disease. These results suggest that miRNA expression changes may be predictive of melanoma metastasis and/or functionally impact melanoma progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-340. doi:10.1158/1538-7445.AM2011-LB-340

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9072 Background: Prognosis for survival in MM is not uniform with some pts being long-term survivors. Identifying this subset of pts may have implications on surveillance and treatment (tx). Unfortunately, prognostic data available for MM and the utility of AJCC staging in predicting survival is limited. We analyzed prospectively collected data from the NYUCI Interdisciplinary Melanoma Cooperative Group program (IMCG) to identify clinicopathological variables predictive of MM survival. Methods: We identified 185 pts enrolled in the IMCG with MM diagnosed and treated at NYUCI. Demographic, clinical, and tx-related factors were included in the analysis. Kaplan-Meier (KM) survival analysis was used to identify univariate predictors of post-stage IV survival and their independent effect was assessed in a multivariate Cox proportional hazards regression model. Results: Median age at diagnosis (dx) of metastatic MM was 64 years (22–92). Median overall survival: 13.8 months(m) (128 deaths and a median follow up of 18.6 m (4–141) for survivors). Factors identified on univariate analysis at p<0.20 were evaluated in the multivariate model ( table ). Co-morbidities, site and histology of primary melanoma, initial staging, prior loco-regional recurrences, and adjuvant tx of primary melanoma were not associated with MM survival. Univariate analysis also showed significant survival advantage (p value 0.0011) for patients with AJCC stages M1a and M1b (21.6 m and 17.2 m respectively) over those with AJCC stage M1c (9 m). Conclusions: This cohort study of MM identified female gender, nl serum LDH, nl albumin, and solitary organ involvement as independent survival predictors. Patients who received systemic therapy± local measures had survival benefit over those that had surgery and/or radiation alone suggesting a role for systemic treatment in MM. Patients with personal history of another malignancy (n=37) showed a trend towards improved survival. This novel observation needs to be validated and studied further. [Table: see text] No significant financial relationships to disclose.