Melanoma: Kashani-Sabet M

Coit DG, Andtbacka R, Bichakjian CK, Dilawari RA, Dimaio D, Guild V, Halpern AC, Hodi FS, Kashani-Sabet M, Lange JR, Lind A, Martin L, Martini MC, Pruitt SK, Ross MI, Sener SF, Swetter SM, Tanabe KK, Thompson JA, Trisal V, Urist MM, Weber J, Wong MK, Anonymous00048. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #19401060 No free full text.

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Houghton AN, Coit DG, Daud A, Dilawari RA, Dimaio D, Gollob JA, Haas NB, Halpern A, Johnson TM, Kashani-Sabet M, Kraybill WG, Lange JR, Martini M, Ross MI, Samlowski WE, Sener SF, Tanabe KK, Thompson JA, Trisal V, Urist MM, Walker MJ, Anonymous00370. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #16884669 No free full text.

This publication has no abstract.

De Semir D, Nosrati M, Li S, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, Comprehensive Cancer Center, Department of Dermatology, University of California San Francisco, San Francisco, California 94115, USA. · Cell Cycle. · Pubmed #17312399 No free full text.

Abstract: To date, the major function attributed to telomerase has been the elongation of telomeres. Recent studies have assigned new biochemical properties to telomerase by implicating a role in tumor metastasis and cellular differentiation by virtue of its modulation of novel cell signaling pathways such as glycolysis. In this Perspective we will discuss these recent results that have provided additional insight into the involvement of telomerase in cellular processes other than telomere maintenance at chromosome ends.

Homsi J, Kashani-Sabet M, Messina JL, Daud A. · Cutaneous Oncology Division, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. · Cancer Control. · Pubmed #16258493 links to  free full text

Abstract: BACKGROUND: Recent data have changed our views of prognostic factors in cutaneous melanoma. While some newer methods have yielded better prognostic information, some insights have evolved as a result of large-scale population-based analyses. METHODS: We review current data on several different prognostic factors and divide these factors according to their application in localized primary melanoma or metastatic melanoma. For each prognostic factor, the level of evidence supporting its use and its applicability to clinical practice are considered. RESULTS: For localized primary melanoma, the dominant predictors of survival include lesion thickness, ulceration, and lymph node involvement. Factors such as age, sex, anatomic location, and satellite/in-transit lesions are important in localized melanoma. Factors currently being investigated are tumor vascularity, vascular invasion, mitotic rate, tumor regression, and tumor-infiltrating lymphocytes. For metastatic melanoma, the most important prognostic factors are site of metastases and the presence of elevated serum lactic dehydrogenase. The value of these prognostic factors to clinicians caring for melanoma patients is discussed. CONCLUSIONS: A better understanding of prognostic factors in cutaneous melanoma has evolved over the last decade, allowing oncologists to provide appropriate treatment for their patients. Many of the prognostic factors are interrelated. In the near future, it is expected that several molecular genetic factors will provide more insight into the prognosis of patients with melanoma.

Torabian S, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, UCSF Comprehensive Cancer Center, and Department of Dermatology, University of California San Fransisco, California 94115, USA. · Curr Opin Oncol. · Pubmed #15725923 No free full text.

Abstract: PURPOSE OF REVIEW: Given the capricious nature of melanoma, biomarkers that provide significant insight into the behavior of melanoma would greatly aid in identifying patients at risk for disease progression, those whose disease has progressed subclinically, and those who would benefit from currently available systemic therapies. This review focuses on molecular prognostic markers in primary melanoma, markers that aid in the detection of metastatic melanoma, and markers predictive of systemic therapy. RECENT FINDINGS: Significant advances have been made in the field of melanoma biomarkers. Utilization of paraffin-embedded tissue and multiple markers have improved the RT-PCR assays for detection of melanoma cells in lymph node tissue as well as peripheral blood. Lymphangiogenesis has been identified as a novel mechanism for melanoma progression, and candidate markers in the NF-kappaB signaling pathway have been identified to play a key role in melanoma: tumor vasculature interactions. Loss of heterozygosity has been used to identify potential candidates for biochemotherapy. Furthermore, serum S100B protein has been shown to be superior to lactate dehydrogenase in predicting prognosis and response to treatment for patients with advanced melanoma. SUMMARY: Although recent studies have contributed greatly to the development of melanoma markers, it is anticipated that the application of gene expression profiling and proteomics techniques to melanocytic neoplasms will result in the identification of even more effective biomarkers for melanoma than those currently in clinical use.

Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, UCSF Comprehensive Cancer Center, Department of Dermatology, University of California San Francisco, CA 94115, USA. · Expert Opin Biol Ther. · Pubmed #15500403 No free full text.

Abstract: Ribozymes are RNA molecules with the capacity to effect sequence-specific cleavage of other transcripts. Since their initial discovery, there has been considerable interest in the development of ribozymes and other RNA therapeutics for gene therapy, particularly in the realm of cancer. However, as with other gene therapy applications, the delivery of ribozyme-based therapeutics to the target tissues of interest has represented a significant obstacle to the maturation of this technology to the clinical arena. This review will discuss the progress made so far in the use of non-viral methods for the systemic delivery of ribozymes for cancer gene therapy.

Kashani-Sabet M. · Averback Melanoma Laboratory, University of California at San Francisco Cancer Center, 1600 Divisadero Street, Second Floor, Box 1706, San Francisco, CA 94115, USA. · Curr Oncol Rep. · Pubmed #15291985 No free full text.

Abstract: Sophisticated molecular techniques that have recently become available permit analysis of genome-wide changes in gene copy number (DNA) or expression (RNA). These genomic strategies have the potential to transform our view of cancer biology and pathogenesis. This review surveys the studies performed using genome-wide analyses of melanoma, primarily in patient specimens but also in selected experimental models of melanoma. The insights gained and the challenges and potential of these approaches are discussed with respect to their ability to dissect out the molecular events that are responsible for melanoma progression.

Bagheri S, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, UCSF Comprehensive Cancer Center and Department of Dermatology, San Francisco, CA 94115, USA. · Curr Mol Med. · Pubmed #15267221 No free full text.

Abstract: Ribozymes are RNA molecules capable of sequence-specific cleavage of other RNA molecules. Since the discovery of the first group I intron ribozyme in 1982, new classes of ribozymes, each with their own unique reaction, target site specifications, and potential applications, have been identified. These include hammerhead, hairpin, hepatitis delta, varkud satellite, groups I and II intron, and RNase P ribozymes, as well as the ribosome and spliceosome. Meanwhile, ribozyme engineering has enabled the in vitro selection of synthetic ribozymes with unique properties. This, along with advances in ribozyme delivery methods and expression systems, has led to an explosion in the potential therapeutic applications of ribozymes, whether for anti-cancer or anti-viral therapy, or for gene repair.

Zettersten E, Shaikh L, Ramirez R, Kashani-Sabet M. · Melanoma Center and Department of Dermatology Cutaneous Oncology Program, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, 1600 Divisadero Street, San Francisco, CA 94115, USA. · Surg Clin North Am. · Pubmed #12691450 No free full text.

Abstract: Tumor thickness has historically been the single most important factor in risk assessment for stage I and II melanoma patients. However, it is possible to more accurately determine a patient's prognosis by also using other known prognostic indicators, such as ulceration, vascular invasion, and angiogenesis. A probabilistic approach to risk assessment has implications for the appropriate selection of treatment modalities, such as sentinel lymph node biopsy and re-excision margins. Each patient's risk for recurrence also has implications for which follow-up protocol would be most appropriate for the patient. Finally, those risk factors that repeatedly demonstrate an independent impact on prognosis should be used as stratification factors in adjuvant therapy trials.

Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, UCSF Cancer Center, and Department of Dermatology, University of California San Francisco, San Francisco, California 94115, USA. · J Investig Dermatol Symp Proc. · Pubmed #12518796 No free full text.

Abstract: Since their initial discovery, ribozymes have shown great promise not just as a tool in the manipulation of gene expression, but also as a novel therapeutic agent. This review discusses the promises and pitfalls of ribozyme technology, with a special emphasis on cancer-related applications, though relevance to skin disease will also be discussed.

Cleaver JE, Karplus K, Kashani-Sabet M, Limoli CL. · Department of Dermatology and UCSF Cancer Center, University of California, San Francisco, CA 94143-0808, USA. · Mutat Res. · Pubmed #11341991 No free full text.

