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David E Elder

Publications and source records attributed to David E Elder.

At least 19 recordsLinked to original sources
PubMed2006

Reproductive risk factors for cutaneous melanoma in women: a case-control study.

Reproductive hormonal factors may have a potential role in cutaneous melanoma. This study estimated the risk of melanoma in women related to self-reported changes in nevi during pregnancy, while using oral contraceptives and/or hormone replacement therapy. Trained interviewers administered a questionnaire obtaining information about oral contraceptive use, hormone replacement therapy, reproductive history, sun exposure, occupation, and medical history from 318 Caucasian women newly diagnosed between 1991 and 1992 from two pigmented lesion clinics in San Francisco, California, and Philadelphia, Pennsylvania. A total of 395 frequency-matched control participants were recruited from hospital-affiliated outpatient clinics. Clinicians conducted skin examinations to assess the number and type of nevi, extent of freckling, solar damage, and skin type. For women aged less than 55 years, there was an association between a livebirth 5 years before diagnosis (odds ratio = 2.6, 95% confidence interval: 1.3, 5.3) and between number of births and melanoma risk (for > or = 3 births: odds ratio = 3.3, 95% confidence interval: 1.7, 6.5; ptrend < 0.001). Changes in nevi during recent pregnancies were a risk factor for melanoma, based upon small numbers (odds ratio = 2.9, 95% confidence interval: 1.1, 8.1). Oral contraceptive use and hormone replacement therapy were not associated with melanoma risk.

Adult↗
PubMed2006

Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma.

BACKGROUND: Sentinel lymph node (SLN) status is an important prognostic factor for survival for patients with primary cutaneous melanoma. To address the issue of selecting patients at high and low risk for a positive SLN, prognostic factors were sought that predict SLN involvement by examining characteristics of both the primary tumor and the patient within the context of a biological model of melanoma progression. METHODS: The study included 682 patients with primary vertical growth phase (VGP) melanoma and no clinical evidence of metastatic disease who underwent SLN biopsy (1995-2003). Logistic regression and classification tree analyses were used to investigate the association between SLN positivity and Breslow thickness, Clark level, tumor infiltrating lymphocytes (TIL), ulceration, mitotic rate (MR), lesion site, gender, and age. RESULTS.: In all, 88 of the 682 patients had > or =1 positive SLN (12.9%). In the multivariate analysis, MR, TIL, and thickness were found to be independent prognostic factors for SLN positivity. In the classification tree, four different risk groups were defined, ranging from minimal risk (2.1%) to high risk (40.4%). In lesions < r =2.0 mm, MR was important in risk-stratifying patients, and in lesions >2.0 mm TIL was important. CONCLUSIONS: By incorporating biologically based variables such as VGP, TIL, and MR along with thickness into a prognostic model, both patients at high risk and minimal risk for SLN positivity can be identified. If validated, this model can be used in patient management and trial design to select patients to undergo or be spared SLN biopsy.

Adult↗
PubMed2006

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

Adult↗
PubMed2006

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.

BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Australia↗
PubMed2006

Differentiation of normal skin and melanoma using high resolution hyperspectral imaging.

We investigated the use of high resolution hyperspectral imaging microscopy to detect abnormalities in skin tissue using hematoxylin eosin stained preparations of normal and abnormal skin, benign nevi and melanomas. A goal of this study was to provide objective data that could be utilized by any researcher; and form the beginnings of a reference spectral data base. All spectral characterizations were acquired in percent transmission, and absorption, with contiguous wavelength acquisition between 400 and 800 nm; and a spectral resolution of approximately 1 nm. Biopsy sections were characterized with varying sample thickness, staining and magnification in order to determine their impact on spectral characterizations. Spectra were classified using spectral waveform cross correlation analysis, an algorithm that is linearity invariant. Classified spectra were incorporated into spectral libraries; and all spectra acquired from the field of view were correlated with library spectra to a quantified, user determined, confidence threshold (minimum correlation coefficient). The results revealed that all skin conditions in our initial data sets could be objectively differentiated providing that staining and section thickness was controlled. We also demonstrated that it is likely that a reference spectral library database could be created to include bioinformatics and cluster analysis. This would assist multiple laboratories to participate in the input and retrieval of target spectral information.

Biopsy↗
PubMed2006

MC1R germline variants confer risk for BRAF-mutant melanoma.

Germline variants in MC1R, the gene encoding the melanocortin-1 receptor, and sun exposure increase risk for melanoma in Caucasians. The majority of melanomas that occur on skin with little evidence of chronic sun-induced damage (non-CSD melanoma) have mutations in the BRAF oncogene, whereas in melanomas on skin with marked CSD (CSD melanoma) these mutations are less frequent. In two independent Caucasian populations, we show that MC1R variants are strongly associated with BRAF mutations in non-CSD melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations.

