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Sample records for advanced cutaneous melanoma

  1. Cutaneous melanoma: new advances in treatment*

    PubMed Central

    Foletto, Michele Ceolin; Haas, Sandra Elisa

    2014-01-01

    Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011, new drugs were approved by the U.S. Food and Drug Administration, including peginterferon alfa-2b for patients with stage III disease, vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation, and ipilimumab, a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor, to combat metastatic melanoma in patients who do not have the BRAF V600E mutation. Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life. PMID:24770508

  2. Cutaneous manifestations associated with melanoma.

    PubMed

    Vyas, Ritva; Selph, Jacqueline; Gerstenblith, Meg R

    2016-06-01

    Melanoma is a malignancy most commonly arising from the skin; therefore, primary melanoma characteristics are usually the first cutaneous manifestations of melanoma. Cutaneous metastases, which can occur locally or diffusely, are important to detect in a timely manner as treatments for advanced melanoma that impact survival are now available. Melanoma can be associated with local or diffuse pigmentation changes, including depigmentation associated with the leukodermas and hyperpigmentation associated with diffuse melanosis cutis. The leukodermas occur frequently, illustrate the immunogenic nature of melanoma, and may impact prognosis. Paraneoplastic syndromes in association with melanoma are rare, though can occur. PMID:27178692

  3. Cutaneous Melanoma in Women

    PubMed Central

    Roh, Mi Ryung; Eliades, Philip; Gupta, Sameer; Tsao, Hensin

    2015-01-01

    The incidence of cutaneous melanoma (CM) continues to increase in the Caucasian population in the United States. In 2014, women only accounted for 42% of the 76,100 new melanoma cases and only 33% of the 9,710 deaths associated with CM in the US.1 These trends are consistently observed in populations around the world. Indeed, gender disparity in melanoma outcome is so consistently observed that gender has been suggested as an important prognostic factor in melanoma, despite not being formerly incorporated in staging algorithms.2 The source of this gender disparity in melanoma remains unclear but likely represents both biological and behavioral etiologies. Herein, we review the current knowledge of how melanoma differs between men and women. PMID:25844396

  4. Delay in cutaneous melanoma diagnosis

    PubMed Central

    Xavier, Marcus H.S.B.; Drummond-Lage, Ana P.; Baeta, Cyntia; Rocha, Lorena; Almeida, Alessandra M.; Wainstein, Alberto J.A.

    2016-01-01

    Abstract Advanced melanoma is an incurable disease with complex and expensive treatments. The best approach to prevent melanoma at advanced stages is an early diagnosis. A knowledge of factors associated with the process of detecting cutaneous melanomas and the reasons for delays in diagnosis is essential for the improvement of the secondary prevention of the disease. Identify sociodemographic, individual, and medical aspects related to cutaneous melanoma diagnosis delay. Interviews evaluated the knowledge of melanoma, signals, symptoms, persons who were suspected, delays in seeking medical attention, physician's deferrals, and related factors of 211 patients. Melanomas were self-discovered in 41.7% of the patients; healthcare providers detected 29.9% of patients and others detected 27%. The main component in delay was patient-related. Only 31.3% of the patients knew that melanoma was a serious skin cancer, and most thought that the pigmented lesion was not important, causing a delay in seeking medical assistance. Patients (36.4%) reported a wait interval of more than 6 months from the onset of an observed change in a pigmented lesion to the first visit to a physician. The delay interval from the first physician visit to a histopathological diagnosis was shorter (<1 month) in 55.5% of patients. Improper treatments without a histopathological confirmation occurred in 14.7% of patients. A professional delay was related to both inappropriate treatments performed without histopathological confirmation (P = 0.003) and long requirements for medical referrals (P < 0.001). A deficient knowledge in the population regarding melanoma and physicians’ misdiagnoses regarding suspicious lesions contributed to delays in diagnosis. PMID:27495055

  5. Familial cutaneous melanoma.

    PubMed

    Hansson, Johan

    2010-01-01

    Approximately 5-10 % of all cutaneous melanomas occur in families with hereditary melanoma predisposition. Worldwide, approximately 20-40% of kindreds with familial elanoma harbor germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence. In different populations several recurring CDKN2A founder mutations have been described. The risk of melanoma in CDKN2A mutations carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population. Some CDKN2A mutations have been associated not only with melanoma but also with increased risk of other malignancies--most notably pancreatic carcinoma. A much smaller number of families have germline mutations in the CDK4 gene on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A. The management of families with hereditary melanoma is discussed. PMID:20687502

  6. Genotyping of cutaneous melanoma

    PubMed Central

    Glitza, Isabella C.; Davies, Michael A.

    2014-01-01

    Until recently, treatment options for patients with metastatic melanoma were very limited. This landscape has evolved dramatically since the discovery of activating mutations in the BRAF gene in ~45% of cutaneous melanomas. Vemurafenib, dabrafenib, and trametinib have all received regulatory approval for the treatment of metastatic melanoma patients with a BRAFV600 mutation. Based on the necessity to document the presence of a BRAFV600 mutation to prescribe these agents, molecular testing is now the standard of care in this disease. However, the options and rationale for testing are evolving rapidly due to an improved understanding of the molecular drivers and heterogeneity of melanoma. Such testing may identify rational combinatorial approaches to prevent or overcome resistance for the approved BRAF inhibitors. In addition, new clinical strategies have been identified for a number of other molecular changes that are detected in this disease, including somatic changes in NRAS, PTEN, CDKN2A, and c-KIT, among others. This review summarizes the current understanding of the genetic landscape of mutations in melanoma, their associations with clinicopathological features, and their implications for clinical testing and treatment. PMID:25632386

  7. Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

    PubMed Central

    Gönül, Müzeyyen

    2016-01-01

    The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed. PMID:27042173

  8. Revisiting determinants of prognosis in cutaneous melanoma.

    PubMed

    Weiss, Sarah A; Hanniford, Douglas; Hernando, Eva; Osman, Iman

    2015-12-01

    The American Joint Committee on Cancer staging system for cutaneous melanoma is based on primary tumor thickness and the presence of ulceration, mitoses, lymph node spread, and distant metastases as determinants of prognosis. Although this cutaneous melanoma staging system has evolved over time to more accurately reflect patient prognosis, improvements are still needed, because current understanding of the particular factors (genetic mutation, expression alteration, host response, etc) that are critical for predicting patient outcomes is incomplete. Given the clinical and biologic heterogeneity of primary melanomas, new prognostic tools are needed to more precisely identify patients who are most likely to develop advanced disease. Such tools would affect clinical surveillance strategies and aid in patient selection for adjuvant therapy. The authors reviewed the literature on prognostic molecular and immunologic markers in primary cutaneous melanoma, their associations with clinicopathologic and survival outcomes, and their potential for incorporation into current staging models. Overall, the studies considered in this review did not define prognostic markers that could be readily incorporated into the current staging system. Therefore, efforts should be continued in these and other directions to maximize the likelihood of identifying clinically useful prognostic biomarkers for cutaneous melanoma. PMID:26308244

  9. Genetic determinants of cutaneous melanoma predisposition.

    PubMed

    Udayakumar, Durga; Mahato, Bisundev; Gabree, Michele; Tsao, Hensin

    2010-09-01

    In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing. PMID:21051013

  10. Cutaneous melanoma: A current overview.

    PubMed

    Wick, Mark R

    2016-07-01

    Cutaneous melanoma continues to increase in frequency, for unknown reasons, and it can pose considerable diagnostic challenges to clinician and pathologists alike. This review considers current concepts pertaining to that tumor, including those concerning epidemiology, clinical diagnosis, histologic findings, adjunctive diagnostic studies, and prognosis. PMID:27229301

  11. Cutaneous melanoma: uncommon presentations.

    PubMed

    Beyeler, Mirjam; Dummer, Reinhard

    2005-01-01

    Melanoma is the most important nonepithelial skin cancer. The diagnosis is usually made by clinical examination including dermatoscopy and histology. There are, however, variants of melanoma that miss the characteristic signs of pigmented lesions which are easily detectable when using the ABCD rule. PMID:16325067

  12. Biology of Human Cutaneous Melanoma

    PubMed Central

    Elias, Elias G.; Hasskamp, Joanne H.; Sharma, Bhuvnesh K.

    2010-01-01

    A review of the natural behavior of cutaneous melanoma, clinical and pathological factors, prognostic indicators, some basic research and the present and possible futuristic strategies in the management of this disease are presented. While surgery remains to be the most effective therapeutic approach in the management of early primary lesions, there is no standard adjuvant therapy after surgical resection, or for metastatic disease. PMID:24281039

  13. Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

    PubMed Central

    Corrie, P G; Shaw, J; Spanswick, V J; Sehmbi, R; Jonson, A; Mayer, A; Bulusu, R; Hartley, J A; Cree, I A

    2005-01-01

    Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m−2, followed by a fixed dose of 5.0 g m−2 treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m−2 gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m−2 gemcitabine combined with 5.0 g m−2 treosulfan. PMID:15886706

  14. Histological types of polypoid cutaneous melanoma II.

    PubMed

    Knezević, Fabijan; Duancić, Vjekoslav; Sitić, Sanda; Horvat-Knezević, Anica; Benković, Vesna; Ramić, Snjezana; Kostović, Kresimir; Ramljak, Vesna; Vrdoljak, Danko Velemir; Stanec, Mladen; Bozović, Angelina

    2007-12-01

    The aim of this study was to ascertain which histological types of melanoma can clinically and morphologically appear as polypoid melanomas. In 645 cases of primary cutaneous melanoma we have analyzed criteria for diagnosis of polypoid cutaneous melanoma and afterwards we have analyzed growth phase in each polypoid melanoma, histological type of atypical melanocytes, the number of epidermal ridges which are occupied by atypical melanocytes, and distribution according to age, sex and location, as well as the disease free survival. According to the criteria for polypoid melanomas we have found 147 (22.8%) polypoid cutaneous melanomas. Analyzing the growth phases, histological types of atypical melanocytes and the number of affected epidermal ridges in the group of polypoid melanomas we have ascertained 2 (1.4%) ALMs, 4 (2.8%) LMMs, 42 (28.6%) SSMs and 99 (67.2%) NMs. Our conclusion is that polypoid cutaneous melanomas are morphological forms of various histological melanoma types (ALM, LMM, SSM and NM) and they can all display polypoid morphological form. Polypoid cutaneous melanomas are most often of nodular histological type. PMID:18217457

  15. Management of advanced melanoma

    SciTech Connect

    Nathanson, L. )

    1986-01-01

    This book presents papers on the subject of management of advanced melanoma. The topics covered are: non-investigational cytotoxic agents; high-dosage chemotherapy in antologous bone marrow transplantation; Radiotherapy of melanomas; hyperthermia; ureal melanoma; surgical treatment of recurrent a metastatic melanoma; role of interferons in management of melanoma and molecular genetics of melanoma.

  16. Choroidal Metastases From Cutaneous Melanoma.

    PubMed

    Mercado, Carmel L; Toy, Brian C; Kistler, Henry B; Moshfeghi, Darius M

    2016-05-01

    A 92-year-old man presented with months of progressive blurry vision, worsening acutely in his right eye. He denied pain, diplopia, or photopsias. His history was significant for multiple myeloma, prostate cancer, and malignant melanoma of his right shoulder treated with local excision. He had local recurrence with hepatic metastasis of the melanoma treated with radiation and chemotherapy. On examination, his visual acuity was counting fingers in the right eye and 20/60 in the left eye. Amsler grid testing demonstrated metamorphopsia in the right eye. Fundus exam of the right and left eyes revealed multiple, elevated, pigmented choroidal lesions, with associated subretinal fluid in the right macula. This appearance is consistent with hematogenous metastasis of cutaneous malignant melanoma to the choroid and associated serous fluid-causing metamorphopsia. The patient was enrolled in a clinical trial combining plasmid IL-12 with pembrolizumab (Keytruda; Merck, Whitehouse Station, NJ). He passed away 2 months after initial presentation to our clinic. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:497.]. PMID:27183558

  17. Genomic Classification of Cutaneous Melanoma.

    PubMed

    2015-06-18

    We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making. PMID:26091043

  18. Botanicals for the prevention and treatment of cutaneous melanoma

    PubMed Central

    Syed, Deeba N.; Mukhtar, Hasan

    2011-01-01

    Summary Cutaneous melanoma, a cancer of melanocytes, when detected at later stages is arguably one of the most lethal cancers and the cause of more years of lost life than any other cancer among young adults. There is no standard therapy for advanced-stage melanoma and the median survival time for patients with metastatic melanoma is <1 yr. An urgent need for novel strategies against melanoma has directed research towards the development of new chemotherapeutic and biologic agents that can target the tumor by several different mechanisms. Recently, several dietary agents are being investigated for their role in the prevention and treatment of various forms of cancer and may represent the future modality of the treatment. Here, we have reviewed emerging data on botanicals that are showing promise for their potential inhibitory effect against cutaneous melanoma. PMID:21426532

  19. The genomic landscape of cutaneous melanoma.

    PubMed

    Zhang, Tongwu; Dutton-Regester, Ken; Brown, Kevin M; Hayward, Nicholas K

    2016-05-01

    Somatic mutation analysis of melanoma has been performed at the single gene level extensively over the past several decades. This has provided considerable insight into the critical pathways controlling melanoma initiation and progression. During the last 5 yr, next-generation sequencing (NGS) has enabled even more comprehensive mutational screening at the level of multigene panels, exomes and genomes. These studies have uncovered many new and unexpected players in melanoma development. The recent landmark study from The Cancer Genome Atlas (TCGA) consortium describing the genomic architecture of 333 cutaneous melanomas provides the largest and broadest analysis to date on the somatic aberrations underlying melanoma genesis. It thus seems timely to review the mutational landscape of melanoma and highlight the key genes and cellular pathways that appear to drive this cancer. PMID:26833684

  20. Effect of vaccination with N-glycolyl GM3/VSSP vaccine by subcutaneous injection in patients with advanced cutaneous melanoma

    PubMed Central

    Osorio, Marta; Gracia, Elias; Reigosa, Edmundo; Hernandez, Julio; de la Torre, Ana; Saurez, Giselle; Perez, Kirenia; Viada, Carmen; Cepeda, Meylán; Carr, Adriana; Ávila, Yisel; Rodríguez, Migdalia; Fernandez, Luis E

    2012-01-01

    NeuGc-containing gangliosides have been described in melanoma cells and are an attractive target for cancer immunotherapy because they are minimally or not expressed in normal human tissues. Melanoma patients treated with a vaccine based on N-glycolyl gangliosides have shown benefit in progression free survival and overall survival. We conducted a multicenter Phase I/II clinical trial in patients with metastatic cutaneous melanoma treated with the N-gycolyl GM3/very-small-size proteoliposomes vaccine by the subcutaneous route. Selecting the optimal biological dose of the vaccine was the principal objective based on immunogenicity, efficacy, and safety results. Six dose levels were studied and the treatment schedule consisted of five doses administered every 2 weeks and then monthly until 15 doses had been given. Dose levels evaluated were 150, 300, 600, 900, 1200, and 1500 μg with five patients included in each dose level except the 900 μg dose (n = 10). Immunogenicity was determined by antibody titers generated in patients after vaccination. Antitumor effect was measured by response criteria of evaluation in solid tumors and safety was evaluated by common toxicity criteria of adverse events. The vaccine was safe and immunogenic at all doses levels. The most frequent adverse events related to vaccination were mild to moderate injection site reactions and flu-like symptoms. Vaccination induced specific anti-NeuGcGM3 immunoglobulin M and immunoglobulin G antibody responses in all patients. Disease control (objective response or stable disease) was obtained in 38.46% of patients. Global median overall survival was 20.20 months. Two patients achieved overall survival duration of about 4 and 5 years, respectively. The 900 μg dose resulted in overall survival duration of 19.40 months and was selected as the biological optimal dose. PMID:23055778

  1. Cutaneous Melanoma: A Population Health Problem.

    PubMed

    Warren, Hermine

    2015-01-01

    Cutaneous melanoma (CM), generally referred to as melanoma, has been identified as an overall population health problem. Examination of evidence-based research revealed a strong correlation between CM and tanning bed usage, specifically by young females. For these reasons, a preliminary research question/hypothesis was structured that proposed examining different geographical locations, and whether the relationship between melanoma and tanning bed exposure by young females would be affected. Epidemiologic principles will be utilized to provide guidelines and tools for comprehensively examining this health issue and how it might affect morbidity and mortality within the populations where occurrences are identified. Furthermore, to understand some of the contributing factors of this disease, melanoma was discussed in terms of person, place, time, and how tanning bed exposure may significantly heighten CM as a potentially fatal health problem. PMID:26605821

  2. Updates in Therapy for Advanced Melanoma

    PubMed Central

    Singh, Bhavana P.; Salama, April K. S.

    2016-01-01

    Cutaneous melanoma is one of the most aggressive forms of skin cancer, and is correlated with a large proportion of skin cancer-related deaths. Therapy for cutaneous melanoma has advanced greatly through careful identification of therapeutic targets and the development of novel immunotherapeutic approaches. The identification of BRAF as well as other driver mutations, have allowed for a specialized approach to treatment. In addition, immune checkpoint inhibition has dramatically changed the treatment landscape over the past 5–10 years. The successful targeting of CTLA-4, as well as PD-1/PD-L1, has been translated into meaningful clinical benefit for patients, with multiple other potential agents in development. Systemic therapy for cutaneous melanoma is becoming more nuanced and often takes a multifaceted strategy. This review aims to discuss the benefits and limitations of current therapies in systemic melanoma treatment as well as areas of future development. PMID:26784231

  3. Clinical and morphological characteristics of cutaneous melanoma.

    PubMed

    Balaban, Jagoda; Ninković Baroš, Djuka; Grujić, Dragana; Starović, Dragana; Ćelić, Milanka

    2014-01-01

    The incidence of cutaneous melanoma has increased significantly worldwide over the last several decades. The aim of this study is to determine clinical and morphology characteristics of primary melanoma, since some of them are important prognostic factors. This retrospective study included 172 patients. The data were collected by the Consulting team for malignant skin tumors in the Banja Luka Clinical Centre from 2009 to 2011. We did not use dermoscopy as a diagnostic tool in our investigation. We determined that melanoma occurs equally commonly in both sexes, in women in the sixth decade and the seventh in men. The most common sub-type was nodular melanoma (59.5%, P<0.05), followed by superficial spreading (27.8%) and acral lentiginous melanoma (11.4%). The most common localization was on the back in men (34.3%) and on the legs in women (P<0.05). More than half of our patients (55.8%) had melanoma thickness from 1.0 to 4.0 mm, and 38% had a melanoma thicker than 4.0 mm. The average Breslow thickness is 4.6 mm. More women than men had melanoma thicker than 4 mm (P<0.05). Spread of the primary tumor localization was found in 31.4% of patients, more frequently in men than in women (P<0.05). In most cases it was abstraction of lymph nodes (P<0.05). The average thickness of the melanoma in our patients is much higher than the average in the world and the countries of Europe. The results of this study indicate a need for better unique regional registry in this part of Bosnia and Herzegovina and improvement of preventive measures in the early diagnosis of melanoma. PMID:25580786

  4. RASSF8 regulates progression of cutaneous melanoma through nuclear factor-κb

    PubMed Central

    Wang, Jinhua; Hua, Wei; Huang, Sharon K.; Fan, Kun; Takeshima, Ling; Mao, Ying; Hoon, Dave S.B.

    2015-01-01

    Our group previously demonstrated that the RASSF1 gene has a significant tumor suppressor role in cutaneous melanoma. The RASSF8 gene is a member of the N-terminal RASSF gene family. Previously, we identified RASSF8 (HOJ1, NCBI Gene ID:11228) expression in cutaneous melanoma; however the functional role of RASSF8 in melanoma is not known. RASSF8 expression was assessed in melanoma cell lines and tumors of different AJCC stages. Results indicated that RASSF8 expression was low in metastatic melanoma lines and decreased with melanoma progression. We then explored the mechanism of RASSF8 downregulation in melanoma by assessing methylation of RASSF8 and demonstrated that methylation of RASSF8 gene promoter was higher in advanced than in early stages melanomas. Functional activity of RASSF8 in melanoma lines by knockdown and overexpression of RASSF8 demonstrated that RASSF8 expression significantly inhibited cell growth, cell migration and invasion, whereas knockdown of RASSF8 expression significantly increased cell growth, cell migration and invasion of melanoma cells by increasing expression of P65 and its downstream target IL-6. Moreover RASSF8 was found to induce apoptosis in melanoma cells by activating the P53-P21 pathway, and also in vivo studies demonstrated that inhibiting RASSF8 increases the tumorigenic properties of human melanoma xenografts. These results suggest that RASSF8 plays a significant role in suppressing the progression of cutaneous melanoma. PMID:26334503

  5. Characteristics and Treatment of Cutaneous Melanoma of the Foot

    PubMed Central

    Nam, Kyung Wook; Nam, Soo Bong; Kim, Joo Hyung; Kim, Hoon Soo; Choi, Young Jin

    2016-01-01

    Background In East Asia, the foot is the most common site of cutaneous melanoma. The purpose of this study was to investigate the differences between cutaneous melanoma of the foot and melanomas of other sites. Methods We studied 52 patients who underwent surgical treatment for cutaneous melanoma of the foot from September 2000 to January 2015. Through a retrospective review of their medical records, we collected data relating to their sex, age, histopathological subtype, Clark level, tumor thickness, lymph node involvement, stage, and survival rate, and we compared these parameters to those of 61 patients treated for melanoma of other sites. Moreover, we analyzed the surgical procedures, complications, and mortality rates associated with cutaneous melanoma on various parts of the foot. Results Melanoma of the foot differed from other melanomas only in the histopathological subtype. Other clinical features, including survival rate, did not differ significantly between the two groups heel was the most common site of melanoma of the foot (22 cases, 42.3%). The method of reconstruction varied depending on the region involved. Conclusions A comparison of melanoma of the foot to other melanomas showed that melanoma of the foot was associated with a significantly different distribution of histological subtypes. Consistent with previous findings, we found that the acral lentiginous subtype was the most common among melanomas of the foot. Furthermore, in contrast with previous studies, we did not find a worse prognosis or lower survival rate for melanoma of the foot in comparison with other melanomas. PMID:26848447

  6. Selenium for the Prevention of Cutaneous Melanoma

    PubMed Central

    Cassidy, Pamela B.; Fain, Heidi D.; Cassidy, James P.; Tran, Sally M.; Moos, Philip J.; Boucher, Kenneth M.; Gerads, Russell; Florell, Scott R.; Grossman, Douglas; Leachman, Sancy A.

    2013-01-01

    The role of selenium (Se) supplementation in cancer prevention is controversial; effects often depend on the nutritional status of the subject and on the chemical form in which Se is provided. We used a combination of in vitro and in vivo models to study two unique therapeutic windows for intervention in the process of cutaneous melanomagenisis, and to examine the utility of two different chemical forms of Se for prevention and treatment of melanoma. We studied the effects of Se in vitro on UV-induced oxidative stress in melanocytes, and on apoptosis and cell cycle progression in melanoma cells. In vivo, we used the HGF transgenic mouse model of UV-induced melanoma to demonstrate that topical treatment with l-selenomethionine results in a significant delay in the time required for UV-induced melanoma development, but also increases the rate of growth of those tumors once they appear. In a second mouse model, we found that oral administration of high dose methylseleninic acid significantly decreases the size of human melanoma xenografts. Our findings suggest that modestly elevation of selenium levels in the skin might risk acceleration of growth of incipient tumors. Additionally, certain Se compounds administered at very high doses could have utility for the treatment of fully-malignant tumors or prevention of recurrence. PMID:23470450

  7. Selenium for the prevention of cutaneous melanoma.

    PubMed

    Cassidy, Pamela B; Fain, Heidi D; Cassidy, James P; Tran, Sally M; Moos, Philip J; Boucher, Kenneth M; Gerads, Russell; Florell, Scott R; Grossman, Douglas; Leachman, Sancy A

    2013-03-01

    The role of selenium (Se) supplementation in cancer prevention is controversial; effects often depend on the nutritional status of the subject and on the chemical form in which Se is provided. We used a combination of in vitro and in vivo models to study two unique therapeutic windows for intervention in the process of cutaneous melanomagenisis, and to examine the utility of two different chemical forms of Se for prevention and treatment of melanoma. We studied the effects of Se in vitro on UV-induced oxidative stress in melanocytes, and on apoptosis and cell cycle progression in melanoma cells. In vivo, we used the HGF transgenic mouse model of UV-induced melanoma to demonstrate that topical treatment with l-selenomethionine results in a significant delay in the time required for UV-induced melanoma development, but also increases the rate of growth of those tumors once they appear. In a second mouse model, we found that oral administration of high dose methylseleninic acid significantly decreases the size of human melanoma xenografts. Our findings suggest that modestly elevation of selenium levels in the skin might risk acceleration of growth of incipient tumors. Additionally, certain Se compounds administered at very high doses could have utility for the treatment of fully-malignant tumors or prevention of recurrence. PMID:23470450

  8. The genetics of susceptibility to cutaneous melanoma.

    PubMed

    Newton Bishop, Julia A; Bishop, D Timothy

    2005-03-01

    The most common genetic determinants of skin cancer are the genes that control skin color so that the genes expressed as black skin are protective. Within the white population variants at the MC1R locus are shown to increase susceptibility, and recent evidence suggests that polymorphisms in the OCA2 gene interact to modify risk. Other as-yet-unidentified pigment genes may also play a role in susceptibility to melanoma. Thus MC1R variants are the most common low-penetrance melanoma-susceptibility genes so far identified. Other putative low-penetrance susceptibility genes have been explored using candidate gene approaches. Good candidates such as the DNA repair gene XRCC3 and polymorphisms of EGF have been studied but excluded. Other candidates such as BRAF polymorphisms and variants at the CDKN2A locus remain to be fully investigated. More progress has been made in identifying high-penetrance genes, however. The most common (and probably the most penetrant) susceptibility locus is the CDKN2A locus coding for two tumor suppressor proteins, p16 and p14ARF. Mutations at this locus that impact p16, p14ARF or both proteins all increase susceptibility to melanoma. Families inheriting such mutants are at increased risk of cutaneous melanoma, and the penetrance is increased by residence in sunny climates and co-inheritance of MC1R variants. Some families also appear to be at increased risk of pancreatic cancer, but the determinants of susceptibility to pancreatic cancer are not yet understood. Very rare families have germline mutations in the CDK4 gene which impact on the p16 binding site. There are other high-penetrance susceptibility genes, however, which remain undiscovered. There is evidence of one at 1p22. The Melanoma Genetics Consortium (www.genomel.org) continues to explore this and the genetic epidemiology of the CDKN2A locus. PMID:15883616

  9. INFRARED THERMOGRAPHY OF CUTANEOUS MELANOMA METASTASES

    PubMed Central

    Shada, Amber L.; Dengel, Lynn T.; Petroni, Gina R.; Smolkin, Mark E.; Acton, Scott; Slingluff, Craig L.

    2014-01-01

    Background Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions. Materials and methods Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0–5, >5–15, >15–30, and >30 mm. Images were scored on a scale from −1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored. Results IR imaging was able to determine the malignancy of small (0–5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions >5–15 mm, sensitivity was 58% and specificity 98%. For lesions >15–30 mm, sensitivity was 95% and specificity 100%, and for lesions >30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%–100% across all strata, and the negative predictive value was 95% for >15–30 mm lesions and 80% for >30 mm lesions. Conclusions Malignant lesions >15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies. PMID:23043862

  10. Defining the dermoscopic characteristics of fast-growing cutaneous melanomas.

    PubMed

    Tejera-Vaquerizo, Antonio; Arias-Santiago, Salvador; Nagore, Eduardo; Martín-Cuevas, Paula; Orgaz-Molina, Javier; Traves, Victor; Herrera-Acosta, Enrique; Naranjo-Sintes, Ramón; Guillén, Carlos; Herrera-Ceballos, Enrique

    2015-06-01

    A high growth rate in melanomas has been associated with a more aggressive phenotype and worse survival. The aim of this study was to define the dermoscopic characteristics associated with this type of cutaneous melanoma. We carried out a retrospective study of 132 cutaneous melanomas, analyzing certain clinical characteristics and the most important dermoscopic variables related to the melanomas. Fast-growing melanomas were considered to be those with a growth rate of more than 0.5 mm per month. Fast-growing melanomas more often lacked an atypical network, were symmetrical, presented ulceration, and were hypopigmented. The dermoscopic vascular pattern often showed atypical irregular vessels and milky-red areas. The association of these two is a specific characteristic. Fast-growing melanomas have a characteristic phenotype and dermoscopy can be useful for their identification. PMID:25919929

  11. BAP1 PLAYS A SURVIVAL ROLE IN CUTANEOUS MELANOMA

    PubMed Central

    Kumar, Raj; Taylor, Michael; Miao, Benchun; Ji, Zhenyu; Njauw, Jenny Ching-Ni; Jönsson, Göran; Frederick, Dennie Tompers; Tsao, Hensin

    2014-01-01

    Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous/ocular melanoma (CM/OM) predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of cutaneous melanoma is not fully understood. We thus set out to characterize BAP1 in cutaneous melanoma and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared to nevi and normal skin. Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony forming capability, induced apoptosis and inhibited melanoma tumor growth in vivo. On the molecular level, suppression of BAP1 led to a concomitant drop in the protein levels of survivin a member of anti-apoptotic proteins and a known mediator of melanoma survival. Restoration of survivin in melanoma cells partially rescued the growth-retarding effects of BAP1 loss. In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non-transformed melanocytes did suppress proliferation and reduce survivin. Taken together, these studies demonstrate that BAP1 may play a growth-sustaining role in melanoma cells, but that its impact on ubiquitination underpins a complex physiology which is context and cell dependent. PMID:25521456

  12. Nestin expression is associated with aggressive cutaneous melanoma of the nodular type.

    PubMed

    Ladstein, Rita G; Bachmann, Ingeborg M; Straume, Oddbjørn; Akslen, Lars A

    2014-03-01

    The intermediate filament nestin, a neural stem-cell marker, is reported to be expressed more strongly in melanomas compared with benign melanocytic lesions, and increasingly expressed in advanced melanoma stages. However, the prognostic impact of nestin on melanoma has not been well elucidated. The aim of the present study was to evaluate the prognostic influence of nestin expression in cutaneous melanoma in comparison with standard clinico-pathologic variables. In a large series of nodular cutaneous melanoma (n=348), nestin expression was assessed by immunohistochemistry using tissue microarray (TMA) sections. For comparison, nestin staining in corresponding metastases as well as in superficial spreading melanomas and benign nevi was also examined. Nestin was expressed to varying degrees in a majority of nodular melanomas (92%), and was significantly associated with increased tumor thickness, high mitotic count, and the presence of ulceration and tumor necrosis. Also, expression was stronger in the nodular type than in superficial spreading melanomas and benign nevi, but without significant difference when compared with matched metastases from the former. Importantly, strong expression of nestin was significantly associated with reduced survival in multivariate analysis. In conclusion, increased nestin expression was associated with aggressive melanoma features, with independent prognostic impact on multivariate survival analysis when compared with clinico-pathologic factors. PMID:24030749

  13. Established and Emerging Biomarkers in Cutaneous Malignant Melanoma

    PubMed Central

    Verykiou, Stamatina; Ellis, Robert A; Lovat, Penny E

    2014-01-01

    In an era of personalized medicine, disease specific biomarkers play an increasing role in the stratification of high-risk patient groups. Cutaneous malignant melanoma is the most deadly form of skin cancer with an ever-increasing global incidence, especially in patients under 35-years of age. Despite the excellent prognosis for patients diagnosed with early stage disease, metastatic disease still carries significant overall mortality. Biomarkers aim not only to identify high-risk patients, but also to provide potential therapeutic targets for differing patient subgroups. Furthermore, accessibility to tissue samples from a range of disease stages in malignant melanoma, unlike most other solid tissue tumours, provides the unique opportunity to explore the biology of tumour progression that may be relevant in the biology of cancer as a whole. Over the past decade, there have been major advances in targeted therapies, providing new avenues and hope to patients with this devastating disease. This review will focus on most up to date histological, serological and molecular biomarkers in malignant melanoma.