Abstract: The first half of the 20th century has seen an enormous growth in our knowledge of DNA repair, in no small part due to the work of Dirk Bootsma, Philip Hanawalt and Bryn Bridges; those honored by this issue. For the new millennium, we have asked three general questions: (A) Do we know all possible strategies of nucleotide excision repair (NER) in all organisms? (B) How is NER integrated and regulated in cells and tissues? (C) Does DNA replication represent a new frontier in the roles of DNA repair? We make some suggestions for the kinds of answers the next generation may provide. The kingdom of archea represents an untapped field for investigation of DNA repair in organisms with extreme lifestyles. NER appears to involve a similar strategy to the other kingdoms of prokaryotes and eukaryotes, but subtle differences suggest that individual components of the system may differ. NER appears to be regulated by several major factors, especially p53 and Rb which interact with transcription coupled repair and global genomic repair, respectively. Examples can be found of major regulatory changes in repair in testicular tissue and melanoma cells. Our understanding of replication of damaged DNA has undergone a revolution in recent years, with the discovery of multiple low-fidelity DNA polymerases that facilitate replicative bypass. A secondary mechanism of replication in the absence of NER or of one or more of these polymerases involves sister chromatid exchange and recombination (hMre11/hRad50/Nbs1). The relative importance of bypass and recombination is determined by the action of p53. We hypothesise that these polymerases may be involved in resolution of complex DNA structures during completion of replication and sister chromatid resolution. With these fascinating problems to investigate, the field of DNA repair will surely not disappoint the next generation.

Falk MS, Truitt AK, Coakley FV, Kashani-Sabet M, Hawkins RA, Franc B. · Department of Radiology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0628, USA. · Nucl Med Commun. · Pubmed #17325590 No free full text.

Abstract: PURPOSE: To investigate the accuracy of different interpretative approaches and to evaluate the management implications of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in cutaneous malignant melanoma. METHODS: We retrospectively identified 60 consecutive patients who underwent 76 PET/CT scans for cutaneous malignant melanoma. PET/CT reports were classified as positive, negative, or equivocal for regional and distant disease. Scan indication (staging, restaging, surveillance, or therapeutic monitoring), tumour stage, presence or absence of regional or distant disease, and post-scan management changes were determined by review of all available medical records. Maximum standardized uptake values (SUV(max)) of all findings were noted. Diagnostic accuracy of PET/CT was compared using either a high or low threshold interpretation (i.e. subtle, but indeterminate findings coded negative or positive, respectively). The frequency of management changes was compared between patient subgroups (stratified by tumour stage or indication). RESULTS: Using a high threshold interpretative approach, the overall accuracy of PET/CT for disease was 72.4% (55/76), which was significantly (P<0.05) greater than the accuracy of 53.9% (41/76) seen when using a low threshold approach. Per scan accuracy by staging site was 92.1% (70/76) for regional and 76.3% (58/76) for distant disease. PET/CT changed management in 21 of 76 studies (27.6%). When stratified by stage and indication, management changes occurred in all patient subgroups, except for stage I patients (0 of 5). CONCLUSION: When interpreted with a high threshold approach, PET/CT demonstrates high accuracy for the diagnosis of both regional and distant disease in cutaneous malignant melanoma and frequently changes management in patients with stage II-IV disease referred for a variety of indications.

Leong SP, Morita ET, Südmeyer M, Chang J, Shen D, Achtem TA, Allen RE, Kashani-Sabet M. · Department of Surgery, UCSF/Comprehensive Cancer Center at Mount Zion, San Francisco, California 94143-1674, USA. · Clin Nucl Med. · Pubmed #15722817 No free full text.