Adolescent↗
PubMed2006

Identifying individuals at high risk of melanoma: a practical predictor of absolute risk.

PURPOSE: We developed a model to estimate the 5-year absolute risk of melanoma to efficiently identify individuals at increased risk of melanoma for potential interventions. PATIENTS AND METHODS: We used data from a case-control study with 718 non-Hispanic white patients with invasive cutaneous melanoma from melanoma clinics in Philadelphia, PA and San Francisco, CA; matched controls were 945 patients from outpatient clinics with similar catchment areas. All participants underwent extensive interviews and skin examinations. We selected easily obtained clinical characteristics and responses to simple questions for study in order to develop sex-specific relative risk models. These models were combined with incidence and mortality rates by United States geographic areas to develop estimates of the absolute risk of developing melanoma within 5 years. RESULTS: Relative risk models yielded an attributable risk of 86% for men and 89% for women, using at most seven variables. Attributable risks did not vary by age, ultraviolet B flux or hours outdoors. The absolute individual risks varied widely, depending on age, other host characteristics, and geographic area. Individual absolute risk can be estimated using a program available online. CONCLUSION: Our procedures allow for estimating the absolute risk of developing melanoma to assist in the identification of patients at high risk. Such high-risk individuals could undergo interventions including a complete skin examination, counseling to avoid sun exposures, regular self and professional surveillance, or participation in prevention trials. It is important to emphasize that these projections are not intended to identify current melanoma cases.

Adult↗
PubMed2006

Pathology of melanoma.

The purposes of pathologic examination of a lesion suspected of being a malignant melanoma are to provide an accurate diagnosis of melanoma (or not), and to provide prognostic information useful in the clinical management of the patient. In the near future, pathologic attributes will also likely be used to predict responses to therapy, as a guide to the selection of specific therapeutic agents such as "small molecule" inhibitors of signaling pathways.

Humans↗
PubMed2006

Innovations and challenges in melanoma: summary statement from the first Cambridge conference.

Innovations and Challenges in Melanoma, chaired by Michael Atkins and cochaired by Ulrich Keilholz, John Kirkwood, and Jeffrey Sosman, was held July 15 to 16, 2005, in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, surgical oncology, anatomic pathology, dermatology, and immunotherapy who wished to advance the field of melanoma treatment by exchanging information and perspectives regarding recent advances and recommendations for further study. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on how genetics, biology, and data information can enhance our understanding of melanoma biology and help inform the use of therapies for this disease.

Humans↗
PubMed2006

Human leukocyte antigen-A2-restricted CTL responses to mutated BRAF peptides in melanoma patients.

Mutated BRAF (BRAF(V600E)) is a potential immunotherapeutic target for melanoma because of its tumor specificity and expression in the majority of these lesions derived from different patients. BRAF(V600E) is expressed intracellularly and not on the cell surface, therefore providing a target for T cells but not B cells. Demonstration of patients' T cell responses to BRAF(V600E) would suggest the feasibility of active specific immunotherapy targeting the mutation in these patients. In the present study, BRAF(V600E) peptides with putative binding sites for human leukocyte antigen (HLA)-A2 were used to stimulate T lymphocytes of HLA-A2-positive melanoma patients. Four of five patients with BRAF(V600E)-positive lesions showed lymphoproliferative responses to BRAF(V600E) peptide stimulation. These responses were specific for the mutated epitope and HLA-A2 was restricted in three patients. Lymphocytes from these three patients were cytotoxic against HLA-A2-matched BRAF(V600E)-positive melanoma cells. None of the four patients with BRAF(V600E)-negative lesions and none of five healthy donors had lymphoproliferative responses specific for the mutated epitope. The high prevalence (approximately 50%) of HLA-A2 among melanoma patients renders HLA-A2-restricted BRAF(V600E) peptides attractive candidate vaccines for these patients.

Binding Sites↗
PubMed2006

Predictors of regional nodal disease in patients with thin melanomas.

BACKGROUND: Most melanoma patients present with thin ( 0, vertical growth phase (VGP), male sex, and ulceration were statistically significant predictors of RND. Patients at the highest risk according to a classification tree analysis (VGP and MR>0) had an RND rate of 11.9%. The regression model developed predicted well the SLN status in the validation sample. CONCLUSIONS: Investigation of a large pre-SLN population identified MR>0, ulceration, VGP, and male sex as independently predictive of RND in patients with thin melanomas. These factors may help to identify subgroups of these patients that have clinically significant risks of SLN positivity.