  14. Cutaneous malignant melanoma: update on diagnostic and prognostic biomarkers.

    PubMed

    Abbas, Ossama; Miller, Daniel D; Bhawan, Jag

    2014-05-01

    The incidence of cutaneous malignant melanoma has rapidly increased in recent years in all parts of the world, and melanoma is a leading cause of cancer death. As even relatively small melanomas may have metastatic potential, accurate assessment of progression is critical. Although diagnosis of cutaneous malignant melanoma is usually based on histopathologic criteria, these criteria may at times be inadequate in differentiating melanoma from certain types of benign nevi. As for prognosis, tumor (Breslow) thickness, mitotic rate, and ulceration have been considered the most important prognostic indicators among histopathologic criteria. However, there are cases of thin primary melanomas that have ultimately developed metastases despite complete excision. Given this, an accurate assessment of melanoma progression is critical, and development of molecular biomarkers that identify high-risk melanoma in its early phase is urgently needed. Large-scale genomic profiling has identified considerable heterogeneity in melanoma and suggests subgrouping of tumors by patterns of gene expression and mutation will ultimately be essential to accurate staging. This subgrouping in turn may allow for more targeted therapy. In this review, we aim to provide an update on the most promising new biomarkers that may help in the identification and prognostication of melanoma. PMID:24803061

  15. Triggering Receptor Expressed on Myeloid Cells in Cutaneous Melanoma.

    PubMed

    Nguyen, Austin Huy; Koenck, Carleigh; Quirk, Shannon K; Lim, Victoria M; Mitkov, Mario V; Trowbridge, Ryan M; Hunter, William J; Agrawal, Devendra K

    2015-10-01

    The tumor microenvironment plays an important role in the progression of melanoma, the prototypical immunologic cutaneous malignancy. The triggering receptor expressed on myeloid cells (TREM) family of innate immune receptors modulates inflammatory and innate immune signaling. It has been investigated in various neoplastic diseases, but not in melanoma. This study examines the expression of TREM-1 (a proinflammatory amplifier) and TREM-2 (an anti-inflammatory modulator and phagocytic promoter) in human cutaneous melanoma and surrounding tissue. Indirect immunofluorescence staining was performed on skin biopsies from 10 melanoma patients and staining intensity was semiquantitatively scored. Expression of TREM-1 and TREM-2 was higher in keratinocytes than melanoma tissue (TREM-1: p < 0.01; TREM-2: p < 0.01). Whereas TREM-2 was the dominant isoform expressed in normal keratinocytes, TREM-1 expression predominated in melanoma tissue (TREM-1 to TREM-2 ratio: keratinocytes = 0.78; melanoma = 2.08; p < 0.01). The increased TREM ratio in melanoma tissue could give rise to a proinflammatory and protumor state of the microenvironment. This evidence may be suggestive of a TREM-1/TREM-2 paradigm in which relative levels dictate inflammatory and immune states, rather than absolute expression of one or the other. Further investigation regarding this paradigm is warranted and could carry prognostic or therapeutic value in treatment for melanoma. PMID:26184544

  16. Controversies in the diagnosis and treatment of early cutaneous melanoma.

    PubMed

    Orzan, O A; Șandru, A; Jecan, C R

    2015-01-01

    Cutaneous melanoma (CM) is a disease with an unpredictable evolution mainly due to its high metastatic ability. The steadily increasing incidence and the poor outcome in advanced stages made this cancer an interesting field for many research groups. Given that CM is a curable disease in early stages, efforts have been made to detect it as soon as possible, which led to the diversification and refining of diagnosis methods and therapies. But, as the data from trials have been published, doubts about the indications and efficacy of established treatments have arisen. In fact, there is probably no single aspect of early CM that has not given birth to controversy. This article intends to present the current disputes regarding the early detection, diagnosis, treatment and postoperative follow-up of patients with localized CM. After analyzing both pros and cons, several conclusions were drawn, that reflect our experience in managing patients with early CM. PMID:25866567

  17. Controversies in the diagnosis and treatment of early cutaneous melanoma

    PubMed Central

    Orzan, OA; Șandru, A; Jecan, CR

    2015-01-01

    Cutaneous melanoma (CM) is a disease with an unpredictable evolution mainly due to its high metastatic ability. The steadily increasing incidence and the poor outcome in advanced stages made this cancer an interesting field for many research groups. Given that CM is a curable disease in early stages, efforts have been made to detect it as soon as possible, which led to the diversification and refining of diagnosis methods and therapies. But, as the data from trials have been published, doubts about the indications and efficacy of established treatments have arisen. In fact, there is probably no single aspect of early CM that has not given birth to controversy. This article intends to present the current disputes regarding the early detection, diagnosis, treatment and postoperative follow-up of patients with localized CM. After analyzing both pros and cons, several conclusions were drawn, that reflect our experience in managing patients with early CM. PMID:25866567

  18. POLE mutations in families predisposed to cutaneous melanoma.

    PubMed

    Aoude, Lauren G; Heitzer, Ellen; Johansson, Peter; Gartside, Michael; Wadt, Karin; Pritchard, Antonia L; Palmer, Jane M; Symmons, Judith; Gerdes, Anne-Marie; Montgomery, Grant W; Martin, Nicholas G; Tomlinson, Ian; Kearsey, Stephen; Hayward, Nicholas K

    2015-12-01

    Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer. PMID:26251183

  19. Genetic determinants of cutaneous malignant melanoma in Sinclair swine.

    PubMed

    Blangero, J; Tissot, R G; Beattie, C W; Amoss, M S

    1996-03-01

    The role of genetic factors involved in the determination of risk of cutaneous malignant melanoma (CMM) in humans remains unclear owing to genetic heterogeneity and reliance on simplistic models of inheritance. Here, we report a statistical genetic analysis of cutaneous malignant melanoma in Sinclair swine (SSCM), a unique animal model for human CMM. Using complex segregation analysis a two-locus model involving an unknown major locus and a second locus that lies within or close to the swine leukocyte antigen (SLA) complex jointly determine risk of SSCM in pedigreed animals. These loci also influence severity of affection, accounting for approximately 20% of the phenotypic variation in quantitative tumour burden. PMID:8605105

  20. BAP1 has a survival role in cutaneous melanoma.

    PubMed

    Kumar, Raj; Taylor, Michael; Miao, Benchun; Ji, Zhenyu; Njauw, Jenny C-N; Jönsson, Göran; Frederick, Dennie T; Tsao, Hensin

    2015-04-01

    Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous melanoma (CM)/ocular melanoma predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of CM is not fully understood. We thus set out to characterize BAP1 in CM and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared with nevi and normal skin. Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony-forming capability, induced apoptosis, and inhibited melanoma tumor growth in vivo. On the molecular level, suppression of BAP1 led to a concomitant drop in the protein levels of survivin, a member of anti-apoptotic proteins and a known mediator of melanoma survival. Restoration of survivin in melanoma cells partially rescued the growth-retarding effects of BAP1 loss. In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non-transformed melanocytes did suppress proliferation and reduce survivin. Taken together, these studies demonstrate that BAP1 may have a growth-sustaining role in melanoma cells, but that its impact on ubiquitination underpins a complex physiology, which is context and cell dependent. PMID:25521456

  1. Associations between environmental factors and incidence of cutaneous melanoma. Review

    PubMed Central

    2012-01-01

    Background Cutaneous melanoma is one of the most serious skin cancers. It is caused by neural crest-derived melanocytes - pigmented cells normally present in the epidermis and, sometimes, in the dermis. Methods We performed a review of current knowledge on the risk factors of cutaneous melanoma. Relevant studies were identified using the PubMed, Science Direct, Medline, Scopus, Scholar Google and ISI Web of Knowledge databases. Results Melanoma incurs a considerable public health burden owing to the worldwide dramatic rise in incidence since the mid-1960s. Ultraviolet radiation exposure is the predominant environmental risk factor. The role of geographical (latitude) and individual factors such as skin type, life style, vitamin D levels and antioxidant protection, sunburn, and exposure to other environmental factors possibly contributing to melanoma risk (such as cosmetics including sunscreen, photosensitising drugs, and exogenous hormones) are reviewed in this article. Recently, both rare high risk susceptibility genes and common polymorphic genes contributing to melanoma risk have been identified. Conclusions Cutaneous melanoma is a complex cancer with heterogeneous aetiology that continues to increase in incidence. Introduction of new biomarkers may help to elucidate the mechanism of pathogenesis and individual susceptibility to the disease, and make both prevention and treatment more effective. PMID:22759494

  2. Cutaneous melanoma in solid organ transplant patients.

    PubMed

    Russo, I; Piaserico, S; Belloni-Fortina, A; Alaibac, M

    2014-08-01

    Solid organ transplant patients are at greatly increased risk of developing a wide variety of skin cancers, particularly epithelial skin cancers. On the other hand, it is well known that an intact immune system limits the development of benign melanocytic lesions. The eruptive nevi phenomenon, which we can observe in solid organ transplant recipients, is indicative of the relationship between melanocyte proliferation and immune system. Regression of melanocytic nevi after restoration of complete immune responsiveness is a further clinical example the role of immunosurveillance on melanocyte proliferation. However, melanoma incidence in organ transplant recipients appears only 2-3 folds higher than in general population. To this regard, organ transplant recipients who develop de novo melanomas thicker than 2mm seem to have a significantly worse outcome with a greatly increased risk of dying of metastatic melanoma, whereas those who develop a ≤2 mm thickness melanoma seem to have a prognosis similar to that of the general population. Furthermore, there is no evidence supporting an increased risk of melanoma recurrences after transplant in patients with a history of low-risk melanoma. Melanoma is also one of the most frequent and lethal donor-derived malignancies suggesting that a history of invasive melanoma should be considered an absolute contraindication to donation. The aim of this review is to investigate the relationship between immunosuppression and melanoma and to discuss its clinical implications for the management of transplant-associated melanoma. PMID:25068225

  3. Significantly high lymphatic vessel density in cutaneous metastasizing melanoma

    PubMed Central

    Špirić, Z; Erić, M; Eri, Ž; Skrobić, M

    2015-01-01

    Background Cutaneous melanoma has the propensity to early metastatic spread via the lymphatic vessels. Recent studies have found a positive correlation between an increased number of tumor-associated lymphatics and lymph node metastasis. The aim of this study was to determine whether there was a difference in the lymphatic vessel density (LVD) when cutaneous metastasizing melanomas were compared with nonmetastasizing melanomas and nevi. Methods Ninety-five melanoma specimens (45 with lymph node metastasis, 50 nonmetastasizing) and 22 nevi specimens (7 compound, 5 intradermal, 4 blue, and 6 dysplastic) were investigated by immunostaining for the lymphatic endothelial marker D2-40. The quantification of lymphatics was conducted by computer-assisted morphometric analysis. Metastasizing and nonmetastasizing melanoma specimens were matched according to their thickness into three classes ≤2.0 mm, 2.01 – 4.0 mm, >4.0 mm. Results Metastasizing melanomas thick 2.01–4.0 mm and thicker than 4.0 mm, showed a significantly higher intratumoral and peritumoral LVD compared with nonmetastasizing melanomas (2.01–4.0 mm, p =0.006 and p =0.032, respectively; >4.0 mm, p =0.045 and p =0.026, respectively). No significant difference in intratumoral and peritumoral LVD was found between metastasizing and nonmetastasizing melanomas of thickness ≤2.0 mm. Metastasizing melanomas showed a significantly higher intratumoral LVD compared with compound, intradermal, blue and dysplastic nevi p <0.001, p =0.002, p =0.002 and p <0.001, respectively), and significantly higher peritumoral LVD compared with compound nevi (p=0.039). Total average LVD was significantly higher in metastasizing melanomas than in nonmetastasizing melanomas (p <0.001), compound, intradermal, blue and dysplastic nevi (p <0.001, p <0.001, p =0.001 and p <0.001, respectively). Conclusions This study shows higher LVD in metastasizing melanomas compared with nonmetastasizing melanomas and nevi. In melanomas with

  4. Serum level of vitamin D3 in cutaneous melanoma

    PubMed Central

    de Oliveira, Renato Santos; de Oliveira, Daniel Arcuschin; Martinho, Vitor Augusto Melão; Antoneli, Célia Beatriz Gianotti; Marcussi, Ludmilla Altino de Lima; Ferreira, Carlos Eduardo dos Santos

    2014-01-01

    Objective To compare the level of vitamin D3 in cutaneous melanoma patients, with or without disease activity, with reference values and with patients from a general hospital. Methods The serum levels of vitamin D3 were measured in cutaneous melanoma patients, aged 20 to 88 years, both genders, from January 2010 to December 2013. The samples from the general group were processed at Hospital Israelita Albert Einstein (control group). Data analysis was performed using the Statistics software. Results A total of 100 patients were studied, 54 of them men, with mean age of 54.67 years, and 95 Caucasian. Out of these 100 patients, 17 had active disease. The average levels of vitamin D3 in the melanoma patients were lower than the level considered sufficient, but above the average of the control group. Both groups (with or without active disease) of patients showed a similar distribution of vitamin D3 deficiency. Conclusion Vitamin D3 levels in melanoma patients were higher than those of general patients and lower than the reference level. If the reference values are appropriate, a large part of the population had insufficient levels of vitamin D, including those with melanoma, or else, this standard needs to be reevaluated. No difference in vitamin D3 levels was found among melanoma patients with or without active disease. More comprehensive research is needed to assess the relation between vitamin D and melanoma. PMID:25628199

  5. Melanoma Treatments: Advances and Mechanisms.

    PubMed

    Marzuka, Alexander; Huang, Laura; Theodosakis, Nicholas; Bosenberg, Marcus

    2015-11-01

    Advances in the understanding of the molecular pathogenesis of melanoma and in cancer immunology have led to the rational design and recent clinical implementation of a variety of novel therapies for metastatic melanoma. BRAF and MEK inhibitors that target the MAPK pathway have high rates of clinical response in BRAF-mutant melanoma. Therapies that modulate the immune response to melanoma, including monoclonal antibodies that interfere with pathways that inhibit T-cell function, have been shown to be effective in melanoma. Lessons learned from these encouraging results are driving the development of new treatments for melanoma and other cancers. This review will focus on the science and clinical findings related to targeted therapies that inhibit BRAF or MEK as well as the immunotherapies that block the CTLA-4 or PD-1 pathways. Other experimental and combinatorial therapeutic approaches will also be discussed. PMID:25899612

  6. Selected benign cutaneous lesions that may simulate melanoma histologically.

    PubMed

    Wick, Mark R

    2016-07-01

    As cutaneous melanomas manifest a wide spectrum of clinical and pathologic presentations, several other lesions enter into their differential diagnosis. This article considers those entities, including melanocytic hyperplasia, cellular nodules in congenital nevi, atypical lentiginous melanocytic proliferations, "special site" nevi, epithelioid histiocytoma, neurothekeoma, cellular schwannoma, and proliferating scars. PMID:27221234

  7. Integrated analysis of multidimensional omics data on cutaneous melanoma prognosis.

    PubMed

    Jiang, Yu; Shi, Xingjie; Zhao, Qing; Krauthammer, Michael; Rothberg, Bonnie E Gould; Ma, Shuangge

    2016-06-01

    Multiple types of genetic, epigenetic, and genomic changes have been implicated in cutaneous melanoma prognosis. Many of the existing studies are limited in analyzing a single type of omics measurement and cannot comprehensively describe the biological processes underlying prognosis. As a result, the obtained prognostic models may be less satisfactory, and the identified prognostic markers may be less informative. The recently collected TCGA (The Cancer Genome Atlas) data have a high quality and comprehensive omics measurements, making it possible to more comprehensively and more accurately model prognosis. In this study, we first describe the statistical approaches that can integrate multiple types of omics measurements with the assistance of variable selection and dimension reduction techniques. Data analysis suggests that, for cutaneous melanoma, integrating multiple types of measurements leads to prognostic models with an improved prediction performance. Informative individual markers and pathways are identified, which can provide valuable insights into melanoma prognosis. PMID:27141884

  8. Cutaneous melanoma mortality among the socioeconomically disadvantaged in Massachusetts.

    PubMed Central

    Geller, A C; Miller, D R; Lew, R A; Clapp, R W; Wenneker, M B; Koh, H K

    1996-01-01

    OBJECTIVES: To identify groups for melanoma prevention and early detection programs, this study explored the hypothesis that survival with cutaneous melanoma is disproportionately lower for persons of lower socioeconomic status. METHODS: Massachusetts Cancer Registry and Registry of Vital Records and Statistics data (1982 through 1987) on 3288 incident cases and 1023 deaths from cutaneous melanoma were analyzed. Mortality/incidence ratios were calculated and compared, predictors of late stage disease were examined with logistic regression analysis, and a proportional hazards regression analysis that used death registration as the outcome measure for incident cases was performed. RESULTS: Lower socioeconomic status was associated with a higher mortality/incidence ratio after adjustment for age and sex. For education, the mortality/incidence ratio was 0.37 in the lower group vs 0.25 in the higher group (rate ratio = 1.48, 95% confidence interval [CI] = 1.08, 2.03). Late stage disease was independently associated with lower income (rate ratio for lowest vs highest tertile = 1.64, 95% CI = 1.20, 2.25), and melanoma mortality among case patients was associated with lower education (rate ratio = 1.52, 95% CI = 1.09, 213). CONCLUSIONS: Melanoma patients of lower socioeconomic status may be more likely to die from their melanoma than patients of higher socioeconomic status. Low- SES communities may be appropriate intervention targets. PMID:8604786

  9. Clinicopathologic features of incident and subsequent tumors in patients with multiple primary cutaneous melanomas

    PubMed Central

    Murali, Rajmohan; Goumas, Chris; Kricker, Anne; From, Lynn; Busam, Klaus J.; Begg, Colin B.; Dwyer, Terence; Gruber, Stephen B.; Kanetsky, Peter A.; Orlow, Irene; Rosso, Stefano; Thomas, Nancy E.; Berwick, Marianne; Scolyer, Richard A.; Armstrong, Bruce K.

    2011-01-01

    Background 0.6–12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large international multi-center case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas. Methods Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared. Results 473 pairs comprising a subsequent and a first melanoma and 1989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared to first melanomas, subsequent melanomas were: more commonly contiguous with a dysplastic nevus; more prevalent on the head/neck and legs than other sites; and thinner. Compared with single primary melanomas, subsequent melanomas were also more likely to be: associated with a contiguous dysplastic nevus; more prevalent on the head/neck and legs; and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses. Conclusions Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma. PMID:21913010

  10. Tumor-infiltrating lymphocytes predict cutaneous melanoma survival.

    PubMed

    Fortes, Cristina; Mastroeni, Simona; Mannooranparampil, Thomas J; Passarelli, Francesca; Zappalà, Alba; Annessi, Giorgio; Marino, Claudia; Caggiati, Alessio; Russo, Nicoletta; Michelozzi, Paola

    2015-08-01

    Understanding differences in survival across distinct subgroups of melanoma patients may help with the choice of types of therapy. Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the role of TILs in melanoma mortality is controversial. The aim of this study was to investigate independent prognostic factors for melanoma mortality. We carried out a 10-year cohort study on 4133 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 1998 and December 2008. The probability of survival was estimated using Kaplan-Meier methods and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). The 10-year survival rate for melanoma decreased with increasing Breslow thickness (Pfor trend<0.0001) and with age (Pfor trend<0.0001) whereas survival increased with increasing levels of TILs (Pfor trend=0.0001). The 10-year survival rate for melanoma divided into TILs intensity as scanty, moderate, and marked was 88.0, 92.2, and 97.0%, respectively. In the multivariate Cox model, the presence of high levels of TILs in primary invasive melanomas was associated with a lower risk of melanoma death (hazard ratio 0.32; 95% confidence interval 0.13-0.82) after controlling for sex, age, Breslow thickness, histological type, mitotic rate, and ulceration. After including lymph node status in the multivariate analysis, the protective effect of marked TILs on melanoma mortality remained (hazard ratio 0.37; 95% confidence interval 0.15-0.94). The results of this study suggest that the immune microenvironment affects melanoma survival. PMID:25933208

  11. Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients.

    PubMed

    Huang, Sharon K; Hoon, Dave S B

    2016-03-01

    Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective. PMID:26778792

  12. Citrus Consumption and Risk of Cutaneous Malignant Melanoma

    PubMed Central

    Wu, Shaowei; Han, Jiali; Feskanich, Diane; Cho, Eunyoung; Stampfer, Meir J.; Willett, Walter C.; Qureshi, Abrar A.

    2015-01-01

    Purpose Citrus products are widely consumed foods that are rich in psoralens and furocoumarins, a group of naturally occurring chemicals with potential photocarcinogenic properties. We prospectively evaluated the risk of cutaneous malignant melanoma associated with citrus consumption. Methods A total of 63,810 women in the Nurses' Health Study (1984 to 2010) and 41,622 men in the Health Professionals Follow-Up Study (1986 to 2010) were included. Dietary information was repeatedly assessed every 2 to 4 years during follow-up. Incident melanoma cases were identified through self-report and confirmed by pathologic records. Results Over 24 to 26 years of follow-up, we documented 1,840 incident melanomas. After adjustment for other risk factors, the pooled multivariable hazard ratios for melanoma were 1.00 for overall citrus consumption < twice per week (reference), 1.10 (95% CI, 0.94 to 1.30) for two to four times per week, 1.26 (95% CI, 1.08 to 1.47) for five to six times per week, 1.27 (95% CI, 1.09 to 1.49) for once to 1.5 times per day, and 1.36 (95% CI, 1.14 to 1.63) for ≥ 1.6 times per day (Ptrend < .001). Among individual citrus products, grapefruit showed the most apparent association with risk of melanoma, which was independent of other lifestyle and dietary factors. The pooled multivariable hazard ratio for melanoma comparing the extreme consumption categories of grapefruit (≥ three times per week v never) was 1.41 (95% CI, 1.10 to 1.82; Ptrend < .001). Conclusion Citrus consumption was associated with an increased risk of malignant melanoma in two cohorts of women and men. Nevertheless, further investigation is needed to confirm our findings and explore related health implications. PMID:26124488

  13. Video comparator system for early detection of cutaneous malignant melanoma

    NASA Astrophysics Data System (ADS)

    Craine, Eric R.; Craine, Brian L.

    1992-05-01

    The recognized incidence of cutaneous malignant melanoma in the United States is now rising faster than any other cancer, increasing by 83% from 1980 to 1987. Recent revelations that depletion of the earth's ozone layer is accelerating at a more rapid rate than previously believed can only exacerbate current projections for the increased incidence of this deadly disease. Because there is no good treatment for metastatic melanoma even small cancers often prove fatal if not detected early. Melanoma allowed to invade the subcutaneous tissue is associated with a five-year survival rate of only 44%. Ironically, few cancers provide a greater opportunity for early discovery and cure. Cutaneous melanoma is not only located where it is readily observed, but typically undergoes a `radial growth' phase prior to metastasis. During this phase the net growth is superficial and circumferential, gradually increasing the area of the lesion and changing its coloration. Screening measures for the early detection of melanoma must concentrate on two primary tasks: (1) detection of lesion changes indicative of the radial growth stage of malignancy and (2) alerting the patient and physician to the existence of a new or changed lesion on the skin. To accomplish these goals we have experimented with the applicability of a microcomputer based video imaging system which stores an image archive of historical reference images for each patient. With the acquisition of new images of the patient, easily registered with the archival images through a technique we have developed we are able to perform a blink comparison of the image pairs. This technique appears to be far more effective than currently used techniques for detecting changed lesions on a comprehensive basis.