Abstract: We want to define the patterns of lymphatic drainage for primary melanoma to sentinel lymph nodes (SLNs) based on a large lymphoscintigraphic database. Preoperative lymphoscintigraphy was used to identify and classify SLN drainage basins and patterns of drainage. METHODS: Lymphoscintigraphy using intradermally administered technetium-99m labeled sulfur colloid was performed on 400 consecutive patients with malignant melanoma to define lymphatic drainage channels and draining SLN basins before surgery. Primary tumor sites consisted of head and neck, upper extremity, trunk, and lower extremity. Different types of drainage patterns were classified and correlated with different anatomic sites. RESULTS: SLN(s) were identified in over 98% of the patients, whereas lymphatic drainage channels were successfully identified in 90% of the patients. Drainage from the primary site to a single SLN through a single lymphatic channel (type IA) was seen in 186 of 400 patients (47%) as the most common type. In patients with a single SLN within a single basin (type I-V), the percentage of patients with primary lesions in the head and neck, upper extremity, trunk, and lower extremity regions were 61%, 79%, 55%, and 78%, respectively. In cases of multiple lymphatic channels (type VI-VII), the percentages of patients with primary lesions in the head and neck, upper extremity, trunk, and lower extremity regions were 24%, 8%, 36%, and 19%, respectively. CONCLUSION: Various drainage patterns were noted from primary melanomas in different anatomic sites. Preoperative lymphoscintigraphy is important in establishing the SLN basins for harvesting the SLN(s).

Shoo BA, Kashani-Sabet M. · Melanoma Center, Department of Dermatology, University of California, San Francisco, CA 94153, USA. · Semin Cutan Med Surg. · Pubmed #19608060 No free full text.

Abstract: This review highlights melanoma trends observed among African-, Asian-, Latino- and Native-American populations. Melanoma is the most lethal form of skin cancer, accounting for about 75% of all skin cancer deaths. Generally, incidence rates increase with age, peak after age 40, and are greater in men than women. However, these trends do not reflect what is typically seen in minority ethnic groups, where incidence rates are lower. In addition, for some groups, relative disease-specific survival also is lower compared with European-Americans. Melanomas in minority populations also tend to appear in atypical locations and are of unclear etiology. To improve our understanding of the causes of melanoma arising in ethnic minority populations future research efforts are needed. In addition, the general lack of awareness of this disease entity among minority populations and the fact that certain ethnic groups tend to present with advanced disease further highlight the need for educational programs for both patients and health care professionals.

Minor DR, Chin K, Kashani-Sabet M. · California Pacific Medical Center, San Francisco, CA 94115, USA. · Cancer Biother Radiopharm. · Pubmed #19538054 No free full text.

Abstract: The anti-CTLA4 antibody, ipilimumab, has shown clinical activity against melanoma. Diarrhea due to immune-related colitis is the most frequent serious toxicity and, if untreated, may lead to intestinal perforation. Diarrhea treatment guidelines were developed based on clinical experience in over 2000 patients treated with ipilimumab, and these safety guidelines recommend systemic steroids as the first choice for the treatment of severe diarrhea. In this article, we present an alternative approach to the control of immune-related colitis by using the antitumor necrosis factor antibody, infliximab. Patients with metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 3 months. Those who developed grade 2 diarrhea were treated with infliximab 5 mg/kg weeks 0 and 2 with mesalamine and loperamide. Steroids were given only for refractory cases requiring hospitalization. Of the first 3 cases of ipilimumab-induced diarrhea, 2 proved refractory and required hospitalization, but 1 recovered quickly without systemic steroids. We then added hydrocortisone enemas daily to the above regimen, and the next 3 patients recovered from grade 2 ipilimumab-induced colitis without difficulty. Treatment with infliximab, mesalamine, and hydrocortisone enemas may produce a rapid improvement in ipilimumab-induced colitis and avoid the administration of systemic steroids.

Kashani-Sabet M, Rangel J, Torabian S, Nosrati M, Simko J, Jablons DM, Moore DH, Haqq C, Miller JR, Sagebiel RW. · Auerback Melanoma Research Laboratory, Comprehensive Cancer Center and Department of Dermatology, University of California, San Francisco, CA 94115, USA. · Proc Natl Acad Sci U S A. · Pubmed #19332774 links to  free full text

Abstract: 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, SPP1, and WNT2) overexpressed in melanomas. Immunohistochemical marker expression was analyzed in 693 melanocytic neoplasms comprising a training set (tissue microarray of 534 melanomas and nevi), and 4 independent validation sets: tissue sections of melanoma arising in a nevus; dysplastic nevi; Spitz nevi; and misdiagnosed melanocytic neoplasms. Both intensity and pattern of expression were scored for each marker. Based on the differential expression of these 5 markers between nevi and melanomas in the training set, a diagnostic algorithm was obtained. Using this algorithm, the lesions in the validation sets were diagnosed as nevus or melanoma, and the results were compared with the known histological diagnoses. Both the intensity and pattern of expression of each marker were significantly different in melanomas compared to nevi. The diagnostic algorithm exploiting these differences achieved a specificity of 95% and a sensitivity of 91% in the training set. In the validation sets, the multi-marker assay correctly diagnosed a high percentage of melanomas arising in a nevus, Spitz nevi, dysplastic nevi, and misdiagnosed lesions. The multi-marker assay described here can aid in the diagnosis of melanoma.

