Faculty Bibliography

CONTEXT: The incidence of cutaneous melanoma has increased over the past several decades, making its early diagnosis a continuing public health priority. The ABCD (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm) acronym for the appraisal of cutaneous pigmented lesions was devised in 1985 and has been widely adopted but requires reexamination in light of recent data regarding the existence of small-diameter (< or =6 mm) melanomas. EVIDENCE ACQUISITION: Cochrane Library and PubMed searches for the period 1980-2004 were conducted using search terms ABCD and melanoma and small-diameter melanoma. Bibliographies of retrieved articles were also used to identify additional relevant information. EVIDENCE SYNTHESIS: Available data do not support the utility of lowering the diameter criterion of ABCD from the current greater than 6 mm guideline. However, the data support expansion to ABCDE to emphasize the significance of evolving pigmented lesions in the natural history of melanoma. Physicians and patients with nevi should be attentive to changes (evolving) of size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color. CONCLUSIONS: The ABCD criteria for the gross inspection of pigmented skin lesions and early diagnosis of cutaneous melanoma should be expanded to ABCDE (to include 'evolving'). No change to the existing diameter criterion is required at this time

Our purpose was to determine the clinical relevance of the detection of circulating tumor cells (CTCs) expressing urothelial and epithelial markers in bladder cancer patients. Sixty-two patients who presented to Memorial Sloan-Kettering Cancer Center between July 2000 and September 2001 were studied. Peripheral blood was tested by nested RT-PCR assay for uroplakins (UPs) Ia, Ib, II and III as well as for epidermal growth factor receptor (EGFR). We determined the sensitivity and specificity of each individual marker and the combinations of UPIa/UPII and UPIb/UPIII. The latter strategy was based on our data, which showed that UPIa and UPIb form heterodimers with UPII and UPIII, respectively. Forty patients had clinically advanced bladder cancer and 22 had no evidence of disease at the time of assay. Eight of the 22 patients recurred during the follow-up period. All 8 patients were positive at presentation for UPIa/UPII. The combination of UPIa/UPII provided the best sensitivity (75%) of detecting CTCs, with a specificity of 50%. The combination of UPIb/UPIII was the most specific (79%) but had modest sensitivity (31%). Detection of EGFR-positive cells alone and in combination with UPs was inferior to that for UPIa/UPII. Combinations of urothelial markers are superior to single urothelial or epithelial markers in detecting CTCs in bladder cancer patients. Further efforts are under way to confirm the potential predictive value of these markers in a prospectively designed study of a larger cohort of patients.

PURPOSE: The protein encoded by N-myc downstream-regulated gene 1 (NDRG1) is a recently discovered protein whose transcription is induced by androgens and hypoxia. We hypothesized that NDRG1 expression patterns might reveal a biological basis for the disparity of clinical outcome of prostate cancer patients with different ethnic backgrounds. EXPERIMENTAL DESIGN: Patients who underwent radical prostatectomy between 1990 and 2000 at Veterans Administration Medical Center of New York were examined. We studied 223 cases, including 157 African Americans and 66 Caucasians (T2, n = 144; >/=T3, n = 79; Gleason <7, n = 122; >/=7, n = 101). Three patterns of NDRG1 expression were identified in prostate cancer: (a) intense, predominately membranous staining similar to benign prostatic epithelium; (b) intense, nucleocytoplasmic localization; and (c) low or undetectable expression. We then examined the correlations between patients' clinicopathological parameters and different NDRG1 expression patterns. RESULTS: In this study of patients with equal access to care, African-American ethnic origin was an independent predictor of prostate-specific antigen recurrence (P < 0.05). We also observed a significant correlation between different patterns of NDRG1 expression and ethnic origin. Pattern 2 was less frequent in African Americans (21% versus 38%), whereas the reverse was observed for pattern 3 (60% in African Americans versus 44% in Caucasians; P = 0.03). This association remained significant after controlling for both grade and stage simultaneously (P = 0.02). CONCLUSIONS: Our data suggest that different NDRG1 expression patterns reflect differences in the response of prostatic epithelium to hypoxia and androgens in African-American compared with Caucasian patients. Further studies are needed to determine the contribution of NDRG1 to the disparity in clinical outcome observed between the two groups