  14. Pigmentation and skin reaction to sun as risk factors for cutaneous melanoma: Western Canada Melanoma Study.

    PubMed Central

    Elwood, J M; Gallagher, R P; Hill, G B; Spinelli, J J; Pearson, J C; Threlfall, W

    1984-01-01

    Between 1 April 1979 and 31 March 1981, 904 residents of the four western provinces of Canada (population 6.5 million), were diagnosed as suffering from primary cutaneous malignant melanoma. Of 801 patients aged 20-79 years, 665 (83%) were interviewed along with control subjects chosen at random from the general population and matched for age, sex, and province. After exclusion of 70 subjects with lentigo maligna or acral lentiginous melanoma, comparisons of the 595 case-control pairs showed that light hair, skin, and eye colour, a history of heavy freckling in adolescence, and a tendency to burn readily and tan poorly in the sun were significant risk factors for melanoma. The strongest primary associations were with blond hair (relative risk 7.1 compared with black hair), light colour of unexposed skin (relative risk 2.4), and severe freckling (relative risk 2.1). These associations were independent of ethnic origin and of recorded amount of exposure to the sun and were somewhat stronger for superficial spreading than for nodular melanoma. This study is the largest and most detailed of an incident series of melanomas to be published to date. The results were consistent with other studies reporting associations between melanoma and poor tanning ability, a tendency to burn easily, and a history of sunburn and showed that light hair colour was the strongest risk factor for the disease. PMID:6419839

  15. Lifetime risks of cutaneous melanoma by histological subtype and race/ethnicity in the United States.

    PubMed

    Feng, Zhuang; Zhang, Zhenzhen; Wu, Xiao-Cheng

    2013-01-01

    The probability of developing melanoma of the skin in the United States has been previously reported as a whole entity. This study aimed to describe lifetime risks of cutaneous melanoma by histological subtype among different racial and ethnic groups in the United States. Melanoma cases newly diagnosed in 2005-2007 were obtained from 16 registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Lifetime risks of developing melanoma subtypes (nodular melanoma, lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma and desmoplastic melanoma) were examined among non-Hispanic whites, Hispanic whites, Blacks, and Asian/Pacific Islanders. Of the total 43,690 melanoma cases, 18,910 cases (43%) diagnosed with one of the five histological subtypes were included in the study. The results reveal that lifetime risks of melanoma subtypes differ among racial and ethnic groups, and therefore, stratification of the risks by subtype provides useful information in evaluating and counseling patients. PMID:24133782

  16. Solar considerations in the development of cutaneous melanoma.

    PubMed

    Loggie, B W; Eddy, J A

    1988-12-01

    On the basis of these considerations, the possible action spectrum for melanoma can be narrowed considerably, but not confined to any one solar emission band. The physical factors discussed eliminate all but UV, visible, and NIR radiation as possible solar agents. Ionizing radiation fits neither the epidemiologic data nor first-order physical considerations. Wavelengths longer than the NIR wavelengths, although they could conceivably account for the occurrence of melanoma under clothed parts of the body, carry so little energy that they are probably unimportant. Epidemiologic evidence regarding the effects of skin pigment favors UV or visible radiation. A distinction between these two components is not obvious; UV-C and UV-B photons carry greater energy and are more likely to induce biochemical cutaneous effects, but the total flux in the UV-A and visible radiations is far greater. That UV-B radiation may play a role in melanoma is supported; at the same time, one cannot exclude the possibility that the action spectrum for melanoma is, instead, the UV-A, the visible, or even the NIR portion of the sunlight spectrum. The strong differential effect of altitude on the transmission of light of different wavelengths might serve as an important discriminating variable. If solar UV radiation is implicated in the development of melanoma, then altitude should emerge as a significant factor in epidemiologic studies. If visible or IR radiation is the active agent, then differences on the basis of altitude should be small or negligible. Intrinsic solar variations that follow the annual sunspot number appear inadequate in either the UV or the visible band to account directly for the apparent 11-year modulation of melanoma incidence found in some registries. Secondary atmospheric effects brought about by the action of solar UV changes on the ozone layer may be adequate to explain a weak 11-year modulation in melanoma incidence, although continuous measurements of UV-B flux made

  17. Biology of advanced uveal melanoma and next steps for clinical therapeutics.

    PubMed

    Luke, Jason J; Triozzi, Pierre L; McKenna, Kyle C; Van Meir, Erwin G; Gershenwald, Jeffrey E; Bastian, Boris C; Gutkind, J Silvio; Bowcock, Anne M; Streicher, Howard Z; Patel, Poulam M; Sato, Takami; Sossman, Jeffery A; Sznol, Mario; Welch, Jack; Thurin, Magdalena; Selig, Sara; Flaherty, Keith T; Carvajal, Richard D

    2015-03-01

    Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherapies are reviewed, and next steps in the development of clinical therapeutics are discussed. PMID:25113308

  18. Blue Nevus-Like Metastasis of a Cutaneous Melanoma Identified by Fluorescence In Situ Hybridization.

    PubMed

    Campa, Molly; Patel, Mahir; Aubert, Pamela; Hosler, Gregory; Witheiler, Daniel

    2016-09-01

    A blue nevus-like melanoma is a rare melanoma variant arising from or histologically similar to a blue nevus. It can be challenging to distinguish a cellular blue nevus from a blue nevus-like melanoma, particularly in cases of blue nevus-like melanoma lacking a transition from a clearly benign component. We present a case of a 78-year-old man who refused treatment for a previously existing melanoma and subsequently developed a gray nodule near the site of the previous melanoma. After fluorescence in situ hybridization revealed copy number gains in RREB1, this was diagnosed as a blue nevus-like metastatic melanoma. Blue nevus-like metastatic melanoma is most commonly seen near the site of the primary cutaneous melanoma. This entity should be considered in a patient with a history of melanoma and a new blue nevus-like lesion. PMID:27097332

  19. Non-cutaneous melanoma: is there a role for 18F-FDG PET-CT?

    PubMed Central

    Murphy, G; Hussey, D

    2014-01-01

    Non-cutaneous melanomas (NCM) are diverse and relatively uncommon. They often differ from cutaneous melanomas in their epidemiology, genetic profile and biological behaviour. Despite the growing body of evidence regarding the utility of positron emission tomography (PET)/CT in cutaneous melanoma, the data on its use in NCM are scarce. In this review, we will summarize the existing literature and present cases from our experience with NCM to illustrate current knowledge on the potential role and limitations of fluorine-18 fludeoxyglucose PET/CT in NCM. PMID:24901893

  20. The dysplastic naevus syndrome in patients with cutaneous malignant melanoma in Western Australia.

    PubMed

    English, D R; Menz, J; Heenan, P J; Elder, D E; Watt, J D; Armstrong, B K

    1986-09-01

    One hundred and three patients with cutaneous malignant melanoma responded to an invitation to attend a dermatology outpatient clinic. All patients with a family history of melanoma, a history of multiple melanomas, or histological evidence of a dysplastic naevus that was associated with their melanoma were invited. A random sample of other patients with cutaneous malignant melanoma was also invited to attend. First-degree relatives of patients with the dysplastic naevus syndrome (DNS) were invited for a similar examination. DNS was found in 27% of the patients with a family history of melanoma, multiple melanomas, or histological evidence of a dysplastic naevus in association with their melanoma, and in 6% of the remaining patients who were selected at random. DNS was estimated to be present in 12.8% of 17- to 55-year-old patients with cutaneous malignant melanoma in the Perth region, while familial DNS was present in 4.5%. Patients with melanomas with DNS were more likely to be young men and to have numerous naevi, particularly on the lateral surfaces of the arms, shoulders and trunk, than were patients with melanomas without the syndrome. PMID:3747894

  1. Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery

    ClinicalTrials.gov

    2013-03-29

    Recurrent Melanoma; Stage IIB Melanoma (Locally Advanced); Stage IIC Melanoma (Locally Advanced); Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma (Limited, Resectable)

  2. Gene signature of the metastatic potential of cutaneous melanoma: too much for too little?

    PubMed

    Tímár, József; Gyorffy, Balázs; Rásó, Erzsébet

    2010-08-01

    It was expected that with the advent of genomics, oncology may defeat the deadliest forms of cancer including malignant melanoma, but the past years have indicated that this is not the case. Despite the stunning success of genomics in defining markers or gene signatures for breast cancer prognosis and predicting therapies, there is virtually no progression in malignant melanoma. This is happening when experimental oncology or metastasis research is using several rodent and human melanoma models, when our knowledge on the metastatic cascade is actually derived from these models. Our critical analysis of these studies revealed several factors which might be responsible for this failure. First, it is evident, that these studies must be based on rigorous sample collection and basic pathological considerations, where divergent histological types of melanoma cannot be analysed universally. Secondly, without following basic consideration of metastasis biology, the majority of these studies were rarely based on primary tumors but frequently on various types of regional metastases. Third, successful expression profiling studies on other tumors such as breast cancer, provided evidences that the homogeneity of the patient cohort at least by clinicopathological stage is a critical element when defining prognostic signatures. Four studies attempted to define the prognostic signature of skin melanoma but only one based the study on the primary tumor resulting in heterogenous signatures with a minimal overlap (MCM3 and NFKBIZ). Four study attempted to define the invasiveness-signature in the primary tumor based on thickness or growth pattern discrimination identifying a 9-gene overlap which proved to be different from the prognostic signatures. On the other hand, seven studies analyzed various types of metastatic tissues (rarely visceral-, mostly cutaneous or lymphatic metastases) to define the metastasis-signatures, again with minimal overlap (AQP3, LGALS7 and SFN). Using seven

  3. [Cutaneous melanoma - "black death" of modern times? Traces in contemporary literature].

    PubMed

    Bahmer, F A; Bahmer, J A

    2013-11-01

    Cutaneous melanoma, sometimes labeled as "black skin cancer", is increasing in frequency and becoming a more common literary motive. In US literature, Sylvia Plath and Charles Bukowski depicted melanoma more than 50 years ago, later Stephen King and Thomas C. Boyle. In German literature, Charlotte Roche shortly mentioned this tumor. Jörg Pönnighaus, both poet and dermatologist, intensively deals in his poems with the effects melanoma has on patients and doctors alike. Melanoma definitely is not the "Black Death" of modern times. However, the perception of this tumor as extremely malignant and as life-threatening makes melanoma a metaphor of the deadly danger of cancer. PMID:24135905

  4. Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome.

    PubMed

    Garg, Kanika; Maurer, Margarita; Griss, Johannes; Brüggen, Marie-Charlotte; Wolf, Ingrid H; Wagner, Christine; Willi, Niels; Mertz, Kirsten D; Wagner, Stephan N

    2016-08-01

    B cells often infiltrate the microenvironment of human tumors. B cells can both positively and negatively regulate antitumor immune responses. In several human cancers, higher numbers of CD20(+) TAB are associated with a favorable prognosis, whereas in human primary melanomas, this association is contentious. In this study, we determined the association of TAB numbers in cutaneous primary melanoma tissue samples and patients' overall survival. The CD20 immunohistochemistry on archival nonmetastasized and metastasized cutaneous primary melanoma tissues from 2 independent patient cohorts was performed. One cohort was used in class comparison for metastasis, the most important prognostic factor for overall survival, and the other cohort for a subsequent survival analysis. Survival association was further validated with RNA data from a third independent cohort. Whole tissue sections were read automatically via quantitative digital imaging and analysis. Survival data were analyzed by Cox proportional hazard modeling. We discovered that cutaneous primary melanomas without metastasis contain significantly more TAB than primary melanomas that had metastasized. At time of first diagnosis, a higher number of TAB is associated with a significantly better overall survival in patients with cutaneous primary melanomas of >1 mm Breslow depth. Also, higher CD20/CD19 tumor mRNA levels are correlated with a significantly better overall survival. Thus, our data support TAB numbers as a prognostic biomarker in cutaneous primary melanoma patients with a tumor of >1 mm Breslow depth. For a survey in larger studies, whole tissue section analysis seems to be key to accurate assessment of TAB numbers. PMID:27107457

  5. Molecular characterisation of cutaneous melanoma: creating a framework for targeted and immune therapies

    PubMed Central

    Rajkumar, Shivshankari; Watson, Ian R

    2016-01-01

    Large-scale genomic analyses of cutaneous melanoma have revealed insights into the aetiology and heterogeneity of this disease, as well as opportunities to further personalise treatment for patients with targeted and immune therapies. Herein, we review the proposed genomic classification of cutaneous melanoma from large-scale next-generation sequencing studies, including the largest integrative analysis of melanoma from The Cancer Genome Atlas (TCGA) Network. We examine studies that have identified molecular features of melanomas linked to immune checkpoint inhibitor response. In addition, we draw attention to low-frequency actionable mutations and highlight frequent non-coding mutations in melanoma where little is known about their biological function that may provide novel avenues for the development of treatment strategies for melanoma patients. PMID:27336610

  6. Advances in targeted therapy for unresectable melanoma: new drugs and combinations.

    PubMed

    Hao, Mengze; Song, Fengju; Du, Xiaoling; Wang, Guowen; Yang, Yun; Chen, Kexin; Yang, Jilong

    2015-04-01

    Melanoma is the most deadly cutaneous cancer primarily derived from melanocytes with a poor prognosis in advanced stage. The therapy regimen for early stage melanoma patients is surgical resection with adjuvant IFN-alpha-2b therapy. For metastatic lesions, standard chemotherapy such as dacarbazine (DTIC) has not achieved a satisfying response rate. Therefore, new approaches to manage this deadly disease are highly expected to enhance the cure rate and to extend clinical benefits to patients with unresectable melanoma. Fortunately, the targeted therapeutic drugs and immunotherapy such as vemurafenib, dabrafenib, ipilimumab, and trametinib have shown their special advantage in the treatment of advanced melanoma. This article is to overview the advances in targeted therapy for unresectable melanoma patients. PMID:25578781

  7. TERT Promoter Mutation Status as an Independent Prognostic Factor in Cutaneous Melanoma

    PubMed Central

    Murali, Rajmohan; Puig-Butille, Joan Anton; Schilling, Bastian; Livingstone, Elisabeth; Potrony, Miriam; Carrera, Cristina; Schimming, Tobias; Möller, Inga; Schwamborn, Marion; Sucker, Antje; Hillen, Uwe; Badenas, Celia; Malvehy, Josep; Zimmer, Lisa; Scherag, André; Puig, Susana

    2014-01-01

    Background Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. Methods 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. Results TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). Conclusions UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis. PMID:25217772

  8. Biology of Advanced Uveal Melanoma and Next Steps for Clinical Therapeutics

    PubMed Central

    Luke, Jason J.; Triozzi, Pierre L.; McKenna, Kyle C.; Van Meir, Erwin G.; Gershenwald, Jeffrey E.; Bastian, Boris C.; Gutkind, J. Silvio; Bowcock, Anne M.; Streicher, Howard Z.; Patel, Poulam M.; Sato, Takami; Sossman, Jeffery A.; Sznol, Mario; Welch, Jack; Thurin, Magdalena; Selig, Sara; Flaherty, Keith T.; Carvajal, Richard D.

    2014-01-01

    Summary Uveal melanoma is the most common intraocular malignancy though it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15 year period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease and median survival remains poor. Here, as a joint effort between CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherpies are reviewed and next steps in the development of clinical therapeutics are discussed. PMID:25113308

  9. Nivolumab-Based Treatments for Advanced Melanoma

    Cancer.gov

    A summary of results from an international, double-blind, randomized phase III trial testing the combination of nivolumab (Opdivo®) and ipilimumab (Yervoy®) against nivolumab alone and ipilimumab alone in patients with advanced melanoma.

  10. Seminal vesicle metastasis of cutaneous malignant melanoma: An unusual and challenging presentation.

    PubMed

    Foahom Kamwa, Alain D; Mateus, Christine; Thanigasalam, Ruban; Boulay-Coletta, Isabelle; Duchatelle, Véronique; Triller, Marie; Robert, Caroline; Baumert, Hervé

    2015-01-01

    Malignant melanoma is a tumour, which usually involves skin melanocytes. Involvement of the male genitourinary (GU) system by melanoma is an uncommon and challenging diagnosis. We report the first case of seminal vesicle metastasis from a primary cutaneous melanoma in a 58-year-old man, with hemospermia as the only clinical sign. This case highlights the role of multiparametric magnetic resonance imaging, as a more sensitive assessment to early detect metastatic melanoma in the GU system. The patient underwent a robot-assisted laparoscopic bilateral seminal vesiculectomy, which had good functional and oncological results and is still in complete remission at the 1-year follow-up. PMID:26085885

  11. Seminal vesicle metastasis of cutaneous malignant melanoma: An unusual and challenging presentation

    PubMed Central

    Foahom Kamwa, Alain D.; Mateus, Christine; Thanigasalam, Ruban; Boulay-Coletta, Isabelle; Duchatelle, Véronique; Triller, Marie; Robert, Caroline; Baumert, Hervé

    2015-01-01

    Malignant melanoma is a tumour, which usually involves skin melanocytes. Involvement of the male genitourinary (GU) system by melanoma is an uncommon and challenging diagnosis. We report the first case of seminal vesicle metastasis from a primary cutaneous melanoma in a 58-year-old man, with hemospermia as the only clinical sign. This case highlights the role of multiparametric magnetic resonance imaging, as a more sensitive assessment to early detect metastatic melanoma in the GU system. The patient underwent a robot-assisted laparoscopic bilateral seminal vesiculectomy, which had good functional and oncological results and is still in complete remission at the 1-year follow-up. PMID:26085885

  12. Study of the histopathological types of cutaneous melanoma in Palmas-TO from 2001 to 2011*

    PubMed Central

    da Costa, Nilo Fernandes; Fernandes, Nurimar Conceição; Borges, Myrlena Regina Machado Mescouto

    2015-01-01

    BACKGROUND Cutaneous melanoma (CM) is considered serious for causing frequent metastasis, presenting high mortality, resistance to available therapies and incidences in laboring activity. OBJECTIVES To study the histopathological types of cutaneous melanoma in Palmas-TO from 2001 to 2011, according to risk factors, location of lesions, Clark levels and Breslow thickness. METHODS A descriptive, retrospective and quantitative research in reports of the Serviços de Anatomia Patológica in Palmas (SAPP) and Registro de Câncer de Base Populacional de Palmas (RCBPP). RESULTS The years of highest incidences were: 2004 (8 cases/17.8%), 2008 and 2011 (7 cases each/15.6%) and 2010 (6 cases/13.3%). Among the 45 cases studied, there were predominance in patients between 41 and 60 years old, women, caucasians, farmers, located in trunk, in situ type, superficial extensive and metastatic cutaneous, Clark levels I (20%) and IV (17.7%), Breslow thickness ≤1 mm (35.5%) and 2.01 to 4 mm (24.4%). CONCLUSIONS The most common histopathological types were: cutaneous melanoma in situ, superficial extensive and metastatic, followed by nodular cutaneous melanoma, and finally, by other forms. In this study, Clark levels and Breslow thickness pointed to greater importance of thin melanomas and sun exposure without appropriate protection in farmers. PMID:26560208

  13. Clinical significance of serum laminin and type-IV collagen levels in cutaneous melanoma patients

    PubMed Central

    TAS, FARUK; BILGIN, ELIF; KARABULUT, SENEM; DURANYILDIZ, DERYA

    2016-01-01

    Laminin and type-IV collagen constitute a significant portion of the extracellular matrix. The objective of the present study was to evaluate whether the serum concentrations of laminin and type-IV collagen may serve as biomarkers for cutaneous melanoma. Sixty pathologically confirmed melanoma patients were enrolled in the study. Serum laminin and type-IV collagen levels were assessed using an ELISA. Thirty healthy controls were also examined. No significant differences in the baseline serum levels of laminin were identified between melanoma patients and healthy controls (P=0.45). However, the baseline serum levels of type-IV collagen were significantly elevated in melanoma patients compared with those in the control group (P<0.001). Clinical parameters, including patient age, gender, localization of lesion, histopathology, stage of disease, serum lactate dehydrogenase concentrations and responsiveness to chemotherapy were found not to be associated with the serum levels of laminin and type-IV collagen (P>0.05). Furthermore, the serum levels of laminin and type-IV collagen had no prognostic value regarding the outcome for melanoma patients (P=0.36 and P=0.26, respectively). While laminin levels showed no diagnostic value, the serum concentrations of type-IV collagen were indicated to serve as a diagnostic marker in patients with cutaneous melanoma. In conclusion, type-IV collagen levels may be used as a diagnostic marker for cutaneous melanoma, while being void of any prognostic value. PMID:27330797

  14. TLR7 Gln11Leu single nucleotide polymorphism and susceptibility to cutaneous melanoma

    PubMed Central

    ELEFANTI, LISA; SACCO, GIORGIA; STAGNI, CAMILLA; RASTRELLI, MARCO; MENIN, CHIARA; RUSSO, IRENE; ALAIBAC, MAURO

    2016-01-01

    Cutaneous melanoma is a life-threatening skin cancer. Its incidence is rapidly increasing, and early diagnosis is the main factor able to improve its poor prognosis. Toll-like receptors (TLRs) are transmembrane glycoproteins that recognize pathogen- and damage-associated molecular patterns, against which TLRs activate the innate immune response and initiate the adaptive immune response. Genetic variations of these receptors may alter the immune system, and are involved in evolution and susceptibility to various diseases, including cancer. The aim of the present study was to evaluate whether the presence of TLR7 glutamine (Gln) 11 leucine (Leu) polymorphism confers an increased susceptibility to cutaneous melanoma. For that purpose, a case-control study was performed with 182 melanoma cases and 89 controls. To highlight the possible association between the aforementioned polymorphism and the susceptibility to melanoma, 93 cases of single melanoma and 89 cases of multiple primary melanoma (MPM) were compared in the present study. Since the TLR7 gene is localized on the chromosome X, the allelic frequency of the Gln11Leu polymorphism was analyzed separately in males and females. The distribution of allele frequencies between melanoma cases and controls (P=0.245) and between single melanoma and MPM cases (P=0.482) was not significant. Therefore, the present results do not suggest an association between TLR7 Gln11Leu polymorphism and susceptibility to cutaneous melanoma. Further studies are required to analyze the influence of other TLR polymorphisms on the susceptibility to malignant melanoma and the involvement of innate immunity in this malignancy. PMID:27347137

  15. Dermatoscopic pitfalls in differentiating pigmented Spitz naevi from cutaneous melanomas.

    PubMed

    Argenziano, G; Scalvenzi, M; Staibano, S; Brunetti, B; Piccolo, D; Delfino, M; De Rosa, G; Soyer, H P

    1999-11-01

    Epiluminescence microscopy (ELM, skin surface microscopy, dermoscopy, dermatoscopy) is a valuable method for improving the diagnostic accuracy in pigmented skin lesions. Specific ELM criteria are already recognized for differentiating pigmented Spitz naevi (PSN) from cutaneous melanomas (CM). Our purpose was to describe the ELM appearance of a series of PSN with emphasis on PSN and CM with overlapping features. Thirty-six consecutive patients with PSN, and three cases of CM (selected from a larger database) exhibiting ELM 'spitzoid' features, were evaluated clinically, dermatoscopically and histopathologically. Most PSN (27 of 36; 75%) displayed two typical ELM patterns, namely, the starburst (19 of 36; 53%) or the globular pattern (eight of 36; 22%), which were correlated to different histopathological findings. In nine of 36 (25%) PSN, atypical ELM features which are more commonly seen in CM were observed. These PSN with an atypical pattern were characterized by an uneven distribution of colours and structures, and an irregular diffuse pigmentation resembling blue-white veil or irregular extensions (black blotches). These atypical lesions mostly occurred in children and showed no history of growth. In contrast, in three examples of CM, the typical ELM criteria of malignancy were less recognizable and either the characteristic starburst or globular pattern usually seen in PSN was present. These three lesions occurred in adults and had a recent history of change in colour, shape or size. The overlap in ELM features of some PSN and CM represents a major diagnostic pitfall when ELM examination is considered alone. In these atypical cases, clinical history including the age of the patient may be the only clue to enable a correct diagnosis. PMID:10583158

  16. Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma

    PubMed Central

    Samuels, Yardena; Azizi, Esther; Qutob, Nouar; Inzelberg, Lilah; Domany, Eytan; Schechtman, Edna; Friedman, Eitan

    2016-01-01

    Objective: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. Methods: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. Results: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). Conclusions: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD. PMID:27123489

  17. Adjuvant radiotherapy for cutaneous melanoma: Comparing hypofractionation to conventional fractionation

    SciTech Connect

    Chang, Daniel T.; Amdur, Robert J.; Morris, Christopher G. M.S.; Mendenhall, William M. . E-mail: mendewil@shands.ufl.edu

    2006-11-15

    Purpose: To examine locoregional control after adjuvant radiotherapy (RT) for cutaneous melanoma and compare outcomes between conventional fractionation and hypofractionation. Methods and Materials: Between January 1980 and June 2004, 56 patients with high-risk disease were treated with adjuvant RT. Indications for RT included: recurrent disease, cervical lymph node involvement, lymph nodes >3 cm, more than three lymph nodes involved, extracapsular extension, gross residual disease, close or positive margins, or satellitosis. Hypofractionation was used in 41 patients (73%) and conventional fractionation was used in 15 patients (27%). Results: The median age was 61 years (21->90). The median follow-up among living patients was 4.4 years (range, 0.6-14.4 years). The primary site was located in the head and neck in 49 patients (87%) and below the clavicles in 7 patients (13%). There were 7 in-field locoregional failures (12%), 3 out-of-field regional failures (5%), and 24 (43%) distant failures. The 5-year in-field locoregional control (ifLRC) and freedom from distant metastases (FFDM) rates were 87% and 43%, respectively. The 5-year cause-specific (CSS) and overall survival (OS) was 57% and 46%, respectively. The only factor associated with ifLRC was satellitosis (p = 0.0002). Nodal involvement was the only factor associated with FFDM (p = 0.0007), CSS (p = 0.0065), and OS (p = 0.016). Two patients (4%) who experienced severe late complications, osteoradionecrosis of the temporal bone and radiation plexopathy, and both received hypofractionation (5%). Conclusions: Although surgery and adjuvant RT provides excellent locoregional control, distant metastases remain the major cause of mortality. Hypofractionation and conventional fractionation are equally efficacious.

  18. Multiple primary cutaneous melanomas in patients with FAMMM syndrome and sporadic atypical mole syndrome (AMS): what's worse?

    PubMed

    Tchernev, Georgi; Ananiev, Julian; Cardoso, José-Carlos; Chokoeva, Anastasiya Atanasova; Philipov, Stanislav; Penev, Plamen Kolev; Lotti, Torello; Wollina, Uwe

    2014-08-01

    Atypical Mole Syndrome is the most important phenotypic risk factor for cutaneous melanoma, a malignancy that accounts for about 80% of deaths from skin cancer. Since early diagnosis of melanoma is of great prognostic relevance, the identification of Atypical Mole Syndrome carriers (sporadic and familial) is essential, as well as the recommendation of preventative measures that must be undertaken by these patients.We report two rare cases concerning patients with multiple primary skin melanomas in the setting of a familial and a sporadic syndrome of dysplastic nevi: the first patient is a 67-year-old patient with a history of multiple superficial spreading melanomas localized on his back. The second patient presented with multiple primary melanomas in advanced stage in the context of the so-called sporadic form of the syndrome of dysplastic nevi-AMS (atypical mole syndrome). In the first case, excision of the melanomas was carried out with an uneventful post-operative period. In the second case, disseminated metastases were detected, involving the right fibula, the abdominal cavity as well as multiple lesions in the brain. The patient declined BRAF mutation tests as well as chemotherapy or targeted therapies, and suffered a rapid deterioration in his general condition leading to death. We classified the second case as a sporadic form of the atypical mole syndrome, associated with one nodular and two superficial spreading melanomas.There are no data in the literature to allow us to understand if, in patients with multiple primary melanomas, there is any difference in terms of prognosis between those with and without a family history of a similar phenotype. To answer this and other questions related to these rare cases, further studies with a significant number of patients should be carried out. PMID:25096163

  19. Cutaneous melanoma in the State of São Paulo: a spatial approach*

    PubMed Central

    Amancio, Camila Trolez; Nascimento, Luiz Fernando Costa

    2014-01-01

    BACKGROUND Cutaneous melanoma is a skin cancer with low incidence but high mortality rates. Several factors are associated with increased risk of melanoma, such as excessive sun exposure, fair skin, and family history, among others. Little is known about the spatial distribution of this cancer in Brazil. OBJECTIVE To identify, through the use of geostatistical tools, spatial clusters of municipalities in the state of São Paulo based on their incidence of cutaneous melanoma. METHODS This was an ecological and exploratory study of data on new cases obtained from Fundação Oncocentro for the period 1 January 2006-31 December 2011. Cases were separated by gender and rates per 100,000 inhabitants were calculated and used to compile thematic maps, Moran maps and kernel maps, using TerraView software. RESULTS There were 3,172 new cases of cutaneous melanoma in the study period. High rates were identified in the North, Northwest, Southwest, and Southeast regions of São Paulo state. Global Moran's I values were statistically significant (p<0.05) at 0.12, 0.08, and 0.16, respectively, for males, females, and all cases. Areas such as the Southeast, North, and Northwest of São Paulo were identified as being of high priority for intervention. CONCLUSION Spatial clusters of municipalities with high incidence rates of cutaneous melanoma in the state of São Paulo were identified. These data can serve as an important input for public health agencies. PMID:24937818

  20. Features of Cutaneous Malignant Melanoma Metastatic to the Retina and Vitreous

    PubMed Central

    Breazzano, Mark P.; Barker-Griffith, Ann E.

    2015-01-01

    Background/Aims To report a case of cutaneous malignant melanoma with cerebral metastasis found to have vitreoretinal metastasis upon referral for neovascular glaucoma. Methods The clinical history and ocular examination findings, including histologic, cytologic, genetic, and immunohistochemical features of the vitreoretinal metastatic tumor, were reviewed. Additionally, the histologic and immunohistochemical features of the primary skin tumor and brain metastasis were also assessed. Results A 62-year-old woman with cutaneous malignant melanoma metastatic to the right frontal lobe (BRAF V600E negative) was evaluated for blurred vision in the right eye. Neovascular glaucoma, iritis, and posterior synechiae with no view of the retina or vitreous were evident on examination. Vitreoretinal biopsy and enucleation specimen both showed widespread neoplastic involvement of the retina and residual vitreous strands after vitrectomy. Choroid, trabeculum, and other intraocular structures were devoid of tumor burden. Diagnosis of cutaneous malignant melanoma metastatic to the retina and vitreous was confirmed, and the patient expired shortly thereafter. Conclusion Cutaneous malignant melanoma metastatic to the eye has a relatively greater preference for the retina and frequently presents with uveitis and glaucoma. Neovascular glaucoma in these cases may likely be attributable to unusually increased vascular endothelial growth factor production by the intraocular melanoma tumor cells. PMID:27172390

  1. Molecular biology of malignant melanoma and other cutaneous tumors.

    PubMed

    Pons, M; Quintanilla, M

    2006-07-01

    Skin cancer is the most common cancer worldwide. Its incidence is doubling every 15-20 years likely because of an aging population, changes in behaviour towards sun exposure, and increased UV light fluency at the earth surface due to ozone depletion. In this review, we summarize the most important genetic changes contributing to the development of malignant melanoma, basal cell carcinoma and squamous cell carcinoma, the main tumor entities arising in the skin. While our understanding of the oncogenes and tumor suppressor genes involved in the development and progression of skin tumors is still fragmentary, recent advances have shown alterations affecting conserved signalling pathways that control cellular proliferation and viability. These pathways include INK4alpha/Rb, ARF/p53, RAS/MAPKs, and sonic hedgehog/Gli. PMID:16870533

  2. Topical immunotherapy with diphencyprone for in transit and cutaneously metastatic melanoma.

    PubMed

    Damian, Diona L; Saw, Robyn P M; Thompson, John F

    2014-03-01

    Topical diphencyprone (DPCP) can be used to treat in transit and cutaneously metastastatic melanoma. To date, 50 patients have received DPCP therapy for at least 1 month at our institution, with complete clearance of cutaneous disease in 46% and partial response in a further 38% of patients. Topical immunotherapy with DPCP is inexpensive and well-tolerated and should be considered in patients with skin metastases unsuitable for or refractory to other forms of therapy. PMID:24522938

  3. Mortality due to cutaneous melanoma in south region of Brazil: a spatial approach*

    PubMed Central

    Ferreira, Flávia Regina; Nascimento, Luiz Fernando Costa

    2016-01-01

    Background Cutaneous melanoma is a skin cancer with low incidence but high mortality rates. The South region of Brazil has the highest death rates by melanoma per 100,000 inhabitants of the country. Little is known about the spatial distribution of this malignancy in southern Brazil. Objectives Identify the spatial patterns of deaths from cutaneous melanoma in South region of Brazil, using geoprocessing tools. Methods This is an ecological and exploratory study of death information by cutaneous melanoma obtained from portal Datasus, for Brazil's southern region, from January 2008 to December 2012. Deaths were separated by gender and rates per 100,000 inhabitants were calculated and used to compile thematic maps, Moran maps and Kernel maps, using TerraView software. It was adopted an alpha = 5%. Results There were data on 2378 deaths from cutaneous melanoma in the study period. High rates were identified in the northern and littoral regions of Rio Grande do Sul; the northeast of Santa Catarina; and west of Paraná - for the total population, with minor differences detected and indicated regarding gender. The global Moran index presented p-values of 0.03, 0.04 and 0.03, respectively, for male, female and overall deaths. All the micro-regions that showed high priority for intervention were detected in the Rio Grande do Sul. Conclusion Spatial clusters of micro-regions with high death rates from cutaneous melanoma in South region of Brazil were identified, serving as an important tool for health managers. PMID:27579737

  4. Drug Seems to Extend Survival for Advanced Melanoma Patients

    MedlinePlus

    ... html Drug Seems to Extend Survival for Advanced Melanoma Patients One-third of study participants lived 5 ... HealthDay News) -- More than one-third of advanced melanoma patients were still alive five years after starting ...