Torabian SZ, de Semir D, Nosrati M, Bagheri S, Dar AA, Fong S, Liu Y, Federman S, Simko J, Haqq C, Debs RJ, Kashani-Sabet M. · Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA. · Am J Pathol. · Pubmed #19179607 No free full text.

Abstract: IkappaBgamma is one member of a family of proteins that can inhibit the nuclear localization of nuclear factor-kappaB. However, the other specific functions of IkappaBgamma are still poorly understood, and its effects on tumor metastasis have not yet been characterized. We examined the consequences of targeting IkappaBgamma in melanoma cells using a hammerhead ribozyme. We developed stable transformant B16-F10 melanoma cell lines that express a ribozyme that targets mouse IkappaBgamma (IkappaBgamma-144-Rz). Tail-vein injection of B16-F10 cells that stably express IkappaBgamma-144-Rz into mice resulted in a significant reduction of the metastatic potential of these cells. IkappaBgamma-144-Rz-expressing B16 cells were shown to have increased transcriptional activity of nuclear factor-kappaB. We then showed that IkappaBgamma-144-Rz-expressing cells demonstrated both reduced invasion and increased apoptosis, suggesting the existence of pathways through which IkappaBgamma promotes melanoma metastasis. Using gene expression profiling, we identified a differentially expressed gene set that is regulated by the stable suppression of IkappaBgamma that may participate in mediating its anti-metastatic effects; we also confirmed the altered expression levels of several of these genes by quantitative real time polymerase chain reaction. Plasmid-mediated expression of IkappaBgamma-144-Rz produced a significant inhibition of the metastatic progression of B16-F10 cells to the lung and resulted in significant anti-invasive and pro-apoptotic effects on murine Lewis lung carcinoma cells. Our results suggest a novel role for IkappaBgamma in promoting the metastatic progression of melanoma.

Rangel J, Nosrati M, Leong SP, Haqq C, Miller JR, Sagebiel RW, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, UCSF Comprehensive Cancer Center, Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA. · Am J Surg Pathol. · Pubmed #18580492 No free full text.

Abstract: 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 prognostic marker for melanoma was assessed using immunohistochemical analysis of a melanoma tissue microarray containing primary cutaneous melanomas from 301 patients. High RGS1 expression was significantly correlated with increased tumor thickness (P=0.0083), mitotic rate (P=0.04), and presence of vascular involvement (P<0.02). Kaplan-Meier analysis demonstrated a significant association between increasing RGS1 expression and reduced relapse-free survival (P=0.0032) as well as disease-specific survival (DSS) (P=0.018) survival. Logistic regression analysis showed RGS1 overexpression to be significantly correlated to sentinel lymph node metastasis (P=0.04). Multivariate Cox regression analysis showed that increasing RGS1 immunostaining had an independent impact on the relapse-free survival (P=0.0069) and DSS (P=0.0077) of this melanoma cohort. In the analysis of DSS, RGS1 expression level was the most powerful factor predicting DSS. RGS1 immunostaining retained independent prognostic impact even when sentinel lymph node status was included in the prognostic model (P=0.0039). These results validate the role of RGS1 as a novel prognostic marker for melanoma given its impact on the survival associated with melanoma.