BACKGROUND: Many factors have been identified as important determinants that increase the risk of malignant melanoma (MM) developing. Patients with classic atypical mole syndrome (CAMS) have multiple such factors and are known to be at high risk for MMs developing. OBJECTIVE: We sought to evaluate the risk for newly diagnosed MMs developing in patients with CAMS and in a heterogeneous group of patients at high risk (ie, those with high-risk non-CAMS [HRNCAMS]) who had 1 or more risk factors: personal history of nonmelanoma skin cancers; family history of melanoma; biopsy specimen-confirmed dysplastic nevi; and meeting 1 or 2 of the 3 CAMS criteria. We also aimed to report our experience treating these patients at high risk with annual total cutaneous examination, total cutaneous photography, and dermoscopy. METHODS: Consecutive medical records from a private dermatology practice were reviewed. A total of 258 patients were selected who fulfilled the criteria of having: (1) total cutaneous photography as an aid for follow-up; (2) total cutaneous examination at least once per year; (3) at least 6 months of clinical follow-up; and (4) no personal history of melanomas. A total of 160 patients with CAMS and 98 with HRNCAMS were included in this study. The 10-year risk for MM developing in these 2 cohorts was computed using the Kaplan-Meier method. RESULTS: In the CAMS cohort, 28 new MMs developed in 19 patients resulting in a cumulative 10-year risk of 14% (95% confidence interval: 7-20). In the HRNCAMS cohort, 10 new MMs developed in 9 patients, and the cumulative 10-year risk was 10% (95% confidence interval: 2-17). The difference between the 2 groups was not statistically significant (P=.91). The MMs diagnosed in both cohorts were either in situ or less than 1 mm in Breslow thickness. There were no MM metastases or MM-related deaths in either cohort during a mean follow-up period of 120 months for the CAMS and 98 months for the HRNCAMS group. CONCLUSION: Both the patients with CAMS and HRNCAMS were at very high risk for MMs developing. The combination of total cutaneous photography, total cutaneous examination, and dermoscopy were used in treating our patients. No MM 1 mm or greater in thickness developed during follow-up in either group

We examined mutations in BRAF exons 11 and 15 and N-RAS exons 2 and 3, in 77 metastatic melanoma cases and 11 melanoma cell lines. Significant differences in the mutation rates observed at different metastatic sites could not be detected. The most frequent mutation, the V599E amino acid substitution in BRAF exon 15, was observed in 31 of 77 (40%) tissues and 5 of 11 (45%) cell lines. Tandem base-pair substitutions encoding V599R and V599K amino acid changes were observed in two cases. Novel findings with respect to melanoma include a cell line possessing a 2 base-pair substitution in BRAF exon 11 and a case harboring mutations in both BRAF exon 11 and N-RAS exon 3. Our data show that BRAF mutation is common in melanoma metastases, regardless of their site, that mutations include both exons 11 and 15, and suggest that anti-RAS/RAF strategies may be effective in metastatic melanoma patients

PURPOSE: The purpose is to investigate the clinical relevance of altered patterns of p27 and Skp2 expression in African-American patients with localized prostate cancer. The abundance of p27, an inhibitor of cell proliferation, is controlled by Skp2-dependent proteolysis. EXPERIMENTAL DESIGN: A well-characterized cohort of 162 African-Americans who underwent radical prostatectomy at the Veterans Affairs Medical Center of New York between 1990 and 2000 was studied. We analyzed p27 and Skp2 expression by immunohistochemistry. Altered expression of p27 (defined as <40% tumor cells expressing the protein) and Skp2 (defined as > or ==' BORDER='0'>20% tumor cells expressing the protein) were correlated with clinicopathological parameters and time to prostate-specific antigen (PSA) recurrence. RESULTS: Altered expression of p27 and Skp2 was observed in 112 of 162 (69.1%) and 93 of 162 (57.4%) cases, respectively. Inverse patterns of Skp2 and p27 protein expression were seen in 87 of 162 (53.7%) cases. A marginally significant association was found between Skp2 overexpression and extracapsular extension (P = 0.065). Moreover, patients with Skp2 overexpression had a 2.77 years decreased median time to PSA recurrence compared with patients with low Skp2 expression; however, the difference was not statistically significant. In multivariate analysis, only tumor grade and stage independently predicted PSA recurrence in this cohort. CONCLUSIONS: Our data suggest a role for Skp2 overexpression in prostate cancer pathogenesis that might not be exclusively related to p27 degradation. More studies are needed to determine the mechanistic role of Skp2 in prostate cancer

Transformation of normal melanocytes into melanoma cells is accomplished by the activation of growth stimulatory pathways, typically leading to cellular proliferation, and the inactivation of apoptotic and tumor suppressor pathways. Small molecule inhibitors of proteins in the growth stimulatory pathways are under active investigation, and their application to melanoma patients would represent a new treatment strategy to inhibit cell proliferation or induce cell death. We provide a general overview of the mechanisms of oncogene activation and the functions of oncogenes. Lastly, we review oncogenic events in melanoma

Overexpression of the oncogene HDM2 is observed in a substantial proportion of melanomas, including noninvasive and thin lesions, suggesting that HDM2 overexpression may be an early event in melanocyte transformation. To determine the role of HDM2 in the clinical progression of melanoma, we examined whether its expression was associated with patient survival. From November 1972 through November 1982, 134 patients with melanoma who participated in the New York University Melanoma Cooperative Group were studied, if representative tissues and follow-up were available. HDM2 protein expression was assessed immunohistochemically. Unexpectedly, we observed that HDM2 overexpression was statistically significantly associated with improved disease-free survival (relative risk [RR] = 0.47, 95% confidence interval [CI] = 0.24 to 0.89; two-sided chi(2) P =.021) and overall survival (RR = 0.55, 95% CI = 0.33 to 0.94; two-sided chi(2) P =.027) in multivariable analysis. HDM2 overexpression appears to be an independent predictor of survival for patients with primary melanoma; however, larger prospective studies are required for validation