Richard W Sagebiel

• California Pacific Medical Center Research Institute

Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose IFNα-2b versus observation. Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imagi...

Targeted therapy relies on the classification of tumors according to the major molecular drivers of the malignant phenotype, which can then help decide the therapeutic treatment. However, a substantial subset of solid tumors does not express these markers, exemplified by the triple-negative subtype of breast cancer. Shared molecular factors that pr...

Positron emission tomography/computed tomography (PET/CT) is an important tool to identify occult melanoma metastasis. To date, it is controversial which patients with primary cutaneous melanoma should have staging PET/CT. In this retrospective analysis of more than 800 consecutive patients with cutaneous melanoma, we sought to identify factors pre...

Significance Microphthalmia-associated transcription factor (MITF) is a master regulator of survival of the melanocyte lineage, exerting its effects through a cascade of transcriptional activation by interacting with a consensus DNA-binding sequence on the promoters of target genes. This study found that MITF regulates expression of bromodomain pla...

Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma c...

Individualized approaches to prognosis are crucial to effective management of cancer patients. We developed a methodology to assign individualized 5-year disease-specific death probabilities to 1,222 patients with melanoma and to 1,225 patients with breast cancer. For each cancer, three risk subgroups were identified by stratifying patients accordi...

Ulceration is an important prognostic factor in melanoma whose biologic basis is poorly understood. Here we assessed the prognostic impact of pleckstrin homology domain-interacting protein (PHIP) copy number and its relationship to ulceration. PHIP copy number was determined using fluorescence in situ hybridization (FISH) in a tissue microarray coh...

Supplementary Figure 1. Dot plot presenting the significant correlation between the immunohistochemical score and the percentage of cells with three or more copies of the PHIP locus in primary melanoma (P < 0.0001, linear regression analysis). Supplementary Table 1. FISH results as counts of signals from BAC clones mapping the PHIP locus and the fl...

Clinical and histologic characteristics of the melanoma sample (N = 1,222). (DOCX)

Clinical and histologic characteristics of the breast cancer sample (N = 1,225). (DOCX)

Relative weights in differentiating predictive potency of prognostic factors included in the breast cancer sample (N = 1,225). (DOCX)

Additional methods not included in the main text. (DOC)

Relative weights in differentiating predictive potency of prognostic factors included in the melanoma sample (N = 1,222). (DOCX)

Background Although p53 is inactivated by point mutations in many tumors, melanomas infrequently harbor mutations in the p53 gene. Here we investigate the biological role of microRNA-18b (miR-18b) in melanoma by targeting the MDM2-p53 pathway.Methods Expression of miR-18b was examined in nevi (n = 48) and melanoma (n = 92) samples and in melanoma c...

Background: A minority of patients with T1 melanoma will have a positive sentinel lymph node (SLN) biopsy (SLNB) finding. Identifying who will develop metastatic disease is important in determining prognosis and treatment. Objective: We sought to identify clinical and histologic features predictive of a positive SLNB result and determine its pro...

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 wild-type 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...

Sunbed/sunlamp use was recently classified as carcinogenic. This report considers characteristics of those who use sunbeds/sunlamps and the effect of sunbed/sunlamp use on their risk for melanoma within a large case-control study carried out in 1991-1992. Females were more likely than males to have used sunbeds/sunlamps. Use by females increased st...

Histopathologic analysis remains the gold standard for the pathologic diagnosis of melanoma. Numerous histologic criteria are used to diagnose melanoma, but none alone are sufficient to establish this diagnosis. Therefore, differentiating between benign pigmented lesions and melanoma may be controversial. Although several studies have examined the...

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 identifie...

The histopathological diagnosis of melanoma can be challenging. No currently used molecular markers accurately distinguish between nevus and melanoma. Recent transcriptome analyses have shown the differential expression of several genes in melanoma progression. Here, we describe a multi-marker diagnostic assay using 5 markers (ARPC2, FN1, RGS1, SPP...