Rangel J, Nosrati M, Torabian S, Shaikh L, Leong SP, Haqq C, Miller JR, Sagebiel RW, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, University of California-San Francisco Comprehensive Cancer Center, San Francisco, California 94115, USA. · Cancer. · Pubmed #18023025 links to  free full text

Abstract: BACKGROUND: Osteopontin has been suggested as a marker of disease progression in patients with melanoma because of its overexpression in recent microarray analyses. However, its prognostic role in melanoma has not been fully defined. METHODS: Osteopontin expression status was examined using immunohistochemical analysis of a tissue microarray that contained primary cutaneous melanomas from 345 patients. The correlation between osteopontin expression and several histologic markers for melanoma was assessed by using the Chi-square test and the Le directional test. The impact of osteopontin expression on recurrence-free survival (RFS) and disease-specific survival (DSS) of patients with melanoma was examined using Cox regression and Kaplan-Meier analyses. The impact of increasing osteopontin expression on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. RESULTS: High osteopontin expression was associated with increased tumor thickness (P = .037), Clark level (P = .035), and mitotic index (P = .046). Kaplan-Meier analysis demonstrated an association between osteopontin expression and reduced RFS (P < .03) and DSS (P = .05). Multivariate Cox regression analysis demonstrated that high osteopontin immunostaining had an independent impact on the DSS of this melanoma cohort (P = .049). In addition, osteopontin expression was significantly predictive of SLN metastasis (P = .009) and SLN burden, as assessed by the mean number of SLN metastases (P = .0025). Multivariate logistic regression analysis demonstrated an independent role for osteopontin expression in predicting SLN status (P = .0062). CONCLUSIONS: The current results validated the role of osteopontin as an independent prognostic marker for melanoma and provided new evidence for its predictive role in melanoma lymph node metastasis.

Wall JK, Florero M, Accortt NA, Allen R, Kashani-Sabet M, Morita E, Leong SP. · Department of Surgery, UCSF, San Francisco, CA 94115, USA. · Arch Surg. · Pubmed #17709729 links to  free full text

Abstract: OBJECTIVE: To determine the impact of multiple lymphatic channels (MLCs) on outcome in melanoma. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care center. PATIENTS: Of 1198 consecutive selective sentinel lymphadenectomies performed from 1995 to 2000 for primary invasive melanoma, 502 patients were identified with extremity or truncal melanoma that drained to a single nodal basin. Three cohorts were formed based on lymphatic channels (none, single, and multiple). Tumors with drainage to multiple nodal basins as well as all head and neck tumors were excluded. MAIN OUTCOME MEASURES: Multiple variables, including patterns of lymphatic drainage, were analyzed for impact on disease-free and overall survival. RESULTS: Demographics were similar among groups, with a median follow-up of 5.6 years. Univariate analysis revealed MLCs as an independent risk factor for both disease-free (P = .04) and overall survival (P = .003). Multivariate analysis confirmed that tumor depth, sentinel lymph node status, and MLCs were risk factors for both disease-free and overall survival. Kaplan-Meier analysis showed worse survival in the MLCs group. CONCLUSIONS: Our study reveals that MLCs are an independent risk factor for recurrence and mortality in melanoma. Multiple lymphatic channels may facilitate the process of metastasis.

Mitchell MS, Abrams J, Thompson JA, Kashani-Sabet M, DeConti RC, Hwu WJ, Atkins MB, Whitman E, Ernstoff MS, Haluska FG, Jakowatz JG, Das Gupta TK, Richards JM, Samlowski WE, Costanzi JJ, Aronson FR, Deisseroth AB, Dudek AZ, Jones VE. · University of California, San Diego, School of Medicine and Cancer Center, San Diego, CA, USA. · J Clin Oncol. · Pubmed #17513813 No free full text.

Abstract: PURPOSE: To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose interferon alfa-2b (IFN-alpha-2b) with the OS achieved using high-dose IFN-alpha-2b. PATIENTS AND METHODS: An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-alpha-2b (arm 1) or high-dose IFN-alpha-2b alone for 1 year (arm 2). Active specific immunotherapy was injected subcutaneously (SC) weekly for 4 weeks, at week 8, and bimonthly thereafter. IFN-alpha-2b SC was begun on week 4 and continued thrice weekly at 5 MU/m2 for 2 years. IFN-alpha-2b in arm 2 was administered according to the Eastern Cooperative Oncology Group 1684 study regimen. RESULTS: Median follow-up time was 32 months for all patients and 42 months for surviving patients. Median OS time exceeds 84 months in arm 1 and is 83 months in arm 2 (P = .56). Five-year OS rate is 61% in arm 1 and 57% in arm 2. Estimated 5-year relapse-free survival (RFS) rate is 50% in arm 1 and 48% in arm 2, with median RFS times of 58 and 50 months, respectively. The incidence of serious adverse events as a result of treatment was the same in both arms, but more severe neuropsychiatric toxicity was seen in arm 2. CONCLUSION: OS and RFS achieved by active specific immunotherapy and low-dose IFN-alpha-2b were indistinguishable from those achieved by high-dose IFN-alpha-2b. Long RFS and OS times were observed in both treatment arms.