Female↗
PubMed2006

Precursors to melanoma and their mimics: nevi of special sites.

Melanocytic nevi, which are benign tumors of melanocytes, may have occasional cosmetic significance but, for the most part, they are important only in relation to melanoma. Nevi are the most important simulants of melanoma, both clinically and histologically, and can usually be reliably distinguished from melanomas using published criteria. Some lesions are characterized by greater degrees of atypia and may be more difficult to diagnose. Dysplastic nevi are among the most important simulants of melanoma. Nevi may also be important as potential precursors of melanoma; however, most nevi are stable and will not progress to malignancy. Nevi are vastly more common than melanomas and the rate of progression of individual lesions is very low. Therefore, nevi are not as a rule managed by wholesale excision to prevent melanoma. Nevi are also important as risk markers, identifying individuals at greater risk of developing melanoma in the future. Dysplastic nevi and, to a lesser extent, common acquired and congenital nevi are among the most important melanoma risk markers. Nevi of special sites have been identified as nevi that may show atypical features suggestive of a dysplastic nevus or of a melanoma. However, they are not risk markers and they are not malignancies. Nevi of genital skin, acral skin, and flexural skin are among the most important 'nevi of special sites'. It is important, in considering the differential diagnosis of a lesion in a special site, to avoid overcalling such a lesion as a melanoma or a dysplastic nevus because this could lead to excessive treatment. Conversely, it is important to avoid undercalling a lesion that is a dysplastic nevus or a melanoma as a nevus of special sites, because in this circumstance a patient could lose the opportunity either for surveillance to recognize a developing melanoma at an early, curable stage, or for definitive treatment of an established malignancy. In this monograph, dysplastic nevi and nevi of special sites are compared and contrasted in relation to melanoma.

Diagnosis, Differential↗
PubMed2005

Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma.

PURPOSE: Tumor cell proliferation is a central feature of melanoma progression. In this study, we characterized three biomarkers of proliferation (Ki67 expression, dermal mitotic rate [MR], and tumorigenicity) in thin (< or = 1.00 mm) primary cutaneous melanomas and examined their association with prognosis. PATIENTS AND METHODS: We used immunohistochemistry to determine Ki67 expression using the monoclonal antibody MIB-1 in lesions from a prospective cohort that included 396 patients with thin invasive primary melanomas seen between 1972 and 1991. A multivariate Cox proportional hazards model was used to define independent prognostic factors, and recursive partitioning was used to develop a prognostic tree identifying risk groups. RESULTS: Dermal Ki67 expression was lower than epidermal Ki67 expression in radial growth phase (RGP) melanomas (n = 171), and dermal Ki67 expression and MR were higher in tumorigenic vertical growth phase (VGP) melanomas (n = 193) compared with RGP and nontumorigenic VGP melanomas (n = 42). Dermal Ki67 expression, MR greater than 0, growth phase, thickness, ulceration, tumor-infiltrating lymphocytes, and sex were associated with metastasis at 10 years, however, only dermal Ki67 expression, MR greater than 0, and sex were independent prognostic factors. Two high-risk groups were identified: men and women with dermal MR greater than 0 and dermal Ki67 expression > or = 20% in tumor cells and men with MR greater than 0 and Ki67 expression less than 20%, with 10-year metastasis rates of 39% and 20%, respectively. CONCLUSION: Proliferation slows as melanoma cells enter the dermis and then increases with the onset of tumorigenic VGP. Ki67 expression and dermal MR provide independent prognostic information that can potentially be used in risk-based management of patients.

Adult↗
PubMed2005

A tumorigenic subpopulation with stem cell properties in melanomas.

Recent studies suggest that cancer can arise from a cancer stem cell (CSC), a tumor-initiating cell that has properties similar to those of stem cells. CSCs have been identified in several malignancies, including those of blood, brain, and breast. Here, we test whether stem cell-like populations exist in human melanomas. In approximately 20% of the metastatic melanomas cultured in growth medium suitable for human embryonic stem cells, we found a subpopulation of cells propagating as nonadherent spheres, whereas in standard medium, adherent monolayer cultures were established. Individual cells from melanoma spheres (melanoma spheroid cells) could differentiate under appropriate conditions into multiple cell lineages, such as melanocytic, adipocytic, osteocytic, and chondrocytic lineages, which recapitulates the plasticity of neural crest stem cells. Multipotent melanoma spheroid cells persisted after serial cloning in vitro and transplantation in vivo, indicating their ability to self-renew. Furthermore, they were more tumorigenic than adherent cells when grafted to mice. We identified similar multipotent spheroid cells in melanoma cell lines and found that the stem cell population was enriched in a CD20+ fraction of melanoma cells. Based on these findings, we propose that melanomas can contain a subpopulation of stem cells that contribute to heterogeneity and tumorigenesis. Targeting this population may lead to effective treatments for melanomas.