A case of fatal metastatic melanoma arising from a very large congenital melanocytic naevus (VLCMN) is reported. Large congenital naevi (LCMN) are naevi >20 cm in diameter. VLCMN is used in this report to mean an extensive LCMN involving a large percentage of the body, including smaller so-called satellite naevi. A 19-year-old man with a large cong...

RGS1 (regulator of G protein signaling 1) encodes a member of the regulator of G protein family. Recently, RGS1 was found to be overexpressed in gene expression-profiling studies of melanoma. However, no analyses have been reported of its expression at the protein level in melanoma. In this study, the potential impact of RGS1 as a molecular prognos...

Although giant congenital melanocytic nevi (CMN) may undergo malignant transformation, their complete surgical removal is commonly difficult to achieve and may require sacrifice of normal skin. We treated a patient with CMN by a combination of full-thickness excision and primary closure of the central atypical portion and split-thickness excision o...

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 contracept...

Ulceration has been shown to be an adverse prognostic factor in primary cutaneous melanoma. However, the extent of ulceration required for histologic identification and biologic significance is unclear. We examined the impact of extent of ulceration on melanoma outcome in a cohort of 235 melanoma patients by evaluating the relationship between perc...

To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma. NCOA3 expression was assessed using immunohistochemical analysis of a melanoma tissue microarray (TMA) containing primary melanomas from 343 patients with defined histology and follow-up. The impact of the presence or absenc...

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. 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 con...

Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic poten...

8007 Background: Nuclear receptor coactivator-3 (NCOA3, also known as AIB1 or SRC-3), a member of the steroid receptor coactivator 1 family, has been shown to be amplified in human breast cancer. We recently identified NCOA3 as differentially expressed in metastatic melanomas by gene expression profiling, suggesting its role as a possible molecular...

To determine the impact of microsatellites as a prognostic factor in primary cutaneous melanoma. Retrospective cohort study. Tertiary referral center. Patients A total of 504 patients with a history of primary melanoma observed for 2 years or having experienced a first relapse. Overall survival (OS) and relapse-free survival (RFS). Forty-five patie...

Selective sentinel lymphadenectomy (SSL) following preoperative lymphoscintigraphy is the most significant recent advance in the management of patients with primary melanoma. This study evaluates the prognostic value of sentinel lymph node (SLN) status and other risk factors in predicting survival and recurrence in patients with primary cutaneous m...

Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melano...

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...

Background: Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable risk factors. This study investigates risk related to dietary factors, which are potentially modifiable. Methods: Newly diagnosed patients with melanoma (n = 502) were recruited from pigment lesion clinics and controls (n...

To examine a model of melanoma progression based on vascular factors and the role of NF-kappa B in the vascular progression of melanoma. A data set of 526 patients from the University of California San Francisco Melanoma Center with 2 years of follow-up or first relapse was studied. The impact of the presence or absence of various prognostic factor...

Harvesting the sentinel lymph node (SLN) is important in the management of patients with primary cutaneous melanoma. Selective sentinel lymphadenectomy (SSL) is generally performed at the time of wide local excision (WLE). The aim of our study was to determine whether delayed SSL is useful in detecting micrometastasis to the regional basin in patie...

Sunlight is the major environmental risk factor for melanoma. Descriptive studies have shown latitudinal variation in population incidence and mortality rates [D. C. Whiteman and A. C. Green, Int. J. Dermatol., 38: 481-489, 1999, and B. K. Armstrong, Australian J. Dermatol., 38 (Suppl. 1): 51-56, 1997]. In analytic studies, individual exposure has...

The vascular supply of the primary tumor is recognized to play an important role in the progression of a number of solid tumors. However, the role of tumor vascularity in the prognostic assessment of melanoma remains unclear. The purpose of this study was to determine the prognostic impact of patterns of vascularity on the outcome associated with c...

To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mu...