Lin YC, You L, Xu Z, He B, Yang CT, Chen JK, Mikami I, Clément G, Shi Y, Kuchenbecker K, Okamoto J, Kashani-Sabet M, Jablons DM. · Thoracic Oncology Laboratory, Department of Surgery, University of California, San Francisco, San Francisco, CA 94115, USA. · Hum Gene Ther. · Pubmed #17472570 No free full text.

Abstract: Silencing of Wnt antagonists with aberrant activation of Wnt signaling is a common phenomenon in various human cancers. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracellular space. In this study, we tried to illuminate the impact of WIF-1 gene expression in melanoma with WIF-1 silencing by in vitro and in vivo studies. We restored the expression of WIF-1 by nonviral gene transfer with a pcDNA3.1 vector. We demonstrated inhibition of melanoma cell growth after WIF-1 restoration in colony formation and proliferation assays in vitro. In addition, the inhibitory effect was related to downregulation of Wnt signaling, which was demonstrated at both the transcriptional and translational levels. Furthermore, by using a xenograft mouse model, we confirmed the effect of WIF-1 expression in suppressing tumor growth by inhibition of Wnt signaling in vivo. Our results suggest the potential for further application of WIF-1 gene therapy in melanoma with WIF-1 silencing.

Grande Sarpa H, Reinke K, Shaikh L, Leong SP, Miller JR, Sagebiel RW, Kashani-Sabet M. · Melanoma Center, Cutaneous Oncology Program, Cancer Center, University of California, San Francisco, CA 94115, USA. · Am J Surg Pathol. · Pubmed #17063079 No free full text.

Abstract: 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 percentage of ulceration in the vertical growth phase of the primary tumor and 2 outcome parameters: sentinel lymph node status and overall survival. We measured the diameter of the ulcerated area in millimeters over the diameter of the entire vertical growth phase. There was a statistically significant relationship between increasing percentage of tumor ulceration and both sentinel lymph node status as well as overall survival, with a binary cut-off point of 2% for sentinel lymph node status and 5% for overall survival. The percentage of ulceration provides additional prognostic information in predicting sentinel lymph node status and in determining survival in melanoma patients. These results suggest that no more than minimal ulceration is required to have a prognostic impact on melanoma survival.

Rangel J, Torabian S, Shaikh L, Nosrati M, Baehner FL, Haqq C, Leong SP, Miller JR, Sagebiel RW, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA 94115, USA. · J Clin Oncol. · Pubmed #17008696 No free full text.

Abstract: PURPOSE: To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma. PATIENTS AND METHODS: 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 absence of various prognostic factors on relapse-free survival (RFS) and disease-specific survival (DSS) of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. The impact of presence or absence of various factors on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. RESULTS: Increasing degree of NCOA3 expression was significantly predictive of SLN metastasis (P = .013) and the mean number of SLN metastases (P = .031). Kaplan-Meier analysis demonstrated a significant association between NCOA3 overexpression and reduced RFS (P = .021) and DSS (P = .030). Logistic regression analysis revealed increasing degree of NCOA3 expression to be an independent predictor of SLN status (P = .017). Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS (P = .0095) and DSS (P = .021). NCOA3 was the most powerful factor predicting DSS, outperforming tumor thickness and ulceration. CONCLUSION: These results identify NCOA3 as a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS, and DSS.

Bagheri S, Nosrati M, Li S, Fong S, Torabian S, Rangel J, Moore DH, Federman S, Laposa RR, Baehner FL, Sagebiel RW, Cleaver JE, Haqq C, Debs RJ, Blackburn EH, Kashani-Sabet M. · Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA. · Proc Natl Acad Sci U S A. · Pubmed #16847266 links to  free full text

Abstract: 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 potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.