Animals↗
PubMed2005

Mitotic rate as a predictor of sentinel lymph node positivity in patients with thin melanomas.

BACKGROUND: Lymphatic mapping and sentinel lymphadenectomy (LM/SL) provide important prognostic information for patients with early-stage melanoma. Although the use of this technique in patients with thin melanomas (< or =1.00 mm) is not routine, risk factors that may predict sentinel lymph node (SLN) positivity in this patient population are under investigation. We sought to determine whether mitotic rate (MR) is associated with SLN positivity in thin-melanoma patients and, therefore, whether it may be used to risk-stratify and select patients for LM/SL. METHODS: Clinical and histopathologic variables were reviewed for 181 patients with thin melanomas who underwent LM/SL from January 1996 through January 2004. Univariate and multivariate logistic regression analyses were performed to identify factors associated with SLN positivity. Risk groups were defined on the basis of the development of a classification tree. RESULTS: The overall SLN positivity rate was 5%. All patients with positive SLNs had an MR of >0. By univariate analysis, MR and thickness were significant predictors of SLN positivity. The association between MR and SLN positivity remained significant controlling for each of the other variables evaluated. On the basis of a classification tree, patients with an MR >0 and tumor thickness > or =.76 mm were identified as a higher-risk group, with an SLN positivity rate of 12.3%. CONCLUSIONS: In patients with thin melanomas, MR >0 seems to be a significant predictor of SLN positivity that may be used to risk-stratify and select patients for LM/SL. To confirm these results, the predictive value of MR for SLN positivity needs to be validated in other populations of thin-melanoma patients.

Female↗
PubMed2005

Functional erythropoietin autocrine loop in melanoma.

Although erythropoietin (Epo) is a known stimulator of erythropoiesis, recent evidence suggests that its biological functions are not confined to hematopoietic cells. To elucidate the role of Epo and erythropoietin receptor (EpoR) in melanoma, we examined the expression and function of these proteins in melanocytes and melanoma cells. We found increased expression of Epo in melanoma cells compared to melanocyte in vitro. EpoR was also strongly expressed in all of the melanoma cell lines and two of the three melanocyte cell lines examined. Epo expression was significantly higher in melanoma than in benign nevi as determined by immunohistochemistry. Although melanoma cells secreted Epo in normoxic condition in vitro, hypoxia and CoCl(2) treatment increased Epo secretion. EpoR in melanoma cells was functional, because exogenous Epo increased melanoma resistance to hypoxic stress, pretreatment of melanoma cells with Epo significantly increased resistance to dacarbazine treatment, and Epo increased the phosphorylation of EpoR, RAF, and MEK. In conclusion, we demonstrated constitutive expression of Epo and EpoR as well as autonomous secretion of Epo by melanoma cells, indicating a novel autocrine loop of Epo in melanoma. The results suggest that the autocrine and paracrine functions of Epo might play a role in malignant transformation of melanocytes and in the survival of melanoma cells in hypoxia and other adverse conditions.

Blotting, Western↗
PubMed2004

Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study.

BACKGROUND: Data addressing the interfamilial heterogeneity of melanoma are limited. In the current study, the authors assessed melanoma risk according to family history of melanoma and other melanoma-associated malignancies and evaluated the familial heterogeneity of melanomas, pancreatic malignancies, and gastrointestinal malignancies. METHODS: The authors obtained patient histories of malignancy in first-degree relatives as part of a clinic-based case-control study. The case group included 737 newly diagnosed patients with invasive melanoma, and the control group included 1021 outpatients from clinics at the same medical centers. To assess heterogeneity of risk among families affected by melanoma, a nonparametric method was used to detect extrabinomial variation. In addition, selected patients with melanoma (n=133) were tested for germline mutations in CDKN2A. RESULTS: The adjusted odds ratio associated with a family history of melanoma was 1.7 (95% confidence interval, 1.1-2.7). Family histories of pancreatic, gastrointestinal, brain, breast, or lymphoproliferative disease did not increase the risk of melanoma significantly. Among case families, significant evidence of familial heterogeneity was found for melanomas, but not for pancreatic or gastrointestinal malignancies. Two mutations in CDKN2A previously associated with melanoma risk were identified among the 133 patients tested in the case group; mutation detection did not differ between families with low and high heterogeneity scores. CONCLUSIONS: Familial heterogeneity testing in the study population did not improve the selection of high-risk families for genetic study. Even in a large case-control study, few families that had multiple members with melanoma were identified, and family members with pancreatic malignancies were rare.

Adult↗