The current study was conducted to examine the role of multiple clinical and histologic factors in the prognostic assessment of patients with thick primary melanoma (> 4 mm, classified as T4). A retrospective analysis was performed in 329 patients with T4 cutaneous melanomas who were seen at the University of California at San Francisco Melanoma Ce...

BACKGROUND The current study was conducted to examine the role of multiple clinical and histologic factors in the prognostic assessment of patients with thick primary melanoma (> 4 mm, classified as T4).METHODSA retrospective analysis was performed in 329 patients with T4 cutaneous melanomas who were seen at the University of California at San Fran...

To examine the role of vascular invasion as a prognostic factor in melanoma. Retrospective survival analysis. Academic medical center. A total of 526 patients with primary cutaneous melanoma from the University of California, San Francisco, Melanoma Center database with 2 years of follow-up or documented relapse. (1) Presence of vascular involvemen...

The sentinel lymph node (SLN) is the first lymph node in the regional nodal basin to receive metastatic cells. In-transit nodes are found between the primary melanoma site and regional nodal basins. To date, this is one of the first reports on micrometastasis to in-transit nodes. Retrospective database and medical records were reviewed from October...

The propensity for spindle cell melanoma to metastasize to the lymph node is relatively low despite its relative thick depth. To date, there are no published reports on the sentinel lymph node (SLN) status in patients diagnosed with spindle cell melanoma and desmoplastic malignant melanoma (DMM). Our purpose was to report our experience on the SLN...

Fine needle aspiration is an accurate technique to diagnose metastatic melanoma. Few reports exist in the literature describing its usefulness in many patients with melanoma confirmed by open biopsy. The purpose of this study was to determine the utility and predictive value of fine needle aspiration in patients with malignant melanoma who presente...

To evaluate discordancy between clinical predictions and lymphatic drainage patterns of primary cutaneous melanoma as determined by preoperative lymphoscintigraphy and intraoperative lymphatic mapping of sentinel lymph nodes (SLNs). Before selective SLN dissection, 226 consecutive patients with melanoma underwent preoperative lymphoscintigraphy. Te...

Few studies have examined the feasibility, safety, and efficacy of an outpatient biochemotherapy regimen of low dose, subcutaneously administered interleukin-2 (IL-2) for patients with metastatic (Stage IV) melanoma. Nineteen patients were treated with intravenous cisplatin and dacarbazine (DTIC), oral tamoxifen, and subcutaneous IL-2 and interfero...

BACKGROUND Few studies have examined the feasibility, safety, and efficacy of an outpatient biochemotherapy regimen of low dose, subcutaneously administered interleukin-2 (IL-2) for patients with metastatic (Stage IV) melanoma.METHODS Nineteen patients were treated with intravenous cisplatin and dacarbazine (DTIC), oral tamoxifen, and subcutaneous...

In mice, significant immunoprotection was achieved using B16 melanoma cells transfected with granulocyte-macrophage colony-stimulating factor (GM-CSF) as vaccines (Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific,...

The Association of Directors of Anatomic and Surgical Pathology has developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for cutaneous melanoma are reported.

To develop a prognostic model, based on clinical and pathological data, to estimate the probability of micrometastasis in the sentinel lymph node in patients with malignant melanoma. Retrospective analytical study. University medical center. Two hundred fifteen patients with American Joint Committee on Cancer stages I and II cutaneous malignant mel...

The Association of Directors of Anatomic and Surgical Pathology have developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for cutaneous melanoma are reported herein.

The Association of Directors of Anatomic and Surgical Pathology have developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for cutaneous melanoma are reported herein.

The clinical spectrum and biologic behavior of melanoma are heterogeneous. Several clinical factors may include sex, location, and age. Histologic prognostic factors may include tumor type, tumor thickness, and mitotic index in relationship to the primary tumor. With respect to metastatic melanoma, the prognostic factors may include lymph node stat...

To determine the optimal approach of selective sentinel lymph node (SLN) dissection in primary malignant melanoma. Consecutive patient study. Prior to selective SLN dissection and wide local excision of the primary melanoma biopsy site, technetium Tc 99m sulfur colloid was injected intradermally around the primary melanoma or biopsy site to mark th...