  5. Pesticide Use and Cutaneous Melanoma in Pesticide Applicators in the Agricultural Heath Study

    PubMed Central

    Dennis, Leslie K.; Lynch, Charles F.; Sandler, Dale P.; Alavanja, Michael C.R.

    2010-01-01

    Background Melanoma rates continue to increase; however, few risk factors other than sun sensitivity and ultraviolet radiation (including sun exposure) have been identified. Although studies of farmers have shown an excess risk of melanoma and other skin cancers, it is unclear how much of this is related to sun exposure compared with other agricultural exposures. Methods We examined dose–response relationships for 50 agricultural pesticides and cutaneous melanoma incidence in the Agricultural Health Study cohort of licensed pesticide applicators, along with ever use of older pesticides that contain arsenic. Logistic regression was used to examine odds ratios (ORs) and 95% confidence intervals (CIs) associated with pesticide exposure adjusted for age, sex, and other potential confounders. Results We found significant associations between cutaneous melanoma and maneb/mancozeb (63 exposure days: OR = 2.4; 95% CI, 1.2–4.9; trend p = 0.006), parathion (≥ 56 exposure days: OR = 2.4; 95% CI, 1.3–4.4; trend p = 0.003), and carbaryl (≥ 56 exposure days: OR = 1.7; 95% CI, 1.1–2.5; trend p = 0.013). Other associations with benomyl and ever use of arsenical pesticides were also suggested. Conclusions Most previous melanoma literature has focused on host factors and sun exposure. Our research shows an association between several pesticides and melanoma, providing support for the hypotheses that agricultural chemicals may be another important source of melanoma risk. PMID:20164001

  6. Lymphatic Invasion as a Prognostic Biomarker in Primary Cutaneous Melanoma

    PubMed Central

    Xu, Xiaowei; Gimotty, Phyllis A.; Guerry, DuPont; Karakousis, Giorgos; Elder, David E.

    2016-01-01

    Melanoma has a propensity for lymph node metastasis. However, the incidence of lymphatic invasion detected by histology alone in primary melanoma is disproportionately low in comparison to the incidence of positive sentinel lymph nodes (SLN). With the discovery of lymphatic endothelial cell markers, such as podoplanin and LYVE-1, lymphatic vessels can be reliably detected in formalin-fixed paraffin-embedded (FFPE) tissues. There is a now consensus that lymphatic invasion detected by immunohistochemical stains in primary melanoma is much more common than previously reported by histological examination alone. Immunohistochemical stains show that lymphangiogenesis and lymphatic invasion in primary melanoma may occur intratumorally or peritumorally, and lymphatic invasion is common across the range of tumor thicknesses in primary vertical growth phase (VGP) melanomas. A number of studies have shown that lymphatic invasion in primary melanoma is associated with a positive sentinel lymph node biopsy and a worse clinical outcome. Although not currently a part of the standard of care for staging of melanoma, the detection of lymphatic invasion in primary melanoma using immunohistochemical markers may be helpful in planning of therapy in some cases and may find a routine role in primary melanoma microscopic attributes in future. PMID:24258984

  7. Comprehensive capture of cutaneous melanoma by the Ontario Cancer Registry: validation study using community pathology reports.

    PubMed

    Tran, Jennifer M; Schwartz, Rodrigo; Fung, Kinwah; Rochon, Paula; Chan, An-Wen

    2016-01-01

    Melanoma is often managed outside hospital settings, creating the potential for underreporting to cancer registries. To our knowledge, completeness of melanoma capture in cancer registries has not been assessed using external data sources since the 1980s. We evaluated the melanoma capture rate from 1993 to 2009 in a provincial cancer registry. We identified all melanoma diagnoses in pathology reports from a major community laboratory in Ontario, Canada. Pathologically confirmed diagnoses were linked to Ontario Cancer Registry (OCR) records using health insurance numbers. We calculated capture rates as the proportion of patients with melanoma confirmed by a pathology report, with a corresponding melanoma diagnosis in OCR. OCR captured 3,798 of 4,275 (88.8, 95 % confidence interval: 87.9, 89.8 %) invasive melanoma diagnoses over the 17-year period. Annual capture rates of 94 % or higher were found for over half the study period. Among all 29,133 melanoma diagnoses in OCR, 27.6 % were registered based on a pathology report alone, compared with 3.4 % for non-cutaneous malignancies. This suggests that comprehensive capture of melanoma cases by a provincial cancer registry is achievable using source data from community laboratories. There is a need for ongoing validation to ensure data remain accurate and complete to reliably inform clinical care, research, and policy. PMID:26537120

  8. [Recommendations for genetic testing and management of individuals genetically at-risk of cutaneous melanoma].

    PubMed

    Avril, M-F; Bahadoran, P; Cabaret, O; Caron, O; de la Fouchardière, A; Demenais, F; Desjardins, L; Frébourg, T; Hammel, P; Leccia, M-T; Lesueur, F; Mahé, E; Martin, L; Maubec, E; Remenieras, A; Richard, S; Robert, C; Soufir, N; Stoppa-Lyonnet, D; Thomas, L; Vabres, P; Bressac-de Paillerets, B

    2015-01-01

    Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly. PMID:25600792

  9. Early solitary small bowel metastasis from stage I cutaneous melanoma

    PubMed Central

    Gavriilidis, Paschalis; Efthimiopoulos, Georgios; Zafiriou, Georgios

    2013-01-01

    Patient Male, 63 Final Diagnosis: Melanoma Symptoms: Gastrointesinal haemorrhage Medication: — Clinical Procedure: Enterectomy Specialty: Oncology Objective: Unusual clinical course Background: It is reported that the time interval between the initial diagnosis of malignant melanoma and the diagnosis of the gastrointestinal metastases is 43.8±11.3 months. Case Report: We present the case of a 63-year-old Caucasian man who was operated on for superficial spreading Stage IB melanoma and 8 months later was diagnosed with solitary small bowel metastasis without other systemic metastases. Conclusions: Small bowel melanoma metastasis should be suspected in any patient with previous history of malignant melanoma who develops symptoms of anemia, gastrointestinal hemorrhage, and non-specific abdominal pain. PMID:24367718

  10. Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine

    PubMed Central

    Amersi, Farin F.; Terando, Alicia M.; Goto, Yasufumi; Scolyer, Richard A.; Thompson, John F.; Tran, Andy N.; Faries, Mark B.; Morton, Donald L.; Hoon, Dave S.B.

    2009-01-01

    Purpose Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers αβ are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins. Experimental Design Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23). Results We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant α4β1 integrin expression. Conclusions Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location. PMID:18245522

  11. Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II*

    PubMed Central

    Castro, Luiz Guilherme Martins; Bakos, Renato Marchiori; Duprat Neto, João Pedreira; Bittencourt, Flávia Vasques; Giacomo, Thais Helena Bello Di; Serpa, Sérgio Schrader; Messina, Maria Cristina de Lorenzo; Loureiro, Walter Refkalefsky; Macarenco, Ricardo Silvestre e Silva; Stolf, Hamilton Ometto; Gontijo, Gabriel

    2016-01-01

    The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed? PMID:26982779

  12. Correlations Between Cutaneous Malignant Melanoma and Other Cancers: An Ecological Study in Forty European Countries

    PubMed Central

    Serrano, Pablo Fernandez-Crehuet; Serrano, Jose Luis Fernandez-Crehuet; Allam, Mohamed Farouk; Navajas, Rafael Fernandez-Crehuet

    2016-01-01

    Background: The presence of noncutaneous neoplasms does not seem to increase the risk of cutaneous malignant melanoma; however, it seems to be associated with the development of other hematological, brain, breast, uterine, and prostatic neoplasms. An ecological transversal study was conducted to study the geographic association between cutaneous malignant melanoma and 24 localizations of cancer in forty European countries. Methods: Cancer incidence rates were extracted from GLOBOCAN database of the International Agency for Research on Cancer. We analyzed the age-adjusted and gender-stratified incidence rates for different localizations of cancer in forty European countries and calculated their correlation using Pearson's correlation test. Results: In males, significant correlations were found between cutaneous malignant melanoma with testicular cancer (r = 0.83 [95% confidence interval (CI): 0.68–0.89]), myeloma (r = 0.68 [95% CI: 0.46–0.81]), prostatic carcinoma (r = 0.66 [95% CI: 0.43–0.80]), and non-Hodgkin lymphoma (NHL) (r = 0.63 [95% CI: 0.39–0.78]). In females, significant correlations were found between cutaneous malignant melanoma with breast cancer (r = 0.80 [95% CI: 0.64–0.88]), colorectal cancer (r = 0.72 [95% CI: 0.52–0.83]), and NHL (r = 0.71 [95% CI: 0.50–0.83]). Conclusions: These correlations call to conduct new studies about the epidemiology of cancer in general and cutaneous malignant melanoma risk factors in particular. PMID:27217938

  13. IgG subclass switching and clonal expansion in cutaneous melanoma and normal skin

    PubMed Central

    Saul, Louise; Ilieva, Kristina M.; Bax, Heather J.; Karagiannis, Panagiotis; Correa, Isabel; Rodriguez-Hernandez, Irene; Josephs, Debra H.; Tosi, Isabella; Egbuniwe, Isioma U.; Lombardi, Sara; Crescioli, Silvia; Hobbs, Carl; Villanova, Federica; Cheung, Anthony; Geh, Jenny L. C.; Healy, Ciaran; Harries, Mark; Sanz-Moreno, Victoria; Fear, David J.; Spicer, James F.; Lacy, Katie E.; Nestle, Frank O.; Karagiannis, Sophia N.

    2016-01-01

    B cells participate in immune surveillance in human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses in cutaneous immunity is underappreciated. We report circulating skin-homing CD22+CLA+B cells in healthy volunteers and melanoma patients (n = 73) and CD22+ cells in melanoma and normal skin samples (n = 189). Normal and malignant skin featured mature IgG and CD22 mRNA, alongside mRNA for the transiently-expressed enzyme Activation-induced cytidine Deaminase (AID). Gene expression analyses of publically-available data (n = 234 GEO, n = 384 TCGA) confirmed heightened humoral responses (CD20, CD22, AID) in melanoma. Analyses of 51 melanoma-associated and 29 normal skin-derived IgG sequence repertoires revealed lower IgG1/IgGtotal representation compared with antibodies from circulating B cells. Consistent with AID, comparable somatic hypermutation frequencies and class-switching indicated affinity-matured antibodies in normal and malignant skin. A melanoma-associated antibody subset featured shorter complementarity-determining (CDR3) regions relative to those from circulating B cells. Clonal amplification in melanoma-associated antibodies and homology modeling indicated differential potential antigen recognition profiles between normal skin and melanoma sequences, suggesting distinct antibody repertoires. Evidence for IgG-expressing B cells, class switching and antibody maturation in normal and malignant skin and clonally-expanded antibodies in melanoma, support the involvement of mature B cells in cutaneous immunity. PMID:27411958

  14. IgG subclass switching and clonal expansion in cutaneous melanoma and normal skin.

    PubMed

    Saul, Louise; Ilieva, Kristina M; Bax, Heather J; Karagiannis, Panagiotis; Correa, Isabel; Rodriguez-Hernandez, Irene; Josephs, Debra H; Tosi, Isabella; Egbuniwe, Isioma U; Lombardi, Sara; Crescioli, Silvia; Hobbs, Carl; Villanova, Federica; Cheung, Anthony; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Sanz-Moreno, Victoria; Fear, David J; Spicer, James F; Lacy, Katie E; Nestle, Frank O; Karagiannis, Sophia N

    2016-01-01

    B cells participate in immune surveillance in human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses in cutaneous immunity is underappreciated. We report circulating skin-homing CD22+CLA+B cells in healthy volunteers and melanoma patients (n = 73) and CD22+ cells in melanoma and normal skin samples (n = 189). Normal and malignant skin featured mature IgG and CD22 mRNA, alongside mRNA for the transiently-expressed enzyme Activation-induced cytidine Deaminase (AID). Gene expression analyses of publically-available data (n = 234 GEO, n = 384 TCGA) confirmed heightened humoral responses (CD20, CD22, AID) in melanoma. Analyses of 51 melanoma-associated and 29 normal skin-derived IgG sequence repertoires revealed lower IgG1/IgGtotal representation compared with antibodies from circulating B cells. Consistent with AID, comparable somatic hypermutation frequencies and class-switching indicated affinity-matured antibodies in normal and malignant skin. A melanoma-associated antibody subset featured shorter complementarity-determining (CDR3) regions relative to those from circulating B cells. Clonal amplification in melanoma-associated antibodies and homology modeling indicated differential potential antigen recognition profiles between normal skin and melanoma sequences, suggesting distinct antibody repertoires. Evidence for IgG-expressing B cells, class switching and antibody maturation in normal and malignant skin and clonally-expanded antibodies in melanoma, support the involvement of mature B cells in cutaneous immunity. PMID:27411958

  15. [Risk factors for cutaneous melanoma: case-control study in Córdoba, Argentina].

    PubMed

    Ruiz Lascano, Alejandro; Kuznitzky, Raquel; Cuestas, Eduardo; Mainardi, Claudio; Albertini, Ricardo; Borello, Adriana; Kurpis, María; Campana, Ricardo; Palazzo, Emilio

    2004-01-01

    Over the past years, considerable effort has been directed toward the identification of risk factors associated with the increasing incidence of cutaneous melanoma in white populations worldwide. Limited data are available from Argentine populations concerning risk factors for malignant melanoma. A case-control study was performed in Cordoba to estimate the risk factors for cutaneous malignant melanoma. The study group comprised 65 patients and 195 controls, matched by age and sex. The following risk factors were significant in the univariate analysis: European grandparents, blonde and brown hair, fair skin tone, light colored and brown eyes, presence of freckles and melanocytic nevi, severe sunburns before the age of 18 years, recreational sun exposure, family history of malignant melanoma. In the multivariate analysis, European grandparents (OR 2.27, IC95% 1.08 to 3.46), fair skin (OR 4.99, IC95% 2.72 to 7.28), severe sunburns before the age of 18 (OR 6.47, IC95% 5.29 to 7.65), and family history of malignant melanoma (OR 1525, IC95% 1467 to 1584), remain as independent risk factors for malignant melanoma. The results of the current study are similar to those obtained in other populations. PMID:15637827

  16. Time trends and latitude dependence of uveal and cutaneous malignant melanoma induced by solar radiation

    PubMed Central

    Moan, Johan; Cicarma, Emanuela; Setlow, Richard; Porojnicu, Alina C; Grant, William B

    2010-01-01

    In order to evaluate the role of solar radiation in uveal melanoma etiology, the time and latitude dependency of the incidence rates of this melanoma type were studied in comparison with those of cutaneous malignant melanoma (CMM). Norway and several other countries with Caucasian populations were included. there is a marked north-south gradient of the incidence rates of CMM in Norway, with three times higher rates in the south than in the north. No such gradient is found for uveal melanoma. Similar findings have been published for CMM in other Caucasian populations, with the exception of Europe as a whole. In most populations the ratios of uveal melanoma incidence rates to those of CMM tend to decrease with increasing CMM rates. This is also true for Europe, in spite of the fact that in this region there is an inverse latitude gradient of CMM, with higher rates in the north than in the south. In Norway the incidence rates of CMM have increased until about 1990 but have been constant or even decreased (for young people) after that time, indicating constant or decreasing sun exposure. The uveal melanoma rates have been increasing after 1990. In most other populations the incidence rates of CMM have been increasing until recently while those of uveal melanoma have been decreasing. These data generally support the assumption that uveal melanomas are not generated by ultraviolet (UV) radiation and that solar UV, via its role in vitamin D photosynthesis, may have a protective effect. PMID:21547141

  17. Time trends and latitude dependence of uveal and cutaneous malignant melanoma induced by solar radiation

    SciTech Connect

    Moan, J.; Setlow, R.; Cicarma, E.; Porojnicu, A. C.; Grant, W. B.; Juzeniene, A.

    2010-01-01

    In order to evaluate the role of solar radiation in uveal melanoma etiology, the time and latitude dependency of the incidence rates of this melanoma type were studied in comparison with those of cutaneous malignant melanoma (CMM). Norway and several other countries with Caucasian populations were included. There is a marked north - south gradient of the incidence rates of CMM in Norway, with three times higher rates in the south than in the north. No such gradient is found for uveal melanoma. Similar findings have been published for CMM in other Caucasian populations, with the exception of Europe as a whole. In most populations the ratios of uveal melanoma incidence rates to those of CMM tend to decrease with increasing CMM rates. This is also true for Europe, in spite of the fact that in this region there is an inverse latitude gradient of CMM, with higher rates in the north than in the south. In Norway the incidence rates of CMM have increased until about 1990 but have been constant, or even decreased (for young people) after that time, indicating constant or decreasing sun exposure. The uveal melanoma rates have been increasing after 1990. In most other populations the incidence rates of CMM have been increasing until recently while those of uveal melanoma have been decreasing. These data generally support the assumption that uveal melanomas are not generated by ultraviolet (UV) radiation and that solar UV, via its role in vitamin D photosynthesis, may have a protective effect.

  18. Estrogen and progesterone receptors in primary cutaneous melanoma.

    PubMed

    Ellis, D L; Wheeland, R G; Solomon, H

    1985-01-01

    Using a variety of techniques, estrogen and progesterone receptors have previously been identified in variable percentages of malignant melanomas. We examined 10 primary superficial spreading melanomas (SSM) with a fluorescent hormone-binding technique for estrogen and progesterone cytoplasmic receptors. Of these 6 SSM were markedly positive for estrogen and progesterone binding. Patients with dysplastic nevus syndrome (DNS) or a family history of DNS were markedly positive for estrogen and progesterone binding. A single patient with lentigo maligna and another patient with lentigo maligna melanoma were negative for estrogen and progesterone binding. None of the 21 control intradermal nevi examined for estrogen and progesterone binding exhibited marked positivity. PMID:3965520

  19. Seasonal variation in diagnosis of invasive cutaneous melanoma in Eastern England and Scotland

    PubMed Central

    Walter, Fiona M.; Abel, Gary A.; Lyratzopoulos, Georgios; Melia, Jane; Greenberg, David; Brewster, David H.; Butler, Helen; Corrie, Pippa G.; Campbell, Christine

    2015-01-01

    Background Worldwide, the incidence of cutaneous melanoma has been reported to be highest in the summer and lowest in the winter. Northern Irish data suggested seasonal variation for women only, especially those with thinner melanomas, sited on limbs. We interrogated two larger UK cancer registries for temporal differences in melanoma diagnosis and associated patient characteristics. Methods Melanomas diagnosed from 2006 to 2010 in the Eastern England and Scottish cancer registries (n = 11,611) were analysed by month of diagnosis, patient demographics and melanoma characteristics, using descriptive and multivariate modelling methods. Results More patients with melanoma were diagnosed in the summer months (June 9.9%, July 9.7%, August 9.8%) than the winter months (December 7.2%, January 7.2%, February 7.1%) and this pattern was consistent in both regions. There was evidence that the seasonal patterns varied by sex (p = 0.015), melanoma thickness (p = 0.002), body site (p = 0.006), and type (superficial spreading melanomas p = 0.005). The seasonal variation was greatest for diagnosis of melanomas occurring on the limbs. Conclusion This study has confirmed seasonal variation in melanoma diagnosis in Eastern England and Scotland across almost all population demographics and melanoma characteristics studied, with higher numbers diagnosed in the summer months, particularly on the limbs. Seasonal patterns in skin awareness and related help-seeking are likely to be implicated. Targeted patient interventions to increase sun awareness and encourage year-long skin inspection are warranted. PMID:26141681

  20. Immune checkpoint inhibitors: therapeutic advances in melanoma

    PubMed Central

    Márquez-Rodas, Ivan; Cerezuela, Pablo; Soria, Ainara; Berrocal, Alfonso; Riso, Aldo; Martín-Algarra, Salvador

    2015-01-01

    In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma. PMID:26605313

  1. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma.

    PubMed

    Corazzari, M; Rapino, F; Ciccosanti, F; Giglio, P; Antonioli, M; Conti, B; Fimia, G M; Lovat, P E; Piacentini, M

    2015-06-01

    The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF(V600E) mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF(V600E) induces a chronic ER stress status directly increasing basal cell autophagy. BRAF(V600E)-mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF(V600E)-mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF(V600E) melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma. PMID:25361077

  2. Prognostic significance of periodic acid-Schiff-positive patterns in primary cutaneous melanoma.

    PubMed

    Warso, M A; Maniotis, A J; Chen, X; Majumdar, D; Patel, M K; Shilkaitis, A; Gupta, T K; Folberg, R

    2001-03-01

    The patterns of periodic acid-Schiff (PAS) staining of extracellular matrix in histological sections of certain melanomas may be predictive of outcome. Recent in vitro and molecular genetic data suggest that the appearance of these patterns in both uveal and cutaneous melanoma is a function of aggressive tumor cells. We studied 96 patients with primary cutaneous melanomas treated at the University of Illinois at Chicago who were monitored for disease-free survival. Survival probabilities were determined by Kaplan-Meier estimates, and prognostic factors were evaluated by multivariate analysis. By univariate analysis, there was a significant decrease in disease-free survival among patients whose tumors contained parallel with cross-linking or network patterns (PXNs; P = 0.0070). Stepwise regression with Cox models that included the combinations of the PAS-positive patterns, tumor thickness, female gender, ulceration, and age yielded a model with thickness and the PAS-positive parallel with cross-linking or networks. Despite the relatively small sample size in this study, the detection of the PAS-positive parallel with cross-linking or networking in cutaneous melanoma was associated with a decrease in disease-free outcome. Additional studies of the prognostic significance of these patterns is warranted on larger data sets. PMID:11297236

  3. Can ultraviolet radiation act as a survival enhancer for cutaneous melanoma?

    PubMed Central

    Mastroeni, Simona; Bonamigo, Renan; Mannooranparampil, Thomas; Marino, Claudia; Michelozzi, Paola; Passarelli, Francesca; Boniol, Mathieu

    2016-01-01

    Some studies have suggested that sun exposure plays a protective role in melanoma survival. This created a paradox as the known carcinogen can act as a cancer promoter and also as a survival enhancer. The aim of this study was to investigate the effect of sun exposure on melanoma mortality using both ambient sun exposure and individual data. A 10-year cohort study was carried out on primary cutaneous melanoma cases (n=972). Residential data were coupled with levels of ultraviolet radiation (UV) to provide a measure of individual exposure. Demographic, histological and clinical data were obtained for all participants. In a subsample, information on pigmentary characteristics, diet, medical history, phenotype and self-reported sun exposure was also collected. Survival analysis and Cox proportional hazards models were used to examine associations. No protective effect was found for UVB or individual sun exposure variables on melanoma mortality. However, an increased risk of mortality was found among patients with cutaneous melanoma located on the lower limbs and in the highest decile of UVB exposure (≥3.298 J/cm2) after controlling for sex, age and Breslow thickness (relative risk: 4.78; 95% confidence interval: 1.30–17.5). The increased risk of mortality for the highest decile of UVB was also confirmed in the subsample after controlling for sex, age, education, use of sun lamps, pigmentary characteristics and diet. The results of the study suggested no protective effect of sun exposure for melanoma mortality and showed that high sun exposure increases the risk of melanoma mortality among patients with melanomas located on the lower limbs. PMID:25646933

  4. Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination.

    PubMed Central

    de Waal, R. M.; van Altena, M. C.; Erhard, H.; Weidle, U. H.; Nooijen, P. T.; Ruiter, D. J.

    1997-01-01

    Cutaneous melanoma has an initial preference for lymphatic spread. Remarkably, melanoma progression toward this metastasizing phenotype is accompanied by intense blood vessel angiogenesis (hemangiogenesis), but lymphangiogenesis, the formation of new lymph vessels in the tumor, has never been reported. To investigate how primary melanoma cells interact with the existing lymphatic microvasculature, and whether lymphangiogenesis occurs, an immunostaining was developed that differentially decorates blood and lymph vessels in frozen tissue sections. The density and distribution of both these vessel types in and around thin (< or = 1.5 mm) and thick (> or = 1.5 mm) primary melanoma lesions and in normal and uninvolved skin were determined. Although especially in thick melanoma lesions a significant increase in blood vessel density was observed, lymphatic density remained unaltered, showing that lymphangiogenesis did not occur. Morphological analysis indicated, however, that melanoma progression is accompanied by a sequence of events that involves hemangiogenesis supporting tumor expansion, especially in the vertical growth phase. Often, stromal sepia are formed around the blood capillaries in the tumor neovasculature protecting them from invasion. Lymph vessels inside the tumor were infrequently observed. However, subepidermal lymph vessels often seemed to be entrapped and penetrated by the expanding tumor mass. In this way, hemangiogenesis, as the driving force behind tumor expansion, might indirectly increase the chance of lymphatic invasion in the absence of lymphangiogenesis. This model explains the paradox that, although melanoma metastasis seems to require angiogenesis, a consistent relation of prognosis with blood capillary density in primary cutaneous melanoma is lacking. Images Figure 1 Figure 2 Figure 3 PMID:9176389

  5. Can ultraviolet radiation act as a survival enhancer for cutaneous melanoma?

    PubMed

    Fortes, Cristina; Mastroeni, Simona; Bonamigo, Renan; Mannooranparampil, Thomas; Marino, Claudia; Michelozzi, Paola; Passarelli, Francesca; Boniol, Mathieu

    2016-01-01

    Some studies have suggested that sun exposure plays a protective role in melanoma survival. This created a paradox as the known carcinogen can act as a cancer promoter and also as a survival enhancer. The aim of this study was to investigate the effect of sun exposure on melanoma mortality using both ambient sun exposure and individual data. A 10-year cohort study was carried out on primary cutaneous melanoma cases (n=972). Residential data were coupled with levels of ultraviolet radiation (UV) to provide a measure of individual exposure. Demographic, histological and clinical data were obtained for all participants. In a subsample, information on pigmentary characteristics, diet, medical history, phenotype and self-reported sun exposure was also collected. Survival analysis and Cox proportional hazards models were used to examine associations. No protective effect was found for UVB or individual sun exposure variables on melanoma mortality. However, an increased risk of mortality was found among patients with cutaneous melanoma located on the lower limbs and in the highest decile of UVB exposure (≥3.298 J/cm) after controlling for sex, age and Breslow thickness (relative risk: 4.78; 95% confidence interval: 1.30-17.5). The increased risk of mortality for the highest decile of UVB was also confirmed in the subsample after controlling for sex, age, education, use of sun lamps, pigmentary characteristics and diet. The results of the study suggested no protective effect of sun exposure for melanoma mortality and showed that high sun exposure increases the risk of melanoma mortality among patients with melanomas located on the lower limbs. PMID:25646933

  6. Update and Review on the Surgical Management of Primary Cutaneous Melanoma

    PubMed Central

    Niknam Leilabadi, Solmaz; Chen, Amie; Tsai, Stacy; Soundararajan, Vinaya; Silberman, Howard; Wong, Alex K.

    2014-01-01

    The surgical management of malignant melanoma historically called for wide excision of skin and subcutaneous tissue for any given lesion, but has evolved to be rationally-based on pathological staging. Breslow and Clark independently described level and thickness as determinant in prognosis and margin of excision. The American Joint Committee of Cancer (AJCC) in 1988 combined features from each of these histologic classifications, generating a new system, which is continuously updated and improved. The National Comprehensive Cancer Network (NCCN) has also combined several large randomized prospective trials to generate current guidelines for melanoma excision as well. In this article, we reviewed: (1) Breslow and Clark classifications, AJCC and NCCN guidelines, the World Health Organization’s 1988 study, and the Intergroup Melanoma Surgical Trial; (2) Experimental use of Mohs surgery for in situ melanoma; and (3) Surgical margins and utility and indications for sentinel lymph node biopsy (SLNB) and lymphadenectomy. Current guidelines for the surgical management of a primary melanoma of the skin is based on Breslow microstaging and call for cutaneous margins of resection of 0.5 cm for MIS, 1.0 cm for melanomas ≤1.0 mm thick, 1–2 cm for melanoma thickness of 1.01–2 mm, 2 cm margins for melanoma thickness of 2.01–4 mm, and 2 cm margins for melanomas >4 mm thick. Although the role of SLNB, CLND, and TLND continue to be studied, current recommendations include SLNB for Stage IB (includes T1b lesions ≤1.0 with the adverse features of ulceration or ≥1 mitoses/mm2) and Stage II melanomas. CLND is recommended when sentinel nodes contain metastatic deposits.

