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Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

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Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wildtype BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmidbased shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.T he successful development of targeted therapy for melanomas harboring BRAF mutations has garnered significant attention, given the promising results of small molecule inhibitors of mutant BRAF (1). However, the molecular basis underlying the metastasis of the ≈50% of all human melanomas that lack a BRAF mutation, and specific targets for the therapy of these melanomas, is unclear. As a result, "triple-negative melanoma" patients, whose tumors harbor wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), neuroblastoma RAS viral (vras) oncogene homolog (NRAS), and phosphatase and tensin homolog (PTEN) (the most common mutations observed in melanoma), are not candidates for most targeted therapies developed to date.The type I insulin-like growth factor receptor (IGF1R) signaling pathway has been recognized to play an increasingly important role in tumorigenesis (2, 3). Binding of IGF1 or IGF2 to IGF1R results in phosphorylation of tyrosine and carboxyl-terminal serine residues that form binding sites for the insulin-receptor substrate (IRS) docking proteins. IRS activation results in PI3K recruitment and AKT activation (4). Efficient docking of IRS proteins is mediated via their pleckstrin homology domain. Pleckstrin homology domain-interacting protein (PHIP), initially identified through interactions with the pleckstrin homology domain of IRS proteins, has been shown to mediate transcriptional responses in pancreatic islet cells (5), and is important for postnatal growth (6). Previously, we identified PHIP as the gene most highly overexpressed in metastatic melanomas, compared with primary tumors by cDNA microarray analysis (7). Although PHIP plays a r...

Purpose: To determine the prognostic significance of a multimarker assay incorporating expression levels of three molecular markers in primary cutaneous melanoma. Experimental Design: We assessed expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of 395 patients. For each marker, we identified optimal cut-points for expression intensity to predict diseasespecific survival (DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative overexpression of all three markers was embodied in a multimarker index, and its prognostic effect on DSS and SLN status was assessed using Cox regression, Kaplan-Meier analysis, and logistic regression. The prognostic effect of this multimarker assay on DSS was assessed in an independent cohort of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections. Results: Increasing multimarker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient cohort. Multivariate logistic regression analysis revealed multimarker expression scores as an independent predictor of SLN status (P = 0.001). Multivariate Cox regression analysis showed the independent effect of the multimarker index on DSS (P < 0.001). The multimarker index was the most significant factor predicting DSS when compared with other clinical and histologic factors, including SLN status (P = 0.002). Multimarker expression scores were also the most significantly predictive of DSS in the independent cohort (P = 0.01). Conclusions: These results describe a multimarker assay with independent prognostic effect on the prediction of survival associated with melanoma in two distinct cohorts. (Clin Cancer Res 2009;15(22):6987-92) Melanoma is estimated to be the fifth most common cancer in the United States in 2009 (1). The unpredictable behavior of melanoma has prompted the search for prognostic factors to better predict its outcome. The vertical thickness of the primary tumor consistently emerges as a dominant prognostic factor for melanoma but does not account adequately for its heterogeneity. Numerous clinical and histologic prognostic factors have been examined for their ability to predict melanoma progression (2). Ulceration was included in the American Joint Cancer Committee (AJCC) staging classification for cutaneous melanoma because of its independent effect on melanoma survival (3, 4). Despite this development, further advances in the prognostic assessment of melanoma are still essential to improve prognostic predictions for all patients diagnosed with melanoma.One such approach to improving the prognostic assessment of cancer is the use of molecular markers. In the genomic era, the sequencing of the human genome and the availability of genome-wide approaches to interrogate the malignant phenotype have raised the promise that molecular markers will be routinely incorporated into the clinical assessment of cancer patients. Recent ...

gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.OBJECTIVE To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. EVIDENCE REVIEWThe MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.FINDINGS The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.CONCLUSIONS AND RELEVANCE More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.

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