To investigate the relationship of number and type of nevi to the development of melanoma. Case-control study. Outpatient clinics in referral hospitals. Cases were 716 consecutive patients with newly diagnosed melanoma identified at 2 melanoma centers between January 1, 1991, and December 31, 1992. Stratified random sampling of patients from outpat...

The evolution of the multidisciplinary melanoma clinics from 1965 to the present is reviewed. The University of California Melanoma Center database is presented as a model of actual visualization of the data in the care of individual melanoma patients. The basis of the ideal melanoma multidisciplinary center is given with common attributes that cou...

Evidence is reviewed separating unusual variants of melanoma from the large group of superficial spreading and nodular (SSM/NOD) histogenetic types. These include (1) the relationship of moles to melanoma of the SSM/ NOD types not found in melanoma arising in lentigo maligna (LMM), desmoplastic neurotrophic melanoma (DNM), mucosal lentiginous melan...

An analysis of the relationship between the anatomic site of cutaneous melanoma, sun exposure, and phenotype was conducted in 355 women with histologically confirmed superficial-spreading melanoma and in 935 control subjects. The most frequent site for superficial-spreading melanoma was the leg. However, when major sun-related and phenotype risk fa...

The recognition of dysplastic nevi from photographs can aid in population surveys of nevi and in epidemiological studies of melanoma risk. The reproducibility of techniques for recognizing nevi as dysplastic or for scoring them according to the degree of dysplasia has not been measured. Using photographs of 300 nevi taken in the course of a case-co...

The number of total body nevi is a major risk marker for malignant melanoma. No previous study has evaluated the accuracy of whole body large nevus (> or = 5 mm) self-counts. Our purpose was to evaluate the accuracy of large nevus self-counts by sex, age, educational level, body site, family history of skin cancer, and nevus characteristics. Self-c...

Assessment of melanoma risk factors can help identify individuals at greatest risk for melanoma. Previous studies were retrospective case-control or prospective without control groups. A prospective group of 3889 employees without previous melanoma or family history of multiple melanoma at the Lawrence Livermore (Calif) National Laboratory were exa...

This study examined whether inter-observer variability in rating tumor characteristics affected results of an investigation of surveillance bias and malignant melanoma at the Lawrence Livermore National Laboratory. The 20 cases from the Laboratory and their 36 non-Laboratory controls belonged to the same pre-paid health plan and were diagnosed with...

Nevi that are clinically atypical and histologically dysplastic have been associated with increased melanoma risk. There are few reproducibility studies or population-based studies of nevus histology. Our purpose was to quantify concordance in histologic diagnosis of melanocytic lesions among a diverse group of pathologists, to assess intraobserver...

A patient survival model is proposed which allows visualization of a data base, and which includes only routine and commonly recorded attributes in most melanoma clinics. It is proposed that a network of such data be collected for meta-analysis (MELNET), which could make stratification within the individual subsets more significant by virtue of the...

Despite important advances in the treatment of melanoma, the prognosis for advanced disease remains discouraging. This fact, in combination with a worldwide epidemic of melanoma among persons of white skin type, has focused attention on identifying melanoma in its early, surgically curable stages. Attention has also been directed toward pinpointing...

Although dysplastic nevi are an important risk factor for melanoma, little is understood about the epidemiology of these nevi. To further characterize some of the correlates of dysplastic nevi, we reexamined patients from one of the original prevalence reports and their first-degree relatives. Our purpose was to characterize the prevalence and corr...

The histologic presence of benign dermal nevus cells in contiguity with primary cutaneous melanoma, as a distinct population separate from malignant melanocytes, was evaluated in a large referral data base. The melanomas were limited to superficial spreading melanoma (SSM) and nodular melanoma (NM). Overall, dermal melanocytic nevi were found assoc...