  7. MDM4 is a key therapeutic target in cutaneous melanoma

    PubMed Central

    Gembarska, Agnieszka; Luciani, Flavie; Fedele, Clare; Russell, Elisabeth A; Dewaele, Michael; Villar, Stéphanie; Zwolinska, Aleksandra; Haupt, Sue; de Lange, Job; Yip, Dana; Goydos, James; Haigh, Jody J; Haupt, Ygal; Larue, Lionel; Jochemsen, Aart; Shi, Hubing; Moriceau, Gatien; Lo, Roger S; Ghanem, Ghanem; Shackleton, Mark; Bernal, Federico; Marine, Jean-Christophe

    2013-01-01

    The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma—a highly chemotherapy-resistant disease—TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I–IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy. PMID:22820643

  8. Current and Future Trials of Targeted Therapies in Cutaneous Melanoma

    PubMed Central

    Madhunapantula, SubbaRao V.; Robertson, Gavin P.; Drabick, Joseph J.

    2013-01-01

    In order to effectively treat melanoma, targeted inhibition of key mechanistic events regulating melanoma development such as cell proliferation, survival, angiogenesis and invasion or metastasis needs to be accomplished. The Mitogen Activated Protein Kinase (MAPK) pathway has been identified as a key player in melanoma development making this cascade an important therapeutic target. However, identification of the ideal pathway member to therapeutically target for maximal clinical benefit remains a challenge. In normal cells, the MAPK pathway relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events, which promote cancer development. Dysregulation of the MAPK pathway occurs frequently in many human cancers including melanoma. Mutations in the B-RAF and RAS genes, genetic or epigenetic modifications are the key aberrations observed in this signaling cascade. Constitutive activation of this pathway causes oncogenic transformation of cells by promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. This review provides an overview of (a) key members of MAPK signaling regulating melanoma development; (b) key proteins which can serve as biomarkers to assess disease progression; (c) the clinical efficacy of various pharmacological agents targeting MAPK pathway; (d) current clinical trials evaluating downstream targets of the MAPK pathway; (e) issues associated with pharmacological agents such as drug resistance, induction of cancers; and finally (e) various strategies overcoming drug resistance. PMID:23288642

  9. An incidental finding of a nodal recurrence of cutaneous malignant melanoma after a 45-year disease-free period

    PubMed Central

    Goodenough, Jenny; Cozon, Caroline Louise; Liew, Se Hwang

    2014-01-01

    We report the case of an 84-year-old woman who had a nodal recurrence of melanoma 45 years after the primary diagnosis of an extremity cutaneous melanoma. It is believed to be the longest disease-free latency period reported between primary melanoma diagnosis and recurrence to date. Late recurrences of melanoma are rare and recurrence after four decades extremely rare. This article suggests melanoma is a disease with a potentially lifelong risk of recurrence and thus clinicians and patients must be vigilant and aware of this risk, particularly if late recurrences are to be recognised early and management optimised. PMID:24895394

  10. Cutaneous autoimmune effects in the setting of therapeutic immune checkpoint inhibition for metastatic melanoma.

    PubMed

    Mochel, Mark C; Ming, Michael E; Imadojemu, Sotonye; Gangadhar, Tara C; Schuchter, Lynn M; Elenitsas, Rosalie; Payne, Aimee S; Chu, Emily Y

    2016-09-01

    Therapeutic immune checkpoint blockade for metastatic melanoma has been associated with vitiligo, pruritus and morbilliform eruptions. Reports of other autoimmune skin disease in this setting are rare. We sought to expand the spectrum of cutaneous immune-mediated effects related to immune checkpoint inhibitor therapy. In this report, we describe two unusual cutaneous reactions related to checkpoint inhibitor therapy, namely bullous pemphigoid (BP) and dermatitis herpetiformis. The development of BP and dermatitis herpetiformis in the context of checkpoint inhibitor therapy is consistent with previous investigations supporting the importance of effector and regulatory T cells in the pathogenesis of these diseases. PMID:27161449

  11. Tumor Cell Adhesion As a Risk Factor for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma

    PubMed Central

    Meves, Alexander; Nikolova, Ekaterina; Heim, Joel B.; Squirewell, Edwin J.; Cappel, Mark A.; Pittelkow, Mark R.; Otley, Clark C.; Behrendt, Nille; Saunte, Ditte M.; Lock-Andersen, Jorgen; Schenck, Louis A.; Weaver, Amy L.; Suman, Vera J.

    2015-01-01

    Purpose Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. Patients and Methods Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. Results ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). Conclusion The addition of cell adhesion–linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis. PMID:26150443

  12. Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

    PubMed

    Orlow, Irene; Reiner, Anne S; Thomas, Nancy E; Roy, Pampa; Kanetsky, Peter A; Luo, Li; Paine, Susan; Armstrong, Bruce K; Kricker, Anne; Marrett, Loraine D; Rosso, Stefano; Zanetti, Roberto; Gruber, Stephen B; Anton-Culver, Hoda; Gallagher, Richard P; Dwyer, Terence; Busam, Klaus; Begg, Colin B; Berwick, Marianne

    2016-01-01

    Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics. PMID:26521212

  13. [GAZING INTO A CRYSTAL BALL AND DETECTING SUBJECTS AT RISK FOR DEVELOPING CUTANEOUS MELANOMA].

    PubMed

    Piérard, G E; Piérard-Franchimont, C; Hermanns-Lê, T; Piérard, S L

    2015-09-01

    Cutaneous melanoma is the deadliest skin cancer showing an increasingly growing incidence in white populations of Europe and United States. Intensive research in recent years has begun to unlock its molecular pathogenesis. Screening the neoplasm at an early stage remains primordial. Hence, targeting populations at risk is likely efficient. In such an attempt, the regular clinical examination benefits from a series of non invasive procedures such as skin surface biopsies, in vivo confocal microscopy, dermoscopy and specular fluorescent light reflectance. PMID:26638445

  14. Pro-Invasive Activity of the Hippo Pathway Effectors YAP and TAZ in Cutaneous Melanoma

    PubMed Central

    Nallet-Staub, Flore; Marsaud, Véronique; Li, Ling; Gilbert, Cristèle; Dodier, Sophie; Bataille, Véronique; Sudol, Marius; Herlyn, Meenhard; Mauviel, Alain

    2014-01-01

    YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial–mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain–dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention. PMID:23897276

  15. Fluorescence in situ detection of human cutaneous melanoma: study of diagnostic parameters of the method.

    PubMed

    Chwirot, B W; Chwirot, S; Sypniewska, N; Michniewicz, Z; Redzinski, J; Kurzawski, G; Ruka, W

    2001-12-01

    Multicenter study of the diagnostic parameters was conducted by three groups in Poland to determine if in situ fluorescence detection of human cutaneous melanoma based on digital imaging of spectrally resolved autofluorescence can be used as a tool for a preliminary selection of patients at increased risk of the disease. Fluorescence examinations were performed for 7228 pigmented lesions in 4079 subjects. Histopathologic examinations showed 56 cases of melanoma. A sensitivity of fluorescence detection of melanoma was 82.7% in agreement with 82.5% found in earlier work. Using as a reference only the results of histopathologic examinations obtained for 568 cases we found a specificity of 59.9% and a positive predictive value of 17.5% (melanomas versus all pigmented lesions) or 24% (melanomas versus common and dysplastic naevi). The specificity and positive predictive value found in this work are significantly lower than reported earlier but still comparable with those reported for typical screening programs. In conclusion, the fluorescence method of in situ detection of melanoma can be used in screening large populations of patients for a selection of patients who should be examined by specialists. PMID:11886507

  16. Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma.

    PubMed

    Nallet-Staub, Flore; Marsaud, Véronique; Li, Ling; Gilbert, Cristèle; Dodier, Sophie; Bataille, Véronique; Sudol, Marius; Herlyn, Meenhard; Mauviel, Alain

    2014-01-01

    YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial-mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain-dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention. PMID:23897276

  17. Increased NY-ESO-1 expression and reduced infiltrating CD3+ T cells in cutaneous melanoma.

    PubMed

    Giavina-Bianchi, Mara; Giavina-Bianchi, Pedro; Sotto, Mirian Nacagami; Muzikansky, Alona; Kalil, Jorge; Festa-Neto, Cyro; Duncan, Lyn M

    2015-01-01

    NY-ESO-1 is a cancer-testis antigen aberrantly expressed in melanomas, which may serve as a robust and specific target in immunotherapy. NY-ESO-1 antigen expression, tumor features, and the immune profile of tumor infiltrating lymphocytes were assessed in primary cutaneous melanoma. NY-ESO-1 protein was detected in 20% of invasive melanomas (16/79), rarely in in situ melanoma (1/10) and not in benign nevi (0/20). Marked intratumoral heterogeneity of NY-ESO-1 protein expression was observed. NY-ESO-1 expression was associated with increased primary tumor thickness (P = 0.007) and inversely correlated with superficial spreading melanoma (P < 0.02). NY-ESO-1 expression was also associated with reduced numbers and density of CD3+ tumor infiltrating lymphocytes (P = 0.017). When NY-ESO-1 protein was expressed, CD3+ T cells were less diffusely infiltrating the tumor and were more often arranged in small clusters (P = 0.010) or as isolated cells (P = 0.002) than in large clusters of more than five lymphocytes. No correlation of NY-ESO-1 expression with gender, age, tumor site, ulceration, lymph node sentinel status, or survival was observed. NY-ESO-1 expression in melanoma was associated with tumor progression, including increased tumor thickness, and with reduced tumor infiltrating lymphocytes. PMID:25954764

  18. Cutaneous malignant melanoma in a Haller's round ray Urobatis halleri.

    PubMed

    Nau, Melissa R; Gardiner, David W; Nilson, Erika; Schmitt, Todd L; Nollens, Hendrik H; St Leger, Judy

    2016-08-01

    Multiple black raised nodular masses were noted on the dorsal surface of an adult male Haller's round ray Urobatis halleri. Biopsy of 2 masses was performed, and histopathology revealed proliferative sheets of melanocytes exhibiting mild anisocytosis and anisokaryosis, supporting a diagnosis of malignant melanoma. Approximately 2 mo following the biopsy procedure, the round ray became acutely anorexic and was found dead in its enclosure. A full necropsy was performed, and tissues were submitted for histopathology. The black raised nodular masses again exhibited histologic features of a melanoma. In addition to the nodular masses present, multiple flat areas of increased pigmentation were also present throughout the course of the case and were not suggestive of neoplasia histologically. The transformation of benign to malignant neoplasia has been well described in other species and may have played a role in the development of multiple tumors in this case. PMID:27503921

  19. Activated Notch1 expression is associated with angiogenesis in cutaneous melanoma.

    PubMed

    Murtas, Daniela; Piras, Franca; Minerba, Luigi; Maxia, Cristina; Ferreli, Caterina; Demurtas, Paolo; Lai, Simone; Mura, Ester; Corrias, Michela; Sirigu, Paola; Perra, Maria Teresa

    2015-08-01

    An early event in melanocytic tumor growth is the upregulation of Notch signaling. When an active form of Notch1 is overexpressed in primary human melanocytes, it increases cell growth, survival and invasive properties, promoting melanoma progression. Recent evidence suggested that tumor initiation and growth are driven by a subset of tumor-initiating cells termed cancer stem cells. Notch1 plays a predominant role in the maintenance of melanoblasts, including melanocyte stem cells, by preventing initiation of apoptosis. Moreover, the importance of Notch1 in the regulation of tumor angiogenesis is supported by growing evidence in various cancers. Nestin has been widely used as a marker for melanocyte stem cells as well as an angiogenic marker to evaluate neovascularity of endothelial cells in tumors. To gain an insight into the impact of Notch1 activation on the maintenance of melanocyte stem cells and angiogenesis in melanoma, the expression levels of activated Notch1 and nestin were analyzed by immunohistochemistry in 114 primary cutaneous melanomas and 35 lymph node metastases. Activated Notch1 and nestin expression was also evaluated in four dysplastic melanocytic nevi. This study provides evidence that activated Notch1 is overexpressed in cutaneous melanoma, in tumor cells as well as in microvessel endothelium, and that it can promote tumor angiogenesis. Indeed, the overexpression of activated Notch1 in both tumor and vascular endothelial cells was significantly associated with microvascular density in melanoma samples. Thus, activated Notch1 inhibitors may provide a therapeutic strategy in the treatment of melanoma by blocking tumor-associated vascularization. PMID:25034654

  20. Multispectral autofluorescence diagnosis of non-melanoma cutaneous tumors

    NASA Astrophysics Data System (ADS)

    Borisova, Ekaterina; Dogandjiiska, Daniela; Bliznakova, Irina; Avramov, Latchezar; Pavlova, Elmira; Troyanova, Petranka

    2009-07-01

    Fluorescent analysis of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), keratoacanthoma and benign cutaneous lesions is carried out under initial phase of clinical trial in the National Oncological Center - Sofia. Excitation sources with maximum of emission at 365, 380, 405, 450 and 630 nm are applied for better differentiation between nonmelanoma malignant cutaneous lesions fluorescence and spectral discrimination from the benign pathologies. Major spectral features are addressed and diagnostic discrimination algorithms based on lesions' emission properties are proposed. The diagnostic algorithms and evaluation procedures found will be applied for development of an optical biopsy clinical system for skin cancer detection in the frames of National Oncological Center and other university hospital dermatological departments in our country.

  1. Ethnicity and Cutaneous Melanoma in the City of Sao Paulo, Brazil: A Case-Control Study

    PubMed Central

    Luiz, Olinda C.; Gianini, Reinaldo José; Gonçalves, Fernanda T.; Francisco, Guilherme; Festa-Neto, Cyro; Sanches, José Antonio; Gattas, Gilka J. F.; Chammas, Roger; Eluf-Neto, José

    2012-01-01

    Background Over the last century the incidence of cutaneous melanoma has increased worldwide, a trend that has also been observed in Brazil. The identified risk factors for melanoma include the pattern of sun exposure, family history, and certain phenotypic features. In addition, the incidence of melanoma might be influenced by ethnicity. Like many countries, Brazil has high immigration rates and consequently a heterogenous population. However, Brazil is unique among such countries in that the ethnic heterogeneity of its population is primarily attributable to admixture. This study aimed to evaluate the contribution of European ethnicity to the risk of cutaneous melanoma in Brazil. Methodology/Principal Findings We carried out a hospital-based case-control study in the metropolitan area of Sao Paulo, Brazil. We evaluated 424 hospitalized patients (202 melanoma patients and 222 control patients) regarding phenotypic features, sun exposure, and number of grandparents born in Europe. Through multivariate logistic regression analysis, we found the following variables to be independently associated with melanoma: grandparents born in Europe—Spain (OR = 3.01, 95% CI: 1.03–8.77), Italy (OR = 3.47, 95% CI: 1.41–8.57), a Germanic/Slavic country (OR = 3.06, 95% CI: 1.05–8.93), or ≥2 European countries (OR = 2.82, 95% CI: 1.06–7.47); eye color—light brown (OR = 1.99, 95% CI: 1.14–3.84) and green/blue (OR = 4.62; 95% CI 2.22–9.58); pigmented lesion removal (OR = 3.78; 95% CI: 2.21–6.49); no lifetime sunscreen use (OR = 3.08; 95% CI: 1.03–9.22); and lifetime severe sunburn (OR = 1.81; 95% CI: 1.03–3.19). Conclusions Our results indicate that European ancestry is a risk factor for cutaneous melanoma. Such risk appears to be related not only to skin type, eye color, and tanning capacity but also to others specific characteristics of European populations introduced in the New World by European immigrants. PMID:22558444

  2. Prognostic factors and disease-specific survival among immigrants diagnosed with cutaneous malignant melanoma in Sweden.

    PubMed

    Simberg-Danell, Caroline; Lyth, Johan; Månsson-Brahme, Eva; Frohm-Nilsson, Margareta; Carstensen, John; Hansson, Johan; Eriksson, Hanna

    2016-08-01

    Little is known about cutaneous malignant melanoma (CMM) among immigrants in Europe. We aimed to investigate clinical characteristics and disease-specific survival among first- and second-generation immigrants in Sweden. This nationwide population-based study included 27,235 patients from the Swedish Melanoma Register diagnosed with primary invasive CMM, 1990-2007. Data were linked to nationwide, population-based registers followed up through 2013. Logistic regression and Cox regression models were used to determine the association between immigrant status, stage and CMM prognosis, respectively. After adjustments for confounders, first generation immigrants from Southern Europe were associated with significantly more advanced stages of disease compared to Swedish-born patients [Stage II vs. I: Odds ratio (OR) = 2.37, 95% CI = 1.61-3.50. Stage III-IV vs I: OR = 2.40, 95% CI = 1.08-5.37]. The ORs of stage II-IV versus stage I disease were increased among men (OR = 1.9; 95% CI = 1.1-3.3; p = 0.020), and women (OR = 4.8; 95% CI = 2.6-9.1; p < 0.001) in a subgroup of immigrants from former Yugoslavia compared to Swedish-born patients. The CMM-specific survival was significantly decreased among women from former Yugoslavia versus Swedish-born women [hazard ratio (HR)=2.2; 95% CI = 1.1-4.2; p = 0.043]. After additional adjustments including stage, the survival difference was no longer significant. No survival difference between the second generation immigrant group and Swedish-born patients were observed. In conclusion, a worse CMM-specific survival in women from former Yugoslavia was associated with more advanced stages of CMM at diagnosis. Secondary prevention efforts focusing on specific groups may be needed to further improve the CMM prognosis. PMID:27004457

  3. EMMPRIN/CD147 is an independent prognostic biomarker in cutaneous melanoma.

    PubMed

    Caudron, Anne; Battistella, Maxime; Feugeas, Jean-Paul; Pages, Cécile; Basset-Seguin, Nicole; Mazouz Dorval, Sarra; Funck Brentano, Elisa; Sadoux, Aurélie; Podgorniak, Marie-Pierre; Menashi, Suzanne; Janin, Anne; Lebbé, Céleste; Mourah, Samia

    2016-08-01

    CD147 has been implicated in melanoma invasion and metastasis mainly through increasing metalloproteinase synthesis and regulating VEGF/VEGFR signalling. In this study, the prognostic value of CD147 expression was investigated in a cohort of 196 cutaneous melanomas including 136 consecutive primary malignant melanomas, 30 lymph nodes, 16 in-transit and 14 visceral metastases. A series of 10 normal skin, 10 blue nevi and 10 dermal nevi was used as control. CD147 expression was assessed by immunohistochemistry, and the association of its expression with the clinicopathological characteristics of patients and survival was evaluated using univariate and multivariate statistical analyses. Univariate analysis showed that high CD147 expression was significantly associated with metastatic potential and with a reduced overall survival (P < 0.05 for both) in primary melanoma patients. CD147 expression level was correlated with histological factors which were associated with prognosis: Clark level, ulceration status and more particularly with Breslow index (r = 0.7, P < 10(-8) ). Multivariate analysis retained CD147 expression level and ulceration status as predicting factors for metastasis and overall survival (P < 0.05 for both). CD147 emerges as an important factor in the aggressive behaviour of melanoma and deserves further evaluation as an independent prognostic biomarker. PMID:27060463

  4. Topical toremifene: a new approach for cutaneous melanoma?

    PubMed

    Maenpaa, J; Dooley, T; Wurz, G; VandeBerg, J; Robinson, E; Emshoff, V; Sipila, P; Wiebe, V; Day, C; DeGregorio, M

    1993-01-01

    The distribution of topically applied toremifene (0.5-1 mg/day for 5 days) in the ultraviolet B (UVB)-induced Monodelphis domestica opossum melanoma model was examined. The mean concentration of toremifene measured in the skin was 1200 nmol/g, or > 500 times that detected in any other tissues (blood, brain, liver, testicles, heart, uterus, eyes). In plasma, toremifene could be detected in only one animal of six (0.04 nmol/ml). Intraperitoneal administration of 0.5 mg toremifene daily for 5 days in three female animals resulted in a mean uterus concentration of 22.9 nmol/g, or 400-fold that achieved by topical administration of 0.5 mg/day in three other female Monodelphis (0.05 nmol/g). The cytostatic effect of toremifene was studied in three human melanoma cell lines and three experimental cell lines derived from UVB-induced melanocytic nevi in M. domestica. Toremifene had a cytostatic effect on all cell lines (50% growth-inhibitory concentrations, 5.8-9.6 microM). Topical toremifene administration yields high local concentration with minimal systemic distribution. In addition, toremifene has a cytostatic effect at achievable concentrations in a variety of melanomatous cell lines. PMID:8339391

  5. Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation.

    PubMed

    Busam, Klaus J; Vilain, Ricardo E; Lum, Trina; Busam, Jonathan A; Hollmann, Travis J; Saw, Robyn P M; Coit, Daniel C; Scolyer, Richard A; Wiesner, Thomas

    2016-06-01

    A number of common driver mutations have been identified in melanoma, but other genetic or epigenetic aberrations are also likely to play a role in the pathogenesis of melanoma and present potential therapeutic targets. Translocations of the anaplastic lymphoma kinase (ALK), for example, have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK expression. In this study, we sought to determine whether ALK was also expressed in nonspitzoid primary and metastatic cutaneous melanomas. ALK immunohistochemistry was performed on 603 melanomas (303 primary and 300 metastatic tumors) from 600 patients. ALK immunohistochemistry expression was identified in 7 primary and 9 metastatic tumors. In 5 of 7 primary tumors and in 6 of 9 metastatic lesions, the majority of tumor cells were immunoreactive for ALK. In the other 2 primary and 3 metastatic lesions, positive staining was identified in less than half of the tumor cells. ALK positivity was found in the presence or absence of BRAF or NRAS mutations. In contrast to prior observations with ALK-positive Spitz tumors, none of the ALK-positive melanomas harbored a translocation. Instead, the ALK-positive melanomas predominantly expressed the recently described ALK isoform, ALK, which lacks the extracellular and transmembrane domains of wild-type ALK, consists primarily of the intracellular tyrosine kinase domain, and originates from an alternative transcriptional initiation site within the ALK gene. The findings are clinically relevant as patients with metastatic melanoma who have ALK expression may potentially benefit from treatment with ALK kinase inhibitors. PMID:26872010

  6. Multicohort model for prevalence estimation of advanced malignant melanoma in the USA: an increasing public health concern.

    PubMed

    Lin, Amy Y; Wang, Peter F; Li, Haojie; Kolker, Jennifer A

    2012-12-01

    The aim of the study was to estimate the current prevalence of advanced cutaneous malignant melanoma in 2010 in the USA and to project prevalence estimates to the year 2015. An excel-based, multicohort natural disease history model was developed. It used incidence, recurrence, all-cause mortality, and US population data from the up-to-date surveillance, epidemiology, and end results program, the US census, and the literature. The prevalence was stratified by tumor stage, sex, and age. The model estimated that there were 800 735 malignant melanoma cases (258 per 100 000 individuals) in the USA in 2010, of which 10.4% were in advanced stages including stage III (22 per 100 000 individuals) and stage IV (four per 100 000 individuals). Among these advanced cases, 58.8% were men. In total, 42.1% of patients with advanced malignant melanoma were 65 years of age and older. Of these elderly patients with an advanced stage of the disease, 65.7% were men. The total number of cases and number of advanced cases were projected to increase from 2010 to 2015 by 24.4 and 21.0%, respectively. There will be approximately one million malignant melanoma cases (306 per 100 000 individuals) in the USA in 2015. The prevalence of advanced malignant melanoma is expected to increase in the next few years. Advanced malignant melanoma disproportionately affects men and the elderly in the USA. PMID:22990665

  7. Cutaneous melanoma frequencies and seasonal trend in 20 years of observation of a population characterised by excessive sun exposure

    PubMed Central

    Bonin, Serena; Albano, Antonio; di Meo, Nicola; Gatti, Alessandro; Stinco, Giuseppe; Zanconati, Fabrizio; Trevisan, Giusto

    2015-01-01

    Background Cutaneous melanoma is an aggressive form of skin cancer. It has become an increasingly common neoplasm in the most developed countries, especially among individuals of European origin. Patients and methods. Anonymous data of patients with cutaneous melanoma were collected from the diagnostic database of the University Hospital of Trieste from 1 January 1990 to 10 December 2013. Our study is based on a population which was constant over the period of observation; it was also well-defined and characterised by unrestrained sun exposure. Results The number of cutaneous melanomas increased during the period of observation with a seasonality trend and gender related differences both for anatomical sites distribution and stage of the disease. Moreover, 6% of our cohort developed multiple melanomas. Conclusions In a well-defined population devoted to excessive sun exposure the frequencies of skin melanomas roughly doubled from 1990 to 2013 following a seasonal trend. In that population, prevention efforts according to gender specific risk behaviour, as well as follow-up programmes both for evaluation of metastatic spreading and for early diagnosis of additional skin melanomas, are crucial due to gender specific differences and to the occurrence of multiple melanomas. PMID:26834525

  8. Analysis of the Clinical and Histopathological Patterns of 100 Consecutive Cases of Primary Cutaneous Melanoma and Correlation with Staging

    PubMed Central

    Nam, Kyung Wook; Bae, Seong Hwan; Song, Kyung Ho; Kim, Hoon Soo; Choi, Young Jin

    2015-01-01

    Background This study analyzed 100 consecutive patients with primary cutaneous melanoma over the course of 13 years to determine whether epidemiological differences correspond to different stages of the disease. We also investigated whether epidemiological characteristics affected the survival rate. Our results were compared with those of selected descriptive studies of melanoma in other East Asian populations, in order to determine whether cutaneous melanoma patterns are similar in East Asian populations. Methods The patients' medical records were reviewed retrospectively, and we analyzed the relationship of epidemiological characteristics to staging and survival rate. Additionally, papers from Hong Kong and Japan describing these phenomena in East Asian populations were subjected to a statistical comparison. Results The ratio of males to females was 1:1.8, and the foot was the most frequent tumor site (49%). Acral lentiginous melanoma occurred most frequently (55%). Nodular melanoma was associated with a higher stage. Stage III-IV tumors with Clark levels of IV-V were significantly associated with a low survival rate. A statistical analysis of comparable papers reported in Hong Kong and Japan showed similar results with regard to age, tumor location, and histopathological subtypes. Conclusions This study provides the first full epidemiological description of 100 consecutive cases of primary cutaneous melanoma in Korea, with results similar to those observed in other East Asian populations. Corresponding to previous findings, nodular melanoma tended to occur at a higher stage than other types, and tumors with high Clark levels and high stages showed a lower survival rate. PMID:26618123

  9. Nivolumab: A Review in Advanced Melanoma.

    PubMed

    Scott, Lesley J

    2015-08-01

    An improved understanding of cancer genetics and immune regulatory pathways, including those associated with evasion of immune surveillance by tumours, has culminated in the development of several targeted therapies. One such strategy that acts to negate evasion of immune surveillance by tumours is inhibition of the programmed cell death receptor-1 (PD-1) checkpoint pathway. Intravenous nivolumab (Opdivo(®)), a PD-1 checkpoint inhibitor, is approved or in pre-registration in various countries for use in adult patients with advanced melanoma, with the recommended monotherapy dosage being a 60-min infusion of 3 mg/kg once every 2 weeks. In well-designed multinational trials, as monotherapy or in combination with ipilimumab (a cytotoxic T-lymphocyte antigen 4 checkpoint inhibitor), nivolumab significantly improved clinical outcomes and had a manageable tolerability profile in adult patients with advanced melanoma with or without BRAF mutations. Nivolumab monotherapy was associated with a higher objective response rate (ORR) than chemotherapy in treatment-experienced patients and a higher ORR and prolonged progression-free survival (PFS) and overall survival than dacarbazine in treatment-naive patients. In combination with ipilimumab, nivolumab was associated with an improved ORR and prolonged PFS compared with ipilimumab monotherapy in treatment-naive patients. In addition, nivolumab monotherapy significantly prolonged PFS and improved ORRs compared with ipilimumab monotherapy. The optimal combination regimen for immune checkpoint inhibitors remains to be fully elucidated, with various combination regimens and different sequences of individual immunotherapies currently being investigated in ongoing clinical trials. Given the significant improvements in outcomes associated with nivolumab in clinical trials, nivolumab monotherapy or combination therapy is a valuable first-line or subsequent treatment option for adult patients with unresectable or metastatic melanoma

  10. Importance of glycolysis and oxidative phosphorylation in advanced melanoma

    PubMed Central

    2012-01-01

    Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy. PMID:23043612

  11. Altered Splicing of JARID1B in Development of Human Cutaneous Melanoma?

    PubMed

    Kuźbicki, Łukasz; Lange, Dariusz; Strączyńska-Niemiec, Anita; Chwirot, Barbara W

    2016-03-01

    Upregulated expression of histone H3K4 demethylase JARID1B has been found in several types of human cancer, but the expression pattern of this protein in benign naevi and human cutaneous melanomas seems to differ from that described for other tumors. We demonstrate that the apparent contradiction may be because of the fact that the malignant transformation of melanocytes is associated not so much with a general enhancement of a total expression of JARID1B but rather with a change in relative expression levels of individual splicing variants of the protein. Our data indicate that parallel immunohistochemical assays of the expression levels of all the isoforms and of the RBP2-H1 variant of JARID1B may be an efficient technique of differentiating between benign naevi and melanomas. PMID:25789538

  12. Quantifying lifetime exposure to ultraviolet radiation in the epidemiology of cutaneous malignant melanoma: A pilot study

    SciTech Connect

    Lea, C.S.; Selvin, S. . Dept. of Biomedical and Environmental Health Sciences Lawrence Berkeley Lab., CA ); Buffler, P.A. . Dept. of Biomedical and Environmental Health Sciences); Scotto, J. . Biostatistics Branch); Berwick, M. (Cancer Pre

    1992-10-01

    This pilot study uses a unique method to calculate cumulative lifetime exposure to, ultraviolet radiation-b to determine if this refined method would indicate differences in lifetime cumulative UVB exposure between age and sex matched controls. Forty-four age and sex matched cases and controls demonstrated no significant difference in mean cumulative lifetime UVB exposure based on the duration and location of residence. This pilot study suggests that further analysis of the dataset should be conducted to determine if the cumulative lifetime exposure hypothesis is of primary importance regarding the association between UVB exposure and development of cutaneous malignant melanoma.