Dysplastic naevi (DN) are the major precursor lesions of malignant melanoma, yet the presumed mode of inheritance or genetic aetiology of DN remains controversial. The inheritance pattern of DN in families from a randomly selected population of 26 dysplastic naevus patients was investigated by estimating the segregation ratio in families ascertaine...

To assess the role of surveillance bias in the observed three-fold excess of cutaneous malignant melanoma (CMM) at the Lawrence Livermore National Laboratory (LLNL) in California, we examined the thickness of CMMs among all 20 laboratory employees who were members of a large prepaid health plan and whose CMM was diagnosed from 1970 through 1984. Fo...

The histopathologic criteria used in the diagnosis of dysplastic nevi have been a source of controversy, as has the clinical significance of these lesions. Several dermatopathologists noted for their work on dysplastic nevi were asked to contribute responses to questions regarding the architectural and cytological criteria used to classify a melano...

The Lawrence Livermore (Calif) National Laboratory (LLNL) has observed a threefold increase in incidence of cutaneous malignant melanoma (CMM) since 1972. A consultant pathologist reviewed 49 of 50 cases of CMM diagnosed from 1969 to 1984 and reclassified 4 cases; this did not significantly affect the elevated rate. A comparison of the thicknesses...

Pediatricians have a long and honorable tradition of efforts to prevent disease. In recent years the scope of these efforts has expanded to include the continuing health of our patients throughout their lives. It is now clear that the task of educating parents and children about the long-term consequences of excessive sun exposure on the health of...

The dysplastic melanocytic nevus remains an issue of controversy despite extensive investigations. On clinical grounds the term atypical melanocytic nevus should be used, while dysplastic melanocytic nevus describes histological characteristics. The association with melanoma is complex. With the clinical picture, dermatoscopy and molecular biologic...

A clinical and histologic review of 25 patients with melanocytic lesions classified as desmoplastic malignant melanoma is reported. All of the lesions were located in sun-exposed sites. The average age was 61.2 years (range, 38 to 83), with a median age of 56. There were 14 female and 11 male patients. Desmoplastic malignant melanoma is a melanocyt...

Review of the currently available data would indicate that the measurement of tumor thickness in millimeters, especially those greater than 1.5 mm in thickness, is the single most important prognostic variable, closely followed by sex and location of the tumor. On the other hand, in thinner tumors, the level of invasion takes precedence over tumor...

A prospective, community practice-based, clinicopathologic correlation was undertaken in 165 melanocytic nevi excised from a group of forty-three patients, each patient having previously had at least one clinically suspected and histologically confirmed dysplastic melanocytic nevus. Eighty-two percent of seventy-two lesions with histologic evidence...

A total of 676 dysplastic moles collected from 487 patients over a 1-year period were reviewed together with demographic data. The associated nevus in 642 cases (95%) had a superficial, or "acquired," pattern within the papillary dermis, in comparison with the nevus in the remaining 34 cases (5%), which showed a deep, or "congenital," pattern. The...

To develop guidelines for the follow-up of patients with primary cutaneous melanoma (clinical Stage I), we studied 295 patients who had presented with a primary melanoma and who subsequently developed evidence of metastatic disease in the course of follow-up. Cox multivariate analysis was used to assess the influence of five variables in predicting...

A total of 844 cutaneous malignant melanomas were examined prospectively for the presence or absence of histologic regression within the primary tumor. Cases were then stratified into three groups according to tumor thickness and survival was compared between substrata with and without regression in each group. The distribution of other major progn...

Limited Wegener's granulomatosis is a form of the disease in which only one or two organ systems are involved. A rare case is reported in which the initial symptoms were in the skin and the lip, complicated by skin lesions exhibiting features of a clinical variant of lupus erythematosus.

A small proportion of "thin" malignant melanomas will metastasize and cause death. To assess the role of discordance between the major indicators of tumor depth (thickness and level) as a possible explanation for this phenomenon, prognosis by level has been examined in 255 cases, with tumors ranging in thickness from 0.6 to 1.1 mm. This is the rang...