  13. Could a specific dietary intake be a risk factor for cutaneous melanoma?

    PubMed

    Hohmann, Clarissa B; Bonamigo, Renan R; Segatto, Majoriê M; Costa, Manuela M; Mastroeni, Simona; Fortes, Cristina

    2016-06-01

    The incidence of cutaneous melanoma (CM) has increased in the last decade. Some risk factors are well known, but there are other possible risk factors being studied, such as those involving nutrition. The objective of this case-control study was to assess the association between diet and CM. Classical risk factors, dietary intake, and body mass index were assessed. Binary logistic regression was used to study the association between dietary intake and the risk for CM. Classical risk factors associated with CM were confirmed. The findings suggest that some foods rich in vitamins A and D and phytochemicals may be related to CM. PMID:27416086

  14. Quality-of-life evaluation in an interferon therapy after radical surgery in cutaneous melanoma patients.

    PubMed

    Rataj, Dorota; Jankowiak, Barbara; Krajewska-Kułak, Elzbieta; Van Damme-Ostapowicz, Katarzyna; Nowecki, Zbigniew I; Rutkowski, Piotr; Niczyporuk, Wiaczesław

    2005-01-01

    Melanoma is the fastest growing solid tumor in men and women, and despite accounting for only 4% of skin cancer cases, it accounts for more than 79% of skin cancer-related deaths. The present study was designed to evaluate the impact of interferon (IFN) treatment on patients' quality of life (QOL) after radical surgery of cutaneous melanoma. The tests were carried out in a group of patients treated in the Department of Soft Tissue and Bone Cancer, Institute of Oncology, in Warsaw. The present study included 2 groups of the patients, 110 persons each. One group consisted of patients who had been subjected to radical surgery of cutaneous melanoma, and the other one consisted of 110 patients treated with a supplementary interferon alfa-2b (IFN-alpha-2b) therapy. Data were collected by means of an anonymous QLQ-C30 (version 2.0.) questionnaire elaborated and provided by the European Organisation for Research and Treatment of Cancer. The QLQ-C30 questionnaire consisted of 43 questions. The IFN-alpha-2b treatment significantly affected patients' physical condition, mental health, and social life. The emotional state of the patients was more affected during IFN-alpha-2b treatment. Somatic symptoms were also increased in those patients. The IFN-alpha-2b therapy also significantly affected family and social life. In spite of several adverse effects, the patients assessed their QOL as good. The IFN-alpha-2b treatment is troublesome for the melanoma patients. It is important that the treating physician and nurse should be aware of the 4 major categories of IFN-alpha-2b toxicity: constitutional, neuropsychiatric, hepatic, and hematologic. A number of steps can be taken to minimize the morbidity associated with IFN-alpha-2b therapy, resulting in an improvement in both QOL and patient compliance. PMID:15915059

  15. Microtubule-Associated Protein 2, a Marker of Neuronal Differentiation, Induces Mitotic Defects, Inhibits Growth of Melanoma Cells, and Predicts Metastatic Potential of Cutaneous Melanoma

    PubMed Central

    Soltani, Mohammad H.; Pichardo, Rita; Song, Ziqui; Sangha, Namrata; Camacho, Fabian; Satyamoorthy, Kapaettu; Sangueza, Omar P.; Setaluri, Vijayasaradhi

    2005-01-01

    Dynamic instability of microtubules is critical for mitotic spindle assembly and disassembly during cell division, especially in rapidly dividing tumor cells. Microtubule-associated proteins (MAPs) are a family of proteins that influence this property. We showed previously that MAP2, a neuron-specific protein that stabilizes microtubules in the dendrites of postmitotic neurons, is induced in primary cutaneous melanoma but is absent in metastatic melanomas. We proposed that induction of a microtubule-stabilizing protein in primary melanoma could disrupt the dynamic instability of microtubules, inhibit cell division and prevent or delay tumor progression. Here we show, by Kaplan-Meier survival and multivariate Cox regression analysis, that patients diagnosed with MAP2+ primary melanomas have significantly better metastatic disease-free survival than those with MAP2− disease. Investigation of the mechanisms that underlie the effect of MAP2 on melanoma progression showed that MAP2 expression in metastatic melanoma cell lines leads to microtubule stabilization, cell cycle arrest in G2-M phase and growth inhibition. Disruption of microtubule dynamics by MAP2 resulted in multipolar mitotic spindles, defects in cytokinesis and accumulation of cells with large nuclei, similar to those seen in vivo in MAP2+ primary melanomas cells. These data suggest that ectopic activation of a neuronal differentiation gene in melanoma during early tumor progression inhibits cell division and correlates with inhibition or delay of metastasis. PMID:15920168

  16. Hypothesis: Is frequent, commercial jet travel by the general public a risk factor for developing cutaneous melanoma?

    PubMed Central

    Arbesman, Harvey

    2015-01-01

    Melanoma incidence has been increasing worldwide over the past 50 years and various risk factors have been identified. Interestingly, multiple studies have shown a multifold increased risk of developing melanoma in jet pilots and airline crew. There has also been a dramatic increase in the availability and frequency of jet travel by the general population during this time period.. Therefore, it is hypothesized that frequent commercial jet travel may represent an additional risk factor for the development of cutaneous melanoma in susceptible individuals of the general public. PMID:26672515

  17. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis

    PubMed Central

    Autier, Philippe; Boyle, Peter; Gandini, Sara

    2012-01-01

    Objective To estimate the burden of melanoma resulting from sunbed use in western Europe. Design Systematic review and meta-analysis. Data sources PubMed, ISI Web of Science (Science Citation Index Expanded), Embase, Pascal, Cochrane Library, LILACS, and MedCarib, along with published surveys reporting prevalence of sunbed use at national level in Europe. Study selection Observational studies reporting a measure of risk for skin cancer (cutaneous melanoma, squamous cell carcinoma, basal cell carcinoma) associated with ever use of sunbeds. Results Based on 27 studies ever use of sunbeds was associated with a summary relative risk of 1.20 (95% confidence interval 1.08 to 1.34). Publication bias was not evident. Restricting the analysis to cohorts and population based studies, the summary relative risk was 1.25 (1.09 to 1.43). Calculations for dose-response showed a 1.8% (95% confidence interval 0% to 3.8%) increase in risk of melanoma for each additional session of sunbed use per year. Based on 13 informative studies, first use of sunbeds before age 35 years was associated with a summary relative risk of 1.87 (1.41 to 2.48), with no indication of heterogeneity between studies. By using prevalence data from surveys and data from GLOBOCAN 2008, in 2008 in the 15 original member countries of the European Community plus three countries that were members of the European Free Trade Association, an estimated 3438 cases of melanoma could be attributable to sunbed use, most (n=2341) occurring among women. Conclusions Sunbed use is associated with a significant increase in risk of melanoma. This risk increases with number of sunbed sessions and with initial usage at a young age (<35 years). The cancerous damage associated with sunbed use is substantial and could be avoided by strict regulations. PMID:22833605

  18. Primary advanced esophago-gastric melanoma: A rare case

    PubMed Central

    Wang, Lin; Zong, Liang; Nakazato, Hidetsugu; Wang, Wen-Yue; Li, Chao-Feng; Shi, Yan-Fen; Zhang, Guo-Chao; Tang, Tao

    2016-01-01

    Primary esophageal or gastric melanoma is a very rare disease with early metastasis. Due to its atypical symptom and less efficiency of chemotherapy and radiotherapy, the prognosis of esophageal or gastric melanoma is still very poor. Surgical resection remains the preferential treatment for esophageal or gastric melanoma. Here we present an extremely rare case of primary advanced esophago-gastric melanoma. Debulking surgery was performed without chemotherapy or radiotherapy. However, abdominal recurrence and hepatic metastases were found within one month by a postoperative follow-up computed tomography. Three and a half months after surgical resection, the patient died of extensive abdominal metastasis. PMID:27004009

  19. Guidelines of the Brazilian Dermatology Society for diagnosis, treatment and follow up of primary cutaneous melanoma - Part I*

    PubMed Central

    Castro, Luiz Guilherme Martins; Messina, Maria Cristina; Loureiro, Walter; Macarenco, Ricardo Silvestre; Duprat Neto, João Pedreira; Giacomo, Thais Helena Bello Di; Bittencourt, Flávia Vasques; Bakos, Renato Marchiori; Serpa, Sérgio Schrader; Stolf, Hamilton Ometto; Gontijo, Gabriel

    2015-01-01

    The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In the first part, the following clinical questions were answered: 1) The use of dermoscopy for diagnosis of primary cutaneous melanoma brings benefits for patients when compared with clinical examination? 2) Does dermoscopy favor diagnosis of nail apparatus melanoma? 3) Is there a prognostic difference when incisional or excisional biopsies are used? 4) Does revision by a pathologist trained in melanoma contribute to diagnosis and treatment of primary cutaneous melanoma? What margins should be used to treat lentigo maligna melanoma and melanoma in situ? PMID:26734867

  20. BRAF Inhibitor-Induced Antitumoral Granulomatous Dermatitis Eruption in Advanced Melanoma.

    PubMed

    Garrido, Maria C; Gutierrez, Carlota; Riveiro-Falkenbach, Erica; Ortiz, Pablo; Rodriguez-Peralto, Jose L

    2015-10-01

    Recent advances in targeting BRAF mutations, which occur in roughly 50% of the melanomas, have improved response rates and overall survival in patients with advanced disease. With the increasingly extensive use of the drug, new, nonpreventable, cutaneous and noncutaneous toxicities keep arising as infrequent adverse effects. We report a 55-year-old man with a history of metastatic melanoma treated with the dabrafenib who presented, 10 months after the initiation of the treatment, with erythematous, slightly squamous, round plaques on his upper trunk and on his left upper arm. Two skin biopsies from the lesions revealed a granulomatous dermatitis in the superficial reticular dermis. One of them showed admixed abundant melanophages from tumoral melanosis. No melanoma cells were seen in any of the specimens. No interruption of the treatment was necessary. Our observation indicates that such a response may represent a positive immune activation triggered by BRAF inhibitors. The erythematous rash was initially concerning for progression of metastatic disease, which suggests that a close monitoring of the patients with advanced melanomas treated with vemurafenib is advisable to prevent unnecessary discontinuation of the therapy. PMID:26381028

  1. New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances.

    PubMed

    Flaherty, Keith T; Fisher, David E

    2011-08-01

    The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. PMID:21670085

  2. First application of dynamic infrared imaging in boron neutron capture therapy for cutaneous malignant melanoma

    SciTech Connect

    Santa Cruz, G. A.; Gonzalez, S. J.; Bertotti, J.; Marin, J.

    2009-10-15

    Purpose: The purpose of this study is to assess the potential of dynamic infrared imaging (DIRI) as a functional, noninvasive technique for evaluating the skin acute toxicity and tumor control within the framework of the Argentine boron neutron capture therapy (BNCT) program for cutaneous malignant melanoma. Methods: Two patients enrolled in the Argentine phase I/II BNCT clinical trial for cutaneous malignant melanoma were studied with DIRI. An uncooled infrared camera, providing a video output signal, was employed to register the temperature evolution of the normal skin and tumor regions in patients subjected to a mild local cooling (cold stimulus). In order to study the spatial correlation between dose and acute skin reactions, three-dimensional representations of the superficial dose delivered to skin were constructed and cameralike projections of the dose distribution were coregistered with visible and infrared images. Results: The main erythematous reaction was observed clinically between the second and fifth week post-BNCT. Concurrently, with its clinical onset, a reactive increase above the basal skin temperature was observed with DIRI in the third week post-BNCT within regions that received therapeutic doses. Melanoma nodules appeared as highly localized hyperthermic regions. 2 min after stimulus, these regions reached a temperature plateau and increased in size. Temperature differences with respect to normal skin up to 10 deg. C were observed in the larger nodules. Conclusions: Preliminary results suggest that DIRI, enhanced by the application of cold stimuli, may provide useful functional information associated with the metabolism and vasculature of tumors and inflammatory processes related to radiation-induced changes in the skin as well. These capabilities are aimed at complementing the clinical observations and standard imaging techniques, such as CT and Doppler ultrasound.

  3. Loss of MiR-664 Expression Enhances Cutaneous Malignant Melanoma Proliferation by Upregulating PLP2

    PubMed Central

    Ding, Zhenhua; Jian, Sun; Peng, Xuebiao; Liu, Yimin; Wang, Jianyu; Zheng, Li; Ou, Chengshan; Wang, Yinghui; Zeng, Weixia; Zhou, Meijuan

    2015-01-01

    Abstract Proteolipid protein 2 (PLP2) has been shown to be upregulated in several cancers, including breast cancer, hepatocellular carcinoma, osteosarcoma, and melanoma. PLP2 specifically binds to phosphatidylinositol 3 kinase to activate the protein kinase B pathway to enhance cell proliferation, adhesion, and invasion in melanoma cells. Therefore, we speculated that PLP2 exhibits oncogenic potential. However, the regulatory mechanisms of PLP2 in cancer cells remain unclear. Herein, we found that microRNA (miR)-664 expression was significantly downregulated in cutaneous malignant melanoma (CMM) cells and tissues compared with normal human melanocytes and benign melanocytic naevi. MiR-664 expression level was significantly correlated with patient survival. Ectopic expression of miR-664 reduced CMM cell proliferation and anchorage-independent growth, whereas the inhibition of miR-664 induced these effects. Furthermore, inhibition of miR-664 in CMM cells resulted in modulation of their entry into the G1/S transitional phase, which was caused by downregulation of the cyclin-dependent kinase inhibitor P21 and upregulation of the cell-cycle regulator cyclin D1. Moreover, we demonstrated that miR-664 downregulated PLP2 expression by directly targeting the PLP2 untranslated region. Taken together, our results suggest that miR-664 may play an important role in suppressing proliferation of CMM cells and present a novel mechanism of miR-mediated direct suppression of PLP2 expression in cancer cells. PMID:26287415

  4. Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

    PubMed Central

    2010-01-01

    Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects. PMID:20540720

  5. BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor and the degree of solar elastosis at the primary tumor site

    PubMed Central

    Bauer, Jürgen; Büttner, Petra; Murali, Rajmohan; Okamoto, Ichiro; Kolaitis, Nicholas A; Landi, Maria Teresa; Scolyer, Richard A.; Bastian, Boris C.

    2011-01-01

    SUMMARY Oncogenic BRAF mutations are more frequent in cutaneous melanoma from sites with little or moderate sun-induced damage than from sites with severe cumulative solar ultraviolet (UV) damage. We studied cutaneous melanomas from geographic regions with different levels of ambient UV radiation to delineate the relative effects of cumulative UV damage, age and anatomic site on the frequency of BRAF mutations. We show that BRAF-mutated melanomas occur in a younger age group on skin without marked solar elastosis, and less frequently affect the head and neck area, compared to melanomas without BRAF mutations. The findings indicate that BRAF-mutated melanomas arise early in life at low cumulative UV doses, whereas melanomas without BRAF mutations require accumulation of high UV doses over time. The effect of anatomic site on the mutation spectrum further suggests regional differences among cutaneous melanocytes. PMID:21324100

  6. Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma.

    PubMed

    Storr, Sarah J; Safuan, Sabreena; Mitra, Angana; Elliott, Faye; Walker, Christopher; Vasko, Mark J; Ho, Bernard; Cook, Martin; Mohammed, Rabab A A; Patel, Poulam M; Ellis, Ian O; Newton-Bishop, Julia A; Martin, Stewart G

    2012-04-01

    The aims of this study were to investigate the role of vascular invasion (blood and lymphatic), vessel density and the presence of tumour-associated macrophages as prognostic markers in 202 cutaneous melanoma patients. Sections of primary melanoma were stained with lymphatic-specific antibody D2-40 to assess lymphatic vessel invasion and density in intratumoural and peritumoural areas; an antibody against endothelial marker CD34 was used to determine blood vessel invasion and density, and an antibody against CD68 was used to determine macrophage counts. Immunohistochemically determined vascular invasion (combined blood and lymphatic) was compared with that determined using haematoxylin and eosin (H&E) staining. The use of immunohistochemistry increased detection of vascular invasion from 8-30% of patients, and histological exam of H&E-stained tissue was associated with a false positive rate of 64%. Lymphatic vessel invasion occurred at a much higher frequency than blood vessel invasion (27 and 4% of patients, respectively). Although immunohistochemically detected vessel invasion was significantly associated with histological markers of adverse prognosis, such as increased Breslow thickness, ulceration and mitotic rate (all P<0.001), no associations with relapse-free or overall survival were observed. High macrophage counts were significantly associated with markers of aggressive disease, such as Breslow thickness, ulceration and mitotic rate (P<0.001, P<0.001, P=0.005, respectively), and lymphatic vessel invasion and high microvessel density (P=0.002 and P=0.003, respectively). These results suggest that vascular invasion is more accurately detected using immunohistochemistry and occurs predominantly via lymphatic vessels. The association of vessel characteristics with histological characteristics of the primary melanoma provides evidence for their biological importance in melanoma, but that they were not associated with clinical outcome attests to the value of

  7. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

    PubMed

    Law, Matthew H; Bishop, D Timothy; Lee, Jeffrey E; Brossard, Myriam; Martin, Nicholas G; Moses, Eric K; Song, Fengju; Barrett, Jennifer H; Kumar, Rajiv; Easton, Douglas F; Pharoah, Paul D P; Swerdlow, Anthony J; Kypreou, Katerina P; Taylor, John C; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M; Dȩbniak, Tadeusz; Duffy, David L; Elder, David E; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M; Goldstein, Alisa M; Gruis, Nelleke A; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A; Chen, Wei V; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubiński, Jan; Mackie, Rona M; Mann, Graham J; Molven, Anders; Montgomery, Grant W; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A; Radford-Smith, Graham L; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C; Craig, Jamie E; Schadendorf, Dirk; Simms, Lisa A; Burdon, Kathryn P; Nyholt, Dale R; Pooley, Karen A; Orr, Nick; Stratigos, Alexander J; Cust, Anne E; Ward, Sarah V; Hayward, Nicholas K; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M; Bishop, Julia A Newton; Demenais, Florence; Amos, Christopher I; MacGregor, Stuart; Iles, Mark M

    2015-09-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology. PMID:26237428

  8. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

    PubMed Central

    Law, Matthew H.; Bishop, D. Timothy; Martin, Nicholas G.; Moses, Eric K.; Song, Fengju; Barrett, Jennifer H.; Kumar, Rajiv; Easton, Douglas F.; Pharoah, Paul D. P.; Swerdlow, Anthony J.; Kypreou, Katerina P.; Taylor, John C.; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Duffy, David L.; Elder, David E.; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Chen, Wei V.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Mann, Graham J.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A.; Radford-Smith, Graham L.; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; Craig, Jamie E.; Schadendorf, Dirk; Simms, Lisa A.; Burdon, Kathryn P.; Nyholt, Dale R.; Pooley, Karen A.; Orr, Nick; Stratigos, Alexander J.; Cust, Anne E.; Ward, Sarah V.; Hayward, Nicholas K.; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M.; Bishop, Julia A. Newton; MacGregor, Stuart; Iles, Mark M.

    2015-01-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10–8), as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes including one involved in telomere biology. PMID:26237428

  9. Epidemiological Profile of Patients with Cutaneous Melanoma in a Region of Southern Brazil

    PubMed Central

    Moreno, Marcelo; Schmitt, Ricardo Ludwig; Lang, Maria Gabriela; Gheno, Vanessa

    2012-01-01

    Cutaneous melanoma (CM) is responsible for 75% of deaths from malignant skin cancer. The incidence of CM in the southern region of Brazil, particularly in the western region of Santa Catarina, is possibly higher than estimated. In this study, the clinical and epidemiological profile of patients with CM treated in the western region of Santa Catarina was examined. A cross-sectional study was performed with patients diagnosed with CM from January 2002 to December 2009, from 78 counties of the western region of the state of Santa Catarina. Data were collected using a protocol adapted from the Brazilian Melanoma Group and 503 patients were evaluated. The incidence and prevalence of CM found in this region are much higher than those found elsewhere in the country. This fact is most likely due to the phenotypic characteristics of the population and the high incidence of UV radiation in this region due to its location in southern Brazil, as is the case in the countries of Oceania. PMID:22548178

  10. Desmoplastic melanoma: recent advances and persisting challenges.

    PubMed

    Wood, Benjamin A

    2013-08-01

    Desmoplastic melanoma is an uncommon variant of melanoma which presents significant challenges to the clinician and histopathologist. In particular, many cases show a bland 'fibroblastic' appearance, mimicking scar and a range of other benign proliferations. This diagnosis can be particularly problematic in small biopsy specimens, a difficulty exacerbated by an immunoprofile which is typically negative for a number of conventional melanocytic markers. The clinical and histological features of desmoplastic melanoma are reviewed, as are the differential diagnoses and some newer techniques which may contribute to assessment of these lesions. In recent years it has become clear that subclassification of desmoplastic melanoma into pure and mixed variants has clinical significance and it is suggested that this classification be employed in routine practice. PMID:23811805

  11. Vasculogenic mimicry has no prognostic significance in pT3 and pT4 cutaneous melanoma.

    PubMed

    Massi, Daniela; Franchi, Alessandro; Paglierani, Milena; Ketabchi, Sheyda; Borgognoni, Lorenzo; Reali, Umberto Maria; Santucci, Marco

    2004-04-01

    The concept of vasculogenic mimicry has been introduced to define periodic acid-Schiff (PAS)-positive channels and loops lined by tumor cells, instead of endothelium, able to contribute to microcirculation in uveal melanomas. Previous studies have shown that the PAS-positive patterns are associated with a poor prognosis in uveal melanoma. The aim of the current study was to investigate whether vasculogenic mimicry has a prognostic impact in pT3 and pT4 cutaneous melanoma. Fifteen patients with pT3 and pT4 cutaneous melanoma who did not experience progression after 10 years of follow-up and 30 matched controls who underwent progression were selected. Tumor sections were stained with PAS reaction, omitting the nuclear counterstaining. For immunohistochemistry, sections were stained with CD31, CD105 (endoglin), and laminin. Differences in the distribution of the PAS-positive patterns and a series of clinicopathological variables were evaluated by the Pearson chi(2) and Mann-Whitney U tests. We observed PAS-positive linear sheets, arcs, elliptical loops, and networks encircling roundish to oval aggregates of melanoma cells. The overall distribution of the PAS-positive patterns did not match with the blood microvessels' architecture as detected by immunohistochemical analysis. No statistically significant differences in the distribution of PAS-positive patterns were found between cases and controls. The presence of a parallel pattern correlated significantly with thickness (P = 0.04), whereas an inverse correlation was found with vessel area (P = 0.05). In conclusion, our results suggest that there is a mismatch between vasculogenic mimicry and tumor angiogenesis and do not support any prognostic role of vasculogenic mimicry in thick cutaneous melanoma. PMID:15116332

  12. Aquaporin 1 protein expression is associated with BRAF V600 mutation and adverse prognosis in cutaneous melanoma.

    PubMed

    Imrédi, Eleonóra; Tóth, Béla; Doma, Viktória; Barbai, Tamás; Rásó, Erzsébet; Kenessey, István; Tímár, József

    2016-06-01

    Despite experimental findings suggesting the prognostic significance of Aquaporin 1 (AQP1) in human melanoma, no published clinical data are available. We studied the expression of AQP1 protein in cutaneous melanoma, correlated our findings with standard histological and genetic markers, and long-term clinical follow-up. Our study evaluated the AQP1 protein expression in 78 melanoma patients, representing two predefined risk cohorts using the immune labeling technique with commercially available anti-AQP1 antibodies on routinely formalin-fixed and paraffin-embedded tumor tissue samples. BRAF V600E mutation analyses were carried out successfully in 70 patients using PCR and restriction fragment length polymorphism analyses, followed by confirmatory analysis with the Sanger sequencing technique. AQP1-expressing melanoma cells were found in 52 cases (66.7%, median H-score=124.24). Significantly higher AQP1 H-scores (P=0.047) were found in the 'high-risk' patients. No correlations were found with the established histological markers, such as mitotic index (P=0.42), Clark level (P=0.95), and Breslow thickness (P=0.51). BRAF V600 mutation analyses were successful in 89%, and showed a two times higher mutation frequency in the 'high-risk' group. The BRAF V600 mutations were significantly associated with AQP1 expression (P=0.014). Long-term follow-up indicated a reduced progression-free survival (P=0.036) and overall survival (P=0.017) for the AQP1-positive cutaneous melanoma patients. AQP1 expression is likely to be associated with an adverse prognosis in cutaneous melanoma. PMID:26848795

  13. Cutaneous malignant melanoma show geographic and socioeconomic disparities in stage at diagnosis and excess mortality.

    PubMed

    Strömberg, Ulf; Peterson, Stefan; Holmberg, Erik; Holmén, Anders; Persson, Bertil; Sandberg, Carin; Nilbert, Mef

    2016-08-01

    Background Preventive measures are needed to counteract the increasing burden of cutaneous malignant melanoma (CMM). As a basis for rational melanoma prevention, we investigated geographic differences and impact from socioeconomic factors related to incidence, clinical stage at diagnosis and outcome. Material and methods All patients with primary invasive CMM diagnosed in 2004-2013 in the southern and the western Swedish health care regions with a population of 2.9 million adults were eligible for the study. Population-based data were obtained from the national Cancer Register and the national Melanoma Quality Register. Geographic and socioeconomic differences in incidence per stage at diagnosis were mapped and correlated to excess mortality. Results Disease mapping based on 9743 cases in 99 municipalities and 20 metropolitan districts showed marked, regional disparities in stage-specific incidence of CMM. The incidence of stage I-II tumors was higher in the western health care region, whereas the incidence of stage III-IV CMMs was higher in the southern region. The divergent incidence patterns per stage at diagnosis were consistent across population strata based on educational level. The geographic disparities in CMM stage influenced relative survival with an excess five-year mortality ratio in the southern region versus the western region of 1.49 (95% confidence interval 1.22-1.82). The excess mortality ratio for patients with low versus high educational level was 1.81 (1.37-2.40). Conclusion Residential region and educational level influenced CMM stage and, thereby, excess mortality. These observations suggest that geographic as well as socioeconomic data should be considered in prevention of CMM. PMID:26935355

  14. Activity of the MEK Inhibitor Trametinib (GSK1120212) in Advanced Melanoma in a Phase I, Dose-escalation Trial

    PubMed Central

    Falchook, Gerald S; Lewis, Karl D; Infante, Jeffrey R; Gordon, Michael S; Vogelzang, Nicholas J; DeMarini, Douglas J; Sun, Peng; Moy, Christopher; Szabo, Stephen A.; Roadcap, Lori T; Peddareddigari, Vijay G R; Lebowitz, Peter F; Le, Ngocdiep T; Burris, Howard A; Messersmith, Wells A; O'Dwyer, Peter J; Kim, Kevin B.; Flaherty, Keith; Bendell, Johanna C.; Gonzalez, Rene; Kurzrock, Razelle; Fecher, Leslie A

    2014-01-01

    Summary Purpose The mitogen-activated extracellular signal-related kinase kinase (MEK) is a member of the RAS/RAF/MEK/ERK signalling cascade, which is commonly activated in melanoma. Direct inhibition of MEK inhibits ERK signalling. Methods We conducted a multicentre, first-in-human, three-part study (dose escalation, cohort expansion, and pharmacodynamic evaluation) to evaluate the oral small-molecule MEK inhibitor trametininb (GSK1120212) in advanced cancer. Intermittent and continuous dosing regimens were evaluated. Safety and efficacy data in patients with melanoma are presented here, with exploratory analyses of available tumour tissues performed on an Illumina genotyping platform. This completed study is registered with ClinicalTrials.gov, number NCT00687622. Findings Ninety-seven melanoma patients, including 81 with cutaneous or unknown primary melanoma (36 BRAF-mutant, 39 BRAF wild-type, six BRAF status unknown) and 16 uveal melanoma patients were enrolled. The most common treatment-related adverse events were rash/dermatitis acneiform (80 out of 97; 82%) and diarrhoea (n=44; 45%), most of which were grade 2 or lower. No cutaneous squamous cell carcinomas were observed. Among the 36 BRAF-mutant patients, 30 were BRAF-inhibitor naïve. Among these 30 patients, 2 complete responses (CRs) and 10 partial responses (PRs) were observed (unconfirmed response rate=40%) including 2 confirmed CRs and 8 confirmed PRs (confirmed response rate=33%); the median progression-free survival was 5·7 months (95% CI, 4·0–7·4). Among the 6 BRAF-mutant patients who received prior BRAF inhibitor therapy, 1 unconfirmed PR was observed. Among 39 patients with BRAF wild-type melanoma, 4 PRs (all confirmed) were observed (confirmed response rate=10%). Conclusions To our knowledge, this is the first demonstration of substantial clinical activity by a MEK inhibitor in melanoma. These data suggest that MEK is a valid therapeutic target. PMID:22805292

  15. Melanoma

    MedlinePlus

    Melanoma is the most serious type of skin cancer. Often the first sign of melanoma is a change in the size, shape, color, or feel of a mole. Most melanomas have a black or black-blue area. Melanoma ...

  16. Advances in noninvasive imaging of melanoma.

    PubMed

    Menge, Tyler D; Pellacani, Giovanni

    2016-03-01

    Melanoma is the most dangerous type of skin cancer and its incidence has risen sharply in recent decades. Early detection of disease is critical for improving patient outcomes. Any pigmented lesion that is clinically concerning must be removed by biopsy for morphologic investigation on histology. However, biopsies are invasive and can cause significant morbidity, and their accuracy in detecting melanoma may be limited by sampling error. The advent of noninvasive imaging devices has allowed for assessment of intact skin, thereby minimizing the need for biopsy; and these technologies are increasingly being used in the diagnosis and management of melanoma. Reflectance confocal microscopy, optical coherence tomography, ultrasonography, and multispectral imaging are noninvasive imaging techniques that have emerged as diagnostic aids to physical exam and/or conventional dermoscopy. This review summarizes the current knowledge about these techniques and discusses their practical applications and limitations. PMID:26963113

  17. Immunotherapy of metastatic melanoma by reversal of immune suppression

    SciTech Connect

    Biggs, M.W.; Eiselein, J.E.

    1997-01-01

    Beginning with the observation that the human enteorvirus, Poliovirus Sabin 1, will lyse human melanoma cells in culture, clinical trials involving two patients with advance melanoma were performed. Parenteral injection of the viable Poliovirus into cutaneous melanoma metastases followed in 24 hours by oral administration of cyclophosphamide. The results of these two trials are described.

  18. Total skin self-examination at home for people treated for cutaneous melanoma: development and pilot of a digital intervention

    PubMed Central

    Murchie, Peter; Allan, Julia L; Brant, William; Dennis, Matthew; Hall, Susan; Masthoff, Judith; Walter, Fiona M; Johnston, Marie

    2015-01-01

    Objectives To develop a digital intervention to prompt, support, and respond to the outcomes of total skin self-examinations (TSSEs) at home by people treated for cutaneous melanoma. Design A complex intervention development study. Setting Northeast Scotland. Participants Semistructured scoping interviews; people previously treated for cutaneous melanoma (n=21). Pilot testing: people treated for melanoma stages 0–2C (n=20); general practitioners (n=6); and a nurse specialist in dermatology (n=1). Intervention A tablet-based digital intervention designed to prompt and support TSSEs comprising instructional videos and electronic reporting (including photographs) to a clinical nurse specialist in dermatology, with subsequent clinical triage. Primary and secondary outcome measures Qualitative assessment of intervention feasibility and acceptability, and quantitative assessment of intentions and confidence to perform TSSEs in pilot participants. Results The majority of pilot participants were strongly positive and adhered well to the intervention (n=15), with 7 of these reporting symptoms of concern at some point during the 6-month pilot. 4 patients complied intermittently, 3 reporting skin problems at least once during the pilot, and 1 withdrew. 2 patients underwent skin surgery as a result of participating in the pilot, with 1 diagnosed as having a recurrent melanoma and the other, a benign lesion. A number of practical issues to improve the usability of the intervention were identified. The proportion of participants reporting intention to check their skin at least monthly increased during the intervention as did confidence to conduct a skin check. Conclusions People previously treated for cutaneous melanoma are prepared to use digital technology to support them in conducting TSSE. An intervention has been developed which is practical, effective and safe, and after addressing minor practical issues, could now be evaluated for clinical outcomes in a randomised

  19. Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT.

    PubMed

    Daniotti, Maria; Ferrari, Andrea; Frigerio, Simona; Casieri, Paola; Miselli, Francesca; Zucca, Elisa; Collini, Paola; Della Torre, Gabriella; Manoukian, Siranoush; Peissel, Bernard; Bono, Aldo; Santinami, Mario; Parmiani, Giorgio; Rivoltini, Licia; Pilotti, Silvana; Rodolfo, Monica

    2009-07-01

    Childhood cutaneous melanoma is a rare disease with increasing incidence. It is not clear whether it differs from adult melanoma in etiology and clinical evolution. To genetically characterize childhood melanoma, 21 pediatric patients were studied by germ-line analysis of CDKN2A, CDK4, and MC1R genes. In addition, alterations in CDKN2A, c-Kit, BRAF, and NRAS genes were evaluated at the somatic level by direct gene sequencing, fluorescence in situ hybridization analysis, and immunohistochemistry. As a control group of susceptible patients, we studied patients from 23 melanoma-prone families. At the germ-line level, CDKN2A and MC1R gene variants were detected in 2/21 and 12/21 pediatric patients and in 9/23 and 19/22 in familial patients. At the somatic level, most lesions (9/14) from pediatric patients showed CDKN2A locus homozygous deletions and a null p16 immunophenotype, whereas most lesions (5/8) from familial patients were disomic and immunoreactive. A c-Kit low-polysomy profile seems to parallel CDKN2A homozygous deletions in pediatric melanoma whereas the single activating mutation observed segregates with familial patients. Loss of KIT protein expression was frequent (7/14) in pediatric melanomas, where metastatic cases were prevalent. BRAF(V600E) mutation occurred at a similar rate (approximately 50%) in lesions from pediatric and familial patients, whereas no NRAS mutations were detected. PMID:19158841

  20. B-Mode Ultrasound Imaging, Doppler Imaging, and Real-Time Elastography in Cutaneous Malignant Melanoma and Lymph Node Metastases

    PubMed Central

    Uematsu, Takayoshi; Kasami, Masako; Kiyohara, Yoshio

    2013-01-01

    Examination by ultrasonography (US) is a rapid, sensitive, cost-effective, and even portable technique for confirming the presence of tumors. However, US is not routinely used worldwide for the diagnostic work-up of cutaneous malignant melanoma. High-resolution US using a 6–14 MHz or 5–13 MHz linear transducer enables the preoperative assessment of tumor size and thickness. Compared with physical examination, US is also very effective in the early detection of lymph node metastases. It can be easily repeated for the follow-up of cutaneous malignant melanoma and lymph node metastases. Ultrasonographic appearance of some lymph nodes may overlap, thus producing diagnostic pitfalls. In such cases with overlapping findings, Doppler imaging and elastography may additionally facilitate the evaluation of cutaneous malignant melanoma and lymph node metastases. US-guided fine needle aspiration cytology (FNAC) finally helps to confirm ultrasonographic results, thus improving the specificity and sensitivity in difficult situations in which US alone gives unclear results in lymph node assessment.

  1. Dabrafenib Plus Trametinib for Advanced Melanoma

    Cancer.gov

    A summary of results from two phase III trials show that patients with metastatic melanoma whose tumors have specific mutations in the BRAF gene lived longer following treatment with dabrafenib (Tafinlar®), a BRAF inhibitor, plus trametinib (Mekinist®), a

  2. Testing Adjuvant Ipilimumab in Advanced Melanoma

    Cancer.gov

    In this clinical trial, patients with stage III or stage IV melanoma that has been completely resected will be randomly assigned to receive post-surgical treatment with either ipilimumab or high-dose interferon alfa-2b, the current standard of care.

  3. Major Changes in Systemic Therapy for Advanced Melanoma.

    PubMed

    Thompson, John A

    2016-05-01

    Over the past 5 years, a host of new agents have radically changed the therapeutic landscape in advanced melanoma; gone are the days when the only active agents were interferon and dacarbazine. Nearly 25 years ago, few patients with stage IV melanoma reached 2-year survival; today, these survival curves have risen substantially. At the NCCN 21st Annual Conference, John A. Thompson, MD, discussed updates with longer duration of patient follow-up for immune checkpoint therapies. He also reviewed some of the newer approvals in advanced melanoma, including the combination of ipilimumab and nivolumab, high-dose ipilimumab, the oncolytic virus therapy talimogene laherparepvec, and the molecularly targeted combination of the BRAF and MEK inhibitors vemurafenib and cobimetinib. PMID:27226502

  4. Comprehensive Genomic Characterization of Cutaneous Malignant Melanoma Cell Lines Derived from Metastatic Lesions by Whole-Exome Sequencing and SNP Array Profiling

    PubMed Central

    Cifola, Ingrid; Pietrelli, Alessandro; Consolandi, Clarissa; Severgnini, Marco; Mangano, Eleonora; Russo, Vincenzo; De Bellis, Gianluca; Battaglia, Cristina

    2013-01-01

    Cutaneous malignant melanoma is the most fatal skin cancer and although improved comprehension of its pathogenic pathways allowed to realize some effective molecular targeted therapies, novel targets and drugs are still needed. Aiming to add genetic information potentially useful for novel targets discovery, we performed an extensive genomic characterization by whole-exome sequencing and SNP array profiling of six cutaneous melanoma cell lines derived from metastatic patients. We obtained a total of 3,325 novel coding single nucleotide variants, including 2,172 non-synonymous variants. We catalogued the coding mutations according to Sanger COSMIC database and to a manually curated list including genes involved in melanoma pathways identified by mining recent literature. Besides confirming the presence of known melanoma driver mutations (BRAFV600E, NRASQ61R), we identified novel mutated genes involved in signalling pathways crucial for melanoma pathogenesis and already addressed by current targeted therapies (such as MAPK and glutamate pathways). We also identified mutations in four genes (MUC19, PAICS, RBMXL1, KIF23) never reported in melanoma, which might deserve further investigations. All data are available to the entire research community in our Melanoma Exome Database (at https://155.253.6.64/MExDB/). In summary, these cell lines are valuable biological tools to improve the genetic comprehension of this complex cancer disease and to study functional relevance of individual mutational events, and these findings could provide insights potentially useful for identification of novel therapeutic targets for cutaneous malignant melanoma. PMID:23704925

  5. New therapeutic options for advanced non-resectable malignant melanoma.

    PubMed

    Stadler, Simone; Weina, Kasia; Gebhardt, Christoffer; Utikal, Jochen

    2015-03-01

    Melanoma is a malignant tumor which is inclined to metastasize promptly into the lymphatic system and other organs such as lung, liver, brain or bone. Therefore early diagnosis remains crucial for improving clinical outcome for melanoma patients. Current chemotherapy and chemo-immunotherapy regimes have shown little clinical benefit with no improvement in overall survival. However, new advances in melanoma biology such as the discovery of predisposed gene signatures and key somatic events have changed clinical practice. New therapeutic approaches are being tested or have been approved by the FDA/EMA recently including targeted therapies, such as BRAF- and MEK-inhibitors, and novel immunotherapies, such as anti-CTLA4 or anti-PD1 therapies. For these therapies an improvement of progression-free and overall survival has been seen in patients with advanced non-resectable melanoma. The following review summarizes recent therapeutic options after the ASCO and ESMO annual meetings 2014 for the treatment of malignant melanoma. PMID:25596540

  6. Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune.

    PubMed

    van den Hurk, Karin; Niessen, Hanneke E C; Veeck, Jürgen; van den Oord, Joost J; van Steensel, Maurice A M; Zur Hausen, Axel; van Engeland, Manon; Winnepenninckx, Véronique J L

    2012-08-01

    Cutaneous malignant melanoma (CMM) is the most life-threatening neoplasm of the skin and is considered a major health problem as both incidence and mortality rates continue to rise. Once CMM has metastasized it becomes therapy-resistant and is an inevitably deadly disease. Understanding the molecular mechanisms that are involved in the initiation and progression of CMM is crucial for overcoming the commonly observed drug resistance as well as developing novel targeted treatment strategies. This molecular knowledge may further lead to the identification of clinically relevant biomarkers for early CMM detection, risk stratification, or prediction of response to therapy, altogether improving the clinical management of this disease. In this review we summarize the currently identified genetic and epigenetic alterations in CMM development. Although the genetic components underlying CMM are clearly emerging, a complete picture of the epigenetic alterations on DNA (DNA methylation), RNA (non-coding RNAs), and protein level (histone modifications, Polycomb group proteins, and chromatin remodeling) and the combinatorial interactions between these events is lacking. More detailed knowledge, however, is accumulating for genetic and epigenetic interactions in the aberrant regulation of the INK4b-ARF-INK4a and microphthalmia-associated transcription factor (MITF) loci. Importantly, we point out that it is this interplay of genetics and epigenetics that effectively leads to distorted gene expression patterns in CMM. PMID:22503822

  7. Whole Body Microwave Irradiation for Improved Dacarbazine Therapeutical Action in Cutaneous Melanoma Mouse Model

    PubMed Central

    Albulescu, Lucian; Iacob, Nicusor; Ighigeanu, Daniel

    2013-01-01

    A cutaneous melanoma mouse model was used to test the efficacy of a new therapeutical approach that uses low doses of cytostatics in conjunction with mild whole body microwave exposure of 2.45 GHz in order to enhance cytostatics antitumoral effect. Materials and Methods. A microwave exposure system for C57BL/6 mouse whole body microwave irradiation was designed; groups of 40 mice (males and females) bearing experimental tumours were subjected to a combined therapy comprising low doses of dacarbazine in combination with mild whole body irradiation. Clinical parameters and serum cytokine testing using xMAP technology were performed. Results. The group that was subjected to combined therapy, microwave and cytostatic, had the best clinical evolution in terms of overall survival, tumour volume, and metastatic potential. At day 14 the untreated group had 100% mortality, while in the combined therapy group 40% of mice were surviving. Quantifying serum IL-1β, IL-6, IL-10, IL-12 (p70), IFN-γ, GM-CSF, TNF-α, MIP-1α, MCP-1, and KC during tumorigenesis and therapy found that the combined experimental therapy decreases all the inflammatory cytokines, except chemokine MCP-1 that was found increased, suggesting an increase of the anti-tumoral immune response triggered by the combined therapy. The overall metastatic process is decreased in the combined therapy group. PMID:24377047

  8. BRAF and Epithelial-Mesenchymal Transition: Lessons From Papillary Thyroid Carcinoma and Primary Cutaneous Melanoma.

    PubMed

    Mitchell, Brendon; Dhingra, Jagdish K; Mahalingam, Meera

    2016-07-01

    The increased prevalence of BRAF mutations in thyroid carcinoma and primary cutaneous melanoma (PCM) hint that dysregulation of BRAF might contribute to the noted association between PCM and thyroid carcinoma. A recent study evaluating the rate of BRAFV600E mutations among patients who had been diagnosed with primary papillary thyroid carcinoma (PTC) and PCM showed that patients with either PCM or PTC were at an increased risk of developing the other as a second primary malignant neoplasm. Furthermore, the authors noted that samples from patients suffering from both malignancies exhibited a higher rate of incidence of the BRAFV600E mutation, compared with patients not suffering from both malignancies. These studies support the hypothesis that the pathogenesis of these 2 malignancies might share a conserved molecular pattern associated with dysregulation of the BRAF protein. One mechanism through which BRAF might contribute to PCM and thyroid carcinoma progression is through induction of epithelial-mesenchymal transition (EMT). Specifically, the Snail/E-cadherin axis has been demonstrated as a pathway dysregulated by BRAF, leading to EMT in both malignancies. Our analysis focuses on the results of these recent investigations, and through a review of select molecules relevant to EMT, looks to provide a context by which to better understand the relevance and role of stromal-parenchymal signaling and the BRAF mutation in the pathogenesis of PTC and PCM. PMID:27145091

  9. There's no such thing as a healthy glow: cutaneous malignant melanoma--the case against suntanning.

    PubMed

    McPhail, G

    1997-06-01

    One of the objectives of the 1992 United Kingdom Government White Paper 'Health of the Nation', is to reduce ill health and death caused by skin cancers by the year 2005. The Europe Against Cancer Programme shares those aims for the entire European population. Skin cancer was the first cancer demonstrated to have a chemical cause, with Percival Pott's 1775 description of squamous cell carcinoma of the scrotum induced by chimney soot, and skin cancers were also the first to be linked with ionising radiation. Currently there is a general consensus amongst researchers which acknowledges solar ultraviolet radiation as the major carcinogenic agent for the development of skin cancers. Changing attitudes and lifestyles affecting sun exposure is deemed responsible for the upward trends in incidence and mortality from skin cancers. The recognition of skin cancer as a preventable malignancy has implications for the health promotion role of nurses and of their multidisciplinary colleagues throughout Europe. This paper reviews the literature relating to sunlight as a risk factor for cutaneous malignant melanoma, and considers the behavioural issues which need to be addressed by healthcare professionals generally, and by nurses specifically, when establishing or participating in health promotion initiatives. PMID:9233166

  10. Checkpoint Blockade for the Treatment of Advanced Melanoma.

    PubMed

    Callahan, Margaret K; Flaherty, Catherine R; Postow, Michael A

    2016-01-01

    Immunotherapy with immune checkpoint inhibition has been improving the outcomes of patients with many different types of malignancies. Immune checkpoint inhibition has been most extensively studied in patients with advanced melanoma and there are three FDA approved antibodies already widely used in clinical practice (ipilimumab, nivolumab, and pembrolizumab). In this chapter, we review the mechanistic basis behind the development of immune checkpoint blocking antibodies. We then discuss specifics regarding each agent, unique clinical considerations in treating patients with this approach, and future directions, including combination strategies. This chapter is focused on melanoma, but the principles related to this immunotherapy approach are applicable to patients with many types of malignancies. PMID:26601865

  11. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines

    PubMed Central

    2012-01-01

    Background TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2. Methods The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733. Results Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays. Conclusions The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake. PMID:22515704

  12. Clinical utility of nivolumab in the treatment of advanced melanoma

    PubMed Central

    Asmar, Ramsey; Yang, Jessica; Carvajal, Richard D

    2016-01-01

    Melanomas are highly immunogenic tumors that evade the immune system by exploiting innate checkpoint pathways, rendering effector T-cells anergic. The immunotherapeutic approach of checkpoint inhibition can restore and invigorate endogenous antitumor T-cell responses and has become an important treatment option for patients with advanced melanoma. The CTLA-4 inhibitor ipilimumab and the PD-1 inhibitors nivolumab and pembrolizumab have been shown to induce durable responses and improve overall survival in metastatic, refractory melanoma. Optimization and validation of pretreatment biomarkers to predict response to these agents is a crucial area of ongoing research. Combination immunotherapy has recently demonstrated superior response rates compared to monotherapy; further investigation is needed to refine combinatorial strategies. PMID:27013881

  13. Immunotherapy for advanced melanoma: Current knowledge and future directions.

    PubMed

    Nakamura, Kenta; Okuyama, Ryuhei

    2016-08-01

    Melanoma is one of the most aggressive cancers and is responsible for a large proportion of skin cancer-related deaths. The recent development of novel immunotherapeutic approaches has led to great advances in melanoma therapy. Because melanoma cells often express tumor-specific neo-antigens, significant therapeutic effects are mediated via immunotherapy-induced activation of cytotoxic T lymphocytes (CTLs); however, the effects depend on the immune status of the patient. At present, various immunotherapies have been approved and new clinical trials are progressing. These immunotherapies act in several ways, including CTL brake release, induction of CTL activation, transfer of CTLs, and modification of the tumor microenvironment to facilitate CTL activation. In the near future, patient-tailored immunotherapies and combination therapies are expected. In addition, it is important to monitor the status of the patient's immune response when selecting the most effective immunotherapy strategy. PMID:27302423

  14. Spatial analysis of incidence of cutaneous melanoma in the Friuli Venezia Giulia region in the period 1995-2005.

    PubMed

    Cecconi, Lorenzo; Busolin, Anna; Barbone, Fabio; Serraino, Diego; Chiarugi, Alessandra; Biggeri, Annibale; Catelan, Dolores

    2016-01-01

    Incidence distribution of cutaneous melanoma depends on phenotypic characteristics of population and geographic location. In Italy, in the period 1999-2003 Friuli Venezia Giulia (FVG) region had the second highest incidence rates for males and the third for females. We analysed melanoma and lip cancer incidence data of the FVG cancer registry for the period 1995-2005. We used Bayesian hierarchical spatial models to describe the spatial pattern by gender. We decomposed the geographical distribution of the risk in two parts: a component linked to chronic exposure and a component related to intermittent exposure. In order to model the chronic component we considered the geographical distribution of incidence cases of lip cancer, for which chronic occupational solar radiation exposure is a documented risk factor. We also analysed the distribution by site and we calculated standardised rates for body surface area. This study documents a significant gradient in the incidence of cutaneous melanoma in FVG. Highstandardisedincidence rates are present in the area of Trieste and in the coastal area. The descriptive analysis by age group and by site, showed risks associated with intermittent exposures in both genders. For the coastal area the risk is especially high for sites traditionally linked to high cumulative exposures (face and neck), especially among men. The results suggest diagnostic preventive interventions in the populations living in the area of Trieste, given the high rates observed in the young age groups. PMID:27087039

  15. Regression of advanced melanoma upon withdrawal of immunosuppression: case series and literature review

    PubMed Central

    Thomas, N.; Sharpless, N.; Collichio, F.

    2013-01-01

    We report two cases of stage IV malignant melanoma arising in patients treated with azathioprine for myasthenia gravis. In both cases, the melanoma metastases regressed upon withdrawal of immunosuppression. One patient remains melanoma free at 10 years, and the second patient experienced an 18-month disease free period. There is one prior case report in the medical literature to support full immune reconstitution for treatment in advanced immunosuppression-related melanoma, and one case series suggesting that transplant patients developing melanoma may benefit from a switch to sirolimus. Virtually, no data exist for the medical management of early stage melanoma in the immunosuppressed patients. We review the limited preclinical data in support of immune reconstitution and the data on immunosuppression as a risk factor for melanoma. We conclude that reduction or withdrawal of immunosuppression may be beneficial in patients with advanced stage melanoma and warrants further consideration in patients with early stage melanoma. PMID:19890737

  16. Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma

    PubMed Central

    Oba, Junna; Wei, Wei; Gershenwald, Jeffrey E.; Johnson, Marcella M.; Wyatt, Cynthia M.; Ellerhorst, Julie A.; Grimm, Elizabeth A.

    2016-01-01

    Abstract The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a “raw” (assay value) and an “adjusted” value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients. PMID:26986135

  17. Tumor necrosis is associated with increased alphavbeta3 integrin expression and poor prognosis in nodular cutaneous melanomas

    PubMed Central

    Bachmann, Ingeborg M; Ladstein, Rita G; Straume, Oddbjørn; Naumov, George N; Akslen, Lars A

    2008-01-01

    Background Tumor necrosis and apoptotic activity are considered important in cancer progression, but these features have not been much studied in melanomas. Our hypothesis was that rapid growth in cutaneous melanomas of the vertical growth phase might lead to tissue hypoxia, alterations in apoptotic activity and tumor necrosis. We proposed that these tumor characteristics might be associated with changes in expression of cell adhesion proteins leading to increased invasive capacity and reduced patient survival. Methods A well characterized series of nodular melanoma (originally 202 cases) and other benign and malignant melanocytic tumors (109 cases) were examined for the presence of necrosis, apoptotic activity (TUNEL assay), immunohistochemical expression of hypoxia markers (HIF-1 α, CAIX, TNF-α, Apaf-1) and cell adhesion proteins (αvβ3 integrin, CD44/HCAM and osteopontin). We hypothesized that tumor hypoxia and necrosis might be associated with increased invasiveness in melanoma through alterations of tumor cell adhesion proteins. Results Necrosis was present in 29% of nodular melanomas and was associated with increased tumor thickness, tumor ulceration, vascular invasion, higher tumor proliferation and apoptotic index, increased expression of αvβ3 integrin and poor patient outcome by multivariate analysis. Tumor cell apoptosis did also correlate with reduced patient survival. Expression of TNF-α and Apaf-1 was significantly associated with tumor thickness, and osteopontin expression correlated with increased tumor cell proliferation (Ki-67). Conclusion Tumor necrosis and apoptotic activity are important features of melanoma progression and prognosis, at least partly through alterations in cell adhesion molecules such as increased αvβ3 integrin expression, revealing potentially important targets for new therapeutic approaches to be further explored. PMID:19061491

  18. Increased UVA exposures and decreased cutaneous Vitamin D(3) levels may be responsible for the increasing incidence of melanoma.

    PubMed

    Godar, Dianne E; Landry, Robert J; Lucas, Anne D

    2009-04-01

    Cutaneous malignant melanoma (CMM) has been increasing at a steady exponential rate in fair-skinned, indoor workers since before 1940. A paradox exists between indoor and outdoor workers because indoor workers get three to nine times less solar UV (290-400 nm) exposure than outdoor workers get, yet only indoor workers have an increasing incidence of CMM. Thus, another "factor(s)" is/are involved that increases the CMM risk for indoor workers. We hypothesize that one factor involves indoor exposures to UVA (321-400 nm) passing through windows, which can cause mutations and can break down vitamin D(3) formed after outdoor UVB (290-320 nm) exposure, and the other factor involves low levels of cutaneous vitamin D(3). After vitamin D(3) forms, melanoma cells can convert it to the hormone, 1,25-dihydroxyvitamin D(3), or calcitriol, which causes growth inhibition and apoptotic cell death in vitro and in vivo. We measured the outdoor and indoor solar irradiances and found indoor solar UVA irradiances represent about 25% (or 5-10 W/m(2)) of the outdoor irradiances and are about 60 times greater than fluorescent light irradiances. We calculated the outdoor and indoor UV contributions toward different biological endpoints by weighting the emission spectra by the action spectra: erythema, squamous cell carcinoma, melanoma (fish), and previtamin D(3). Furthermore, we found production of previtamin D(3) only occurs outside where there is enough UVB. We agree that intense, intermittent outdoor UV overexposures and sunburns initiate CMM; we now propose that increased UVA exposures and inadequately maintained cutaneous levels of vitamin D(3) promotes CMM. PMID:19155143

  19. Elevated pretreatment serum levels of soluble vascular cell adhesion molecule 1 and lactate dehydrogenase as predictors of survival in cutaneous metastatic malignant melanoma.

    PubMed Central

    Franzke, A.; Probst-Kepper, M.; Buer, J.; Duensing, S.; Hoffmann, R.; Wittke, F.; Volkenandt, M.; Ganser, A.; Atzpodien, J.

    1998-01-01

    Very rapid progression of disease with a median survival of 6-9 months is a common feature of metastatic cutaneous malignant melanoma. Nevertheless, substantial variability of survival suggests that metastatic cutaneous malignant melanoma can be divided into several biological subgroups. Pretreatment serum levels of soluble adhesion molecules and various clinical parameters in cutaneous metastatic malignant melanoma were evaluated to determine their prognostic value. In this study pretreatment serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular cell adhesion molecule 1 (sICAM-1), soluble endothelial leukocyte adhesion molecule 1 (sE-selectin) and multiple clinical factors were assessed in relation to overall survival of 97 consecutive patients with metastatic cutaneous malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, both univariate and multivariate Cox proportional-hazards models were used. Elevated pretreatment serum levels of sVCAM-1 (P < 0.005) and of lactate dehydrogenase (P < 0.002) were rendered statistically independent and were significantly associated with unfavourable outcome. Patients were assigned to one of three risk categories (low, intermediate and high) according to a cumulative risk score defined as the function of the sum of these two variables. There were significant differences in overall survival (P < 0.0001) between low- (n = 53, 5-year survival probability of 23.3%), intermediate- (n = 29, 5-year survival probability of 9.9%) and high-risk (n = 15) patients. Elevated pretreatment serum levels of sVCAM-1 and of lactate dehydrogenase correlate with poor outcome in metastatic cutaneous malignant melanoma. These data support risk stratification for future therapeutic trials and identify factors that need to be validated in prospective studies and may potentially influence decision-making in palliative management of patients with disseminated cutaneous

  20. Low Expression of Mir-137 Predicts Poor Prognosis in Cutaneous Melanoma Patients

    PubMed Central

    Li, Nan

    2016-01-01

    Background The present study aimed to measure miR-137 expression in patients with cutaneous melanoma (CM) and to estimate the correlation of miR-137 expression and the prognosis of CM patients. Material/Methods The expression level of miR-137 was assayed by quantitative real-time PCR (qRT-PCR) and presented as mean ±SD. Chi-square was used to evaluate the relationship between miR-137 expression and clinical characteristics. We used a Kaplan-Meier survival curve to determine the overall survival rate of CM patients. Moreover, the correlation between miR-137 expression and the prognosis of CM patients was confirmed by Cox regression analysis. Results The relative expression of miR-137 in CM tissue was 1.59±0.43, while that in paired normal tissue was 2.41±0.54, which was significantly higher. Chi-square analysis showed statistical significance between miR-137 expression and clinical characteristics such as TNM stage, ulcer, and occurrence site (P<0.05). However, no association was found between miR-137 expression and age, sex, or family history (P>0.05). According to the survival curve outcome, patients with low miR-137 expression showed relatively higher mortality (P=0.000) and multivariate analysis verified that low expression of miR-137 predicted poor prognosis of CM patients (HR=8.531, 95% CI=2.950–24.668, P=0.000). Conclusions Compared with paired normal tissues, miR-137 expression was lower in CM tissues. Patients with low miR-137 expression had higher mortality than those with high miR-137 expression, suggesting that low miR-137 expression indicated poor prognosis for CM patients. PMID:26763596

  1. Positron emission tomography in the follow-up of cutaneous malignant melanoma patients: a systematic review

    PubMed Central

    Danielsen, Maria; Højgaard, Liselotte; Kjær, Andreas; Fischer, Barbara MB

    2014-01-01

    Cutaneous malignant melanoma (CMM) has a high risk of dissemination to regional lymph nodes and visceral organs. Recurrences are most frequently seen within the first 2-3 years after initial treatment, but these patients have a life-long risk of relapse. The prognosis is highly dependent on lymph node involvement and distant metastases, accentuating the importance of close surveillance to identify disease progression at an early stage, and thereby detect recurrences amenable to treatment. Positron emission tomography (PET) has already been proven useful in the staging of CMM, but the utility of PET in follow-up programs for asymptomatic patients in high risk of relapse to detect systemic recurrences has yet to be investigated. We performed a systematic literature search in PUBMED, EMBASE and the Cochrane Controlled Trials Register, and identified 7 original studies on the diagnostic value of FDG-PET in the follow-up of CMM. Sensitivity, specificity, positive and negative predictive values were calculated to examine PET’s diagnostic value in detecting relapse. The mean sensitivity of PET was 96% and the specificity was 92%. The positive and negative predictive values were, respectively, 92% and 95%. Overall, PET has a high diagnostic value and the many advantages of PET indicate utility in the routine follow-up program of CMM. However, the number of prospective studies of high quality is scarce, and as the use of PET and PET/CT is becoming more widespread and the technology is expensive, there is an urgent need for systematic assessment of the diagnostic value. PMID:24380042

  2. Local cryosurgery and imiquimod: A successful combination for the treatment of locoregional cutaneous metastasis of melanoma: A case series.

    PubMed

    Rivas-Tolosa, Nancy; Ortiz-Brugués, Ariadna; Toledo-Pastrana, Tomás; Baradad, Manel; Traves, Víctor; Soriano, Virtudes; Sanmartín, Verónica; Requena, Celia; Martí, Rosa; Nagore, Eduardo

    2016-05-01

    Locoregional cutaneous metastases of melanoma (LCMM) represent a therapeutic challenge. Many treatment options are available with varying results. The combination of cryotherapy and imiquimod, two treatments with a possible synergistic effect, has not yet been described for treating this disease. In this paper, we aimed to show the response of LCMM to cryotherapy combined with topical imiquimod 5%. A retrospective review of 20 patients diagnosed with LCMM and treated with cryotherapy combined with topical imiquimod 5% between November 2000 and May 2014 at three institutions was performed. The locoregional cutaneous response was evaluated. After a mean of five sessions, 13 patients (65%) responded to treatment, eight (40%) of these completely and five (25%) partially. Systemic disease progressed in 16 (80%) patients. Cryotherapy followed by topical imiquimod 5% is simple to apply, has minimal adverse effects and provides response rates similar to other, more complex treatment options. PMID:26660713

  3. Cutaneous Melanoma with Brain Metastasis: Report of 193 Patients with New Observations

    PubMed Central

    Gugger, Alenka; Barnhill, Raymond L.; Seifert, Burkhardt; Dehler, Silvia; Moch, Holger; Lugassy, Claire; Marques-Maggio, Ewerton; Rushing, Elisabeth J.; Mihic-Probst, Daniela

    2016-01-01

    Background Brain metastasis is a common endpoint in patients suffering from malignant melanoma. However, little is known about factors that predispose to brain metastases. Objective We performed a retrospective clinical and pathological investigation of melanoma patients with brain metastases in order to better characterise this patient population. Methods 193 melanoma patients with brain metastasis histologically diagnosed between 1990 and 2015 at the University Hospital Zurich were retrospectively identified and further specified for sex, age at diagnosis and detection of brain metastasis, and localisation. In addition, data were extracted regarding the subtype of primary melanoma, Breslow tumour thickness, Clark Level, mutation status, extent of metastatic spread and history of a second melanoma. Results We found a significant male predominance (n = 126/193; 65%; p < 0.001). Breslow tumour thickness showed a wide range from 0.2 to 12.0 mm (n = 99; median 2.3 mm). 14 of 101 melanomas (14%) were classified as T1, thereof 11 (79%) were found in men. In 32 of 193 patients (17%), the primary melanoma was unknown. Conclusions Of special interest in our series is the high incidence of male predominance (79%) in cases of thin metastasing melanoma (14%), implicating genetic or epigenetic (hormonal) gender differences underlying tumour progression. Additionally, the high percentage of unknown primary melanoma (17%), at least partly representing completely regressed melanomas, indicates the importance of immune surveillance in melanoma progression. PMID:27213536

  4. Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma

    PubMed Central

    Dasgupta, Amrita; Katdare, Meena

    2015-01-01

    Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics. PMID:26287245

  5. Melanoma

    MedlinePlus

    ... to other parts of the body very quickly. Melanoma treatment can cause side effects, including pain, nausea, and ... Livingstone; 2013:chap 69. National Cancer Institute: PDQ Melanoma Treatment. Bethesda, MD: National Cancer Institute. Last modified March ...

  6. MGMT promoter methylation is associated with temozolomide response and prolonged progression-free survival in disseminated cutaneous melanoma.

    PubMed

    Tuominen, Rainer; Jewell, Rosalyn; van den Oord, Joost J; Wolter, Pascal; Stierner, Ulrika; Lindholm, Christer; Hertzman Johansson, Carolina; Lindén, Diana; Johansson, Hemming; Frostvik Stolt, Marianne; Walker, Christy; Snowden, Helen; Newton-Bishop, Julia; Hansson, Johan; Egyházi Brage, Suzanne

    2015-06-15

    To investigate the predictive and prognostic value of O(6) -methylguanine DNA methyltransferase (MGMT) inactivation by analyses of promoter methylation in pretreatment tumor biopsies from patients with cutaneous melanoma treated with dacarbazine (DTIC) or temozolomide (TMZ) were performed. The patient cohorts consisted of Belgian and Swedish disseminated melanoma patients. Patients were subdivided into those receiving single-agent treatment with DTIC/TMZ (cohort S, n = 74) and those treated with combination chemotherapy including DTIC/TMZ (cohort C, n = 79). Median follow-up was 248 and 336 days for cohort S and cohort C, respectively. MGMT promoter methylation was assessed by three methods. The methylation-related transcriptional silencing of MGMT mRNA expression was assessed by real-time RT-PCR. Response to chemotherapy and progression-free survival (PFS) and overall survival were correlated to MGMT promoter methylation status. MGMT promoter methylation was detected in tumor biopsies from 21.5 % of the patients. MGMT mRNA was found to be significantly lower in tumors positive for MGMT promoter methylation compared to tumors without methylation in both treatment cohorts (p < 0.005). DTIC/TMZ therapy response rate was found to be significantly associated with MGMT promoter methylation in cohort S (p = 0.0005), but did not reach significance in cohort C (p = 0.16). Significantly longer PFS was observed among patients with MGMT promoter-methylated tumors (p = 0.002). Multivariate Cox regression analysis identified presence of MGMT promoter methylation as an independent variable associated with longer PFS. Together, this implies that MGMT promoter methylation is associated with response to single-agent DTIC/TMZ and longer PFS in disseminated cutaneous melanoma. PMID:25400033

  7. Using Morphed Images to Study Visual Detection of Cutaneous Melanoma Symptom Evolution

    ERIC Educational Resources Information Center

    Dalianis, Elizabeth A.; Critchfield, Thomas S.; Howard, Niki L.; Jordan, J. Scott; Derenne, Adam

    2011-01-01

    Early detection attenuates otherwise high mortality from the skin cancer melanoma, and although major melanoma symptoms are well defined, little is known about how individuals detect them. Previous research has focused on identifying static stimuli as symptomatic vs. asymptomatic, whereas under natural conditions it is "changes" in skin lesions…

  8. Etiology, risk factors, epidemiology, and public health issues in melanoma and other cutaneous neoplasms

    SciTech Connect

    Lee, J.A. )

    1992-04-01

    The cytogenetic features of melanoma, including the contribution of specific genes, are beginning to be unraveled. Reproductive factors have been shown to have little relationship to melanoma. The puzzles over apparent systemic effects of exposure have persisted, however. Evidence was published that the history of reaction to sun exposure altered when a diagnosis of melanoma was made. An interesting suggestion was made that the classic melanoma risk factors are associated with promotion rather than initiation of the disease. There is further evidence that exposure decreases melanoma risk in people who tan well but increases it in those who do not. Also reviewed is the evidence that the ozone layer of the stratosphere began to decrease in thickness under the influence of the chlorofluorocarbon gases.

  9. Review of the role of sentinel node biopsy in cutaneous head and neck melanoma.

    PubMed

    Roy, Jennifer M; Whitfield, Robert J; Gill, P Grantley

    2016-05-01

    Sentinel node biopsy (SNB) is recommended for selected melanoma patients in many parts of the world. This review examines the evidence surrounding the accuracy and prognostic value of SNB and completion neck dissection in head and neck melanoma. Sentinel nodes were identified in an average of 94.7% of head and neck cases compared with 95.3-100% in all melanoma cases. More false-negative sentinel nodes were found in head and neck cases. A positive sentinel node was associated with both lower disease-free survival (53.4 versus 83.2%) and overall survival (40 versus 84%). We conclude that SNB should be offered to all patients with intermediate and high-risk melanomas in the head and neck area. To date, evidence does not exist to demonstrate the safety of avoiding completion lymph node dissection in sentinel node-positive patients with head and neck melanoma. PMID:26362016

  10. Individual risk of cutaneous melanoma in New Zealand: developing a clinical prediction aid

    PubMed Central

    2014-01-01

    Background New Zealand and Australia have the highest melanoma incidence rates worldwide. In New Zealand, both the incidence and thickness have been increasing. Clinical decisions require accurate risk prediction but a simple list of genetic, phenotypic and behavioural risk factors is inadequate to estimate individual risk as the risk factors for melanoma have complex interactions. In order to offer tailored clinical management strategies, we developed a New Zealand prediction model to estimate individual 5-year absolute risk of melanoma. Methods A population-based case–control study (368 cases and 270 controls) of melanoma risk factors provided estimates of relative risks for fair-skinned New Zealanders aged 20–79 years. Model selection techniques and multivariate logistic regression were used to determine the important predictors. The relative risks for predictors were combined with baseline melanoma incidence rates and non-melanoma mortality rates to calculate individual probabilities of developing melanoma within 5 years. Results For women, the best model included skin colour, number of moles > =5 mm on the right arm, having a 1st degree relative with large moles, and a personal history of non-melanoma skin cancer (NMSC). The model correctly classified 68% of participants; the C-statistic was 0.74. For men, the best model included age, place of occupation up to age 18 years, number of moles > =5 mm on the right arm, birthplace, and a history of NMSC. The model correctly classified 67% of cases; the C-statistic was 0.71. Conclusions We have developed the first New Zealand risk prediction model that calculates individual absolute 5-year risk of melanoma. This model will aid physicians to identify individuals at high risk, allowing them to individually target surveillance and other management strategies, and thereby reduce the high melanoma burden in New Zealand. PMID:24884419

  11. Primary angiomatoid melanoma as an exceptional morphologic pattern in cutaneous melanoma. A case report and review of the literature.

    PubMed

    Ramos-Rodríguez, G; Ortiz-Hidalgo, C

    2015-04-01

    We report a case of angiomatoid melanoma on the right thigh of a 59-year-old man. The histologic growth pattern of the tumor mimicked vascular proliferation, and the cells lining the pseudovascular spaces were positive for protein S-100, HMB-45, and MITF-1. The differential diagnosis is with angiosarcoma and pseudovascular adenoid squamous cell carcinoma. The case we present is the fifth reported to date. PMID:25498159

  12. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review.

    PubMed

    2007-03-01

    Exposure to solar ultraviolet (UV) radiation is a known cause of skin cancer. Sunbed use represents an increasingly frequent source of artificial UV exposure in light-skinned populations. To assess the available evidence of the association between sunbed use and cutaneous malignant melanoma (melanoma) and other skin cancers, a systematic review of the literature till March 2006 on epidemiological and biological studies on sunbed use was performed in Pubmed, ISI Web of Science, Embase, Pascal, Cochrane library, Lilacs and Medcarib. Search for keywords in the title and in the abstract was done systematically and supplemented by manual searches. Only case-control, cohort or cross-sectional studies were selected. Data were abstracted by means of a standardized data-collection protocol. Based on 19 informative studies, ever-use of sunbeds was positively associated with melanoma (summary relative risk, 1.15; 95% CI, 1.00-1.31), although there was no consistent evidence of a dose-response relationship. First exposure to sunbeds before 35 years of age significantly increased the risk of melanoma, based on 7 informative studies (summary relative risk, 1.75; 95% CI, 1.35-2.26). The summary relative risk of 3 studies of squamous cell carcinoma showed an increased risk. For basal cell carcinoma, the studies did not support an association. The evidence does not support a protective effect of the use of sunbeds against damage to the skin from subsequent sun exposure. Young adults should be discouraged from using indoor tanning equipment and restricted access to sunbeds by minors should be strongly considered. PMID:17131335

  13. Differentiation of cutaneous melanoma from surrounding skin using laser-induced breakdown spectroscopy

    PubMed Central

    Han, Jung Hyun; Moon, Youngmin; Lee, Jong Jin; Choi, Sujeong; Kim, Yong-Chul; Jeong, Sungho

    2015-01-01

    Laser-induced breakdown spectroscopy (LIBS) has the potential to be used as a surgical tool for simultaneous tissue ablation and elemental analysis of the ablated tissue. LIBS may be used to distinguish melanoma lesions from the surrounding dermis based on the quantitative difference of elements within melanoma lesions. Here, we measured the elements in homogenized pellets and real tissues from excised skin samples of melanoma-implanted mice. In addition, statistical analysis of LIBS spectra using principal component analysis and linear discriminant analysis was performed. Our results showed that this method had high detection sensitivity, highlighting the potential of this tool in clinical applications. PMID:26819817

  14. Cutaneous leishmaniasis: advances in disease pathogenesis, diagnostics and therapeutics.

    PubMed

    Ameen, M

    2010-10-01

    Cutaneous leishmaniasis is one of the most common tropical dermatoses worldwide and is of major public health importance. It is caused by numerous Leishmania protozoa species, which are responsible for its clinical diversity. With changes in vector (sandfly) habitat and increased travel among human populations, its incidence is rising, and in nonendemic countries, including the UK, it is increasingly diagnosed in migrants, returned travellers, and military personnel. Diagnostic tests have not always been sufficiently sensitive, and despite a wide range of treatments, poor therapeutic responses and adverse effects are common. In the past decade, there have been notable advances in molecular diagnostics, in the understanding of host immune responses to infection, and in new therapeutic interventions and vaccine development. PMID:20831602

  15. Modern non-invasive diagnostic techniques in the detection of early cutaneous melanoma.

    PubMed

    Kardynal, Agnieszka; Olszewska, Malgorzata

    2014-03-31

    Over the past few years melanoma has grown into a disease of socio-economic importance due to the increasing incidence and persistently high mortality rates. Melanoma is a malignant tumor with a high tendency to metastasize. Therefore, an extremely important part of the therapeutic process is to identify the disease at an early stage: in situ or stage I. Many tools for early diagnosis of melanoma are available today, including dermoscopy, videodermoscopy and in vivo reflectance confocal microscopy. Other methods such as high frequency ultrasound, optical coherence tomography and electrical impedance spectroscopy may serve as additional diagnostic aids. Modern imaging techniques also allow the monitoring of melanocytic skin lesions over months or years to detect the moment of malignant transformation. This review summarizes the current knowledge about modern diagnostic techniques, which may aid early diagnosis of melanoma. PMID:24748903

  16. Association of MDM2 SNP309, age of onset, and gender in cutaneous melanoma

    PubMed Central

    Firoz, Elnaz F.; Warycha, Melanie; Zakrzewski, Jan; Pollens, Danuta; Wang, Guimin; Shapiro, Richard; Berman, Russell; Pavlick, Anna; Manga, Prashiela; Ostrer, Harry; Celebi, Julide Tok; Kamino, Hideko; Darvishian, Farbod; Rolnitzky, Linda; Goldberg, Judith D.; Osman, Iman; Polsky, David

    2013-01-01

    Purpose In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than age 40; however, among those older than age 50, melanoma is more frequent in men than in women. To investigate this difference, we examined the association between MDM2 SNP309, age at diagnosis, and gender among melanoma patients. Experimental Design Prospectively enrolled melanoma patients (N=227) were evaluated for MDM2 SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples and genotypes were analyzed by PCR-RFLP. Associations between MDM2 SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed. Results The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared to women with TG+TT genotypes (59 years; p=0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages less than 50 compared to women 50 and older, but not 60 and older. At ages less than 50, women with a GG genotype had a 3.89 times greater chance of being diagnosed compared to women with TG+TT genotypes (p=0.01). Similar observations were not seen among men. Conclusions Our data suggest that MDM2 may play an important role in the development of melanoma in women. The MDM2 SNP309 genotype may help identify women at risk for developing melanoma at a young age. PMID:19318491

  17. Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey.

    PubMed

    Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian; Drzewiecki, Krzysztof T; Prause, Jan U; Heegaard, Steffen

    2016-06-01

    Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma and conjunctival melanoma, which are very rare in Black people. The symptoms are not tumour-specific and are related to the organ system affected, and the disease is most often diagnosed at an advanced clinical stage. The diagnosis of a primary tumour is difficult, and metastatic cutaneous melanoma and choroidal melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins is the treatment of choice. The prognosis is poor, with the 5-year survival rate ranging from 0% (gastric melanoma) to 80% (conjunctival melanoma). PMID:27004972

  18. Expression of the RNase III enzyme DROSHA is reduced during progression of human cutaneous melanoma

    PubMed Central

    Jafarnejad, Seyed Mehdi; Sjoestroem, Cecilia; Martinka, Magdalena; Li, Gang

    2016-01-01

    Aberrant expression of miRNAs and their biogenesis factors has been frequently observed in different types of cancer. We recently reported that expression of DICER1 is reduced in metastatic melanoma. Nevertheless, so far very little is known about the expression pattern of other miRNA biogenesis factors in this type of malignancy. Here, we investigated the expression pattern of DROSHA in a large set of melanocytic lesions by tissue microarray and immunohistochemistry (n = 409). We found that nuclear expression of DROSHA is markedly reduced in the early stages of melanoma progression (P = 0.0001) and is inversely correlated with melanoma thickness (P = 0.0001), AJCC stages (P = 0.0001), and ulceration status (P = 0.002). We also confirmed the reduced expression of nuclear DROSHA by a second specific antibody raised against a different region of the DROSHA protein. In addition, we observed that the reduced nuclear expression of DROSHA during melanoma progression is accompanied by an increased cytoplasmic expression of this protein (P = 0.0001). Finally, we found that expression pattern of DROSHA varies from that of DICER1 and concomitant loss of expression of both DICER1 and DROSHA confers the worse outcome for melanoma patients. Our results demonstrate a reduced nuclear expression of DROSHA which further highlights a perturbed miRNA biogenesis pathway in melanoma. In addition, the aberrant subcellular localization of DROSHA indicates possible deregulation in the mechanisms responsible for its proper localization in the nucleus. PMID:23370771

  19. Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma

    PubMed Central

    Wong, Stephen Q.; Behren, Andreas; Mar, Victoria J.; Woods, Katherine; Li, Jason; Martin, Claire; Sheppard, Karen E.; Wolfe, Rory; Kelly, John; Cebon, Jonathan; Dobrovic, Alexander; McArthur, Grant A.

    2015-01-01

    Melanoma is often caused by mutations due to exposure to ultraviolet radiation. This study reports a recurrent somatic C > T change causing a P131L mutation in the RQCD1 (Required for Cell Differentiation1 Homolog) gene identified through whole exome sequencing of 20 metastatic melanomas. Screening in 715 additional primary melanomas revealed a prevalence of ~4%. This represents the first reported recurrent mutation in a member of the CCR4-NOT complex in cancer. Compared to tumors without the mutation, the P131L mutant positive tumors were associated with increased thickness (p = 0.02), head and neck (p = 0.009) and upper limb (p = 0.03) location, lentigo maligna melanoma subtype (p = 0.02) and BRAF V600K (p = 0.04) but not V600E or NRAS codon 61 mutations. There was no association with nodal disease (p = 0.3). Mutually exclusive mutations of other members of the CCR4-NOT complex were found in ~20% of the TCGA melanoma dataset suggesting the complex may play an important role in melanoma biology. Mutant RQCD1 was predicted to bind strongly to HLA-A0201 and HLA-Cw3 MHC1 complexes. From thirteen patients with mutant RQCD1, an anti-tumor CD8+ T cell response was observed from a single patient's peripheral blood mononuclear cell population stimulated with mutated peptide compared to wildtype indicating a neoantigen may be formed. PMID:25544760

  20. Meta-Analysis of the Safety and Efficacy of Interferon Combined With Dacarbazine Versus Dacarbazine Alone in Cutaneous Malignant Melanoma.

    PubMed

    Xin, Yong; Huang, Qian; Zhang, Pei; Yang, Ming; Hou, Xiao-Yang; Tang, Jian-Qin; Zhang, Long Zhen; Jiang, Guan

    2016-04-01

    The aim of this study was to compare the efficacy and safety of interferon (IFN) combined with dacarbazine (DTIC) (experimental group) versus DTIC alone (control group) in cutaneous malignant melanoma. After searching all available databases, eligible articles were identified and subjected to quality assessment. Meta-analysis was performed using RevMan 5.3; combined relative risk (RR) and 95% confidence intervals (95% CIs) were calculated for survival rates, response rates, and adverse events. Eight randomized controlled trials published between 1990 and 2014 involving 795 patients were included in the meta-analysis. Compared with DTIC alone, IFN combined with DTIC significantly increased the overall response rate (RR = 1.59, 95% CI 1.21-2.08, P = 0.0008),the complete response rate (RR = 3.30, 95% CI 1.89-5.76, P < 0.0001), 2-year survival (RR = 1.59, 95% CI 0.99-2.54, P = 0.050) grade ≥3 hematologic toxicity (RR = 2.30, 95% CI 1.32-4.02, P = 0.003), neurotoxicity (RR = 18.15, 95% CI 5.34-61.74, P < 0.00001), and flu-like symptoms (RR = 6.31, 95% CI 1.95-20.39, P = 0.002). The partial response rate, grade ≥3 nausea and vomiting, treatment-related, and 1- and 3-year survival were not significantly different between IFN combined with DTIC and DTIC alone. IFN combined with DTIC may moderately improve the complete response rate, but increases the incidence of adverse events and has no significant effect on 1- and 3-year survival in cutaneous malignant melanoma. PMID:27100429

  1. Meta-Analysis of the Safety and Efficacy of Interferon Combined With Dacarbazine Versus Dacarbazine Alone in Cutaneous Malignant Melanoma

    PubMed Central

    Xin, Yong; Huang, Qian; Zhang, Pei; Yang, Ming; Hou, Xiao-Yang; Tang, Jian-Qin; Zhang, Long Zhen; Jiang, Guan

    2016-01-01

    Abstract The aim of this study was to compare the efficacy and safety of interferon (IFN) combined with dacarbazine (DTIC) (experimental group) versus DTIC alone (control group) in cutaneous malignant melanoma. After searching all available databases, eligible articles were identified and subjected to quality assessment. Meta-analysis was performed using RevMan 5.3; combined relative risk (RR) and 95% confidence intervals (95% CIs) were calculated for survival rates, response rates, and adverse events. Eight randomized controlled trials published between 1990 and 2014 involving 795 patients were included in the meta-analysis. Compared with DTIC alone, IFN combined with DTIC significantly increased the overall response rate (RR = 1.59, 95% CI 1.21–2.08, P = 0.0008),the complete response rate (RR = 3.30, 95% CI 1.89–5.76, P < 0.0001), 2-year survival (RR = 1.59, 95% CI 0.99–2.54, P = 0.050) grade ≥3 hematologic toxicity (RR = 2.30, 95% CI 1.32–4.02, P = 0.003), neurotoxicity (RR = 18.15, 95% CI 5.34–61.74, P < 0.00001), and flu-like symptoms (RR = 6.31, 95% CI 1.95–20.39, P = 0.002). The partial response rate, grade ≥3 nausea and vomiting, treatment-related, and 1- and 3-year survival were not significantly different between IFN combined with DTIC and DTIC alone. IFN combined with DTIC may moderately improve the complete response rate, but increases the incidence of adverse events and has no significant effect on 1- and 3-year survival in cutaneous malignant melanoma. PMID:27100429

  2. A Web-based database of genetic association studies in cutaneous melanoma enhanced with network-driven data exploration tools.

    PubMed

    Athanasiadis, Emmanouil I; Antonopoulou, Kyriaki; Chatzinasiou, Foteini; Lill, Christina M; Bourdakou, Marilena M; Sakellariou, Argiris; Kypreou, Katerina; Stefanaki, Irene; Evangelou, Evangelos; Ioannidis, John P A; Bertram, Lars; Stratigos, Alexander J; Spyrou, George M

    2014-01-01

    The publicly available online database MelGene provides a comprehensive, regularly updated, collection of data from genetic association studies in cutaneous melanoma (CM), including random-effects meta-analysis results of all eligible polymorphisms. The updated database version includes data from 192 publications with information on 1114 significantly associated polymorphisms across 280 genes, along with new front-end and back-end capabilities. Various types of relationships between data are calculated and visualized as networks. We constructed 13 different networks containing the polymorphisms and the genes included in MelGene. We explored the derived network representations under the following questions: (i) are there nodes that deserve consideration regarding their network connectivity characteristics? (ii) What is the relation of either the genome-wide or nominally significant CM polymorphisms/genes with the ones highlighted by the network representation? We show that our network approach using the MelGene data reveals connections between statistically significant genes/ polymorphisms and other genes/polymorphisms acting as 'hubs' in the reconstructed networks. To the best of our knowledge, this is the first database containing data from a comprehensive field synopsis and systematic meta-analyses of genetic polymorphisms in CM that provides user-friendly tools for in-depth molecular network visualization and exploration. The proposed network connections highlight potentially new loci requiring further investigation of their relation to melanoma risk. Database URL: http://www.melgene.org. PMID:25380778

  3. A Web-based database of genetic association studies in cutaneous melanoma enhanced with network-driven data exploration tools

    PubMed Central

    Athanasiadis, Emmanouil I.; Antonopoulou, Kyriaki; Chatzinasiou, Foteini; Lill, Christina M.; Bourdakou, Marilena M.; Sakellariou, Argiris; Kypreou, Katerina; Stefanaki, Irene; Evangelou, Evangelos; Ioannidis, John P.A.; Bertram, Lars; Stratigos, Alexander J.; Spyrou, George M.

    2014-01-01

    The publicly available online database MelGene provides a comprehensive, regularly updated, collection of data from genetic association studies in cutaneous melanoma (CM), including random-effects meta-analysis results of all eligible polymorphisms. The updated database version includes data from 192 publications with information on 1114 significantly associated polymorphisms across 280 genes, along with new front-end and back-end capabilities. Various types of relationships between data are calculated and visualized as networks. We constructed 13 different networks containing the polymorphisms and the genes included in MelGene. We explored the derived network representations under the following questions: (i) are there nodes that deserve consideration regarding their network connectivity characteristics? (ii) What is the relation of either the genome-wide or nominally significant CM polymorphisms/genes with the ones highlighted by the network representation? We show that our network approach using the MelGene data reveals connections between statistically significant genes/ polymorphisms and other genes/polymorphisms acting as ‘hubs’ in the reconstructed networks. To the best of our knowledge, this is the first database containing data from a comprehensive field synopsis and systematic meta-analyses of genetic polymorphisms in CM that provides user-friendly tools for in-depth molecular network visualization and exploration. The proposed network connections highlight potentially new loci requiring further investigation of their relation to melanoma risk. Database URL: http://www.melgene.org. PMID:25380778

  4. Angiotropism in primary cutaneous melanoma with brain metastasis: a study of 20 cases.

    PubMed

    Hung, Tawny; Morin, Jason; Munday, William R; Mackenzie, Ian R A; Lugassy, Claire; Barnhill, Raymond L

    2013-08-01

    Previous clinical and experimental studies suggested that invasion of the brain by metastatic melanoma may follow the external surfaces of vascular channels, that is, angiotropic extravascular migratory metastasis. Such angiotropic invasion seemss analogous to that of neoplastic glial invasion of the nervous system. We, therefore, have retrospectively investigated 20 primary melanoma cases and their respective metastatic brain lesions. The following parameters were analyzed in each primary melanoma: presence of angiotropism, Breslow thickness, Clark level, mitotic rate, sentinel lymph node (SLN) status, and time interval between the primary lesion and the metastasis. The metastatic brain lesions were examined for the presence of angiotropism. Of the 20 cases, 14 showed angiotropism in the primary lesion. The angiotropic group had a significantly deeper Breslow thickness (median 4.4 mm vs. 1.4 mm, P < 0.01) and was more mitotically active (median 11 vs. 4.7 mitoses/mm, P = 0.04). Interestingly, the angiotropic group had an average time lapse of 33 months from the primary lesion to the brain metastasis, whereas the nonangiotropic group had a 57-month time interval. Although the Kaplan-Meier analysis failed to show a survival difference in this small cohort (P = 0.235), there was a trend toward significance. Seven of 20 brain metastases showed angiotropism; however, no significant correlation between angiotropism in the primary melanomas and the corresponding metastatic lesions could be demonstrated. Indeed, angiotropism in the brain metastases was difficult to assess because the available material were generally small partial biopsy samplings and many showed conspicuous necrosis. Ten melanoma patients underwent SLN biopsy. The 3 of 6 positive cases in the angiotropic group had an average time lapse of 32 months from the primary lesion to the brain metastasis, whereas the 4 positive SLN biopsies in the nonangiotropic group had an average of 63 months. This preliminary

  5. Predictive role of preoperative lymphoscintigraphy on the status of the sentinel lymph node in clinically node-negative patients with cutaneous melanoma.

    PubMed

    Solari, Nicola; Gipponi, Marco; Stella, Mattia; Queirolo, Paola; di Somma, Carmine; Villa, Giuseppe; Piccardo, Arnoldo; Gualco, Marina; Cardinale, Francesco; Cafiero, Ferdinando

    2009-08-01

    We reviewed our experience to assess the predictive role of preoperative lymphoscintigraphy with regard to the pathological status of sentinel lymph node (sN) in patients with cutaneous melanoma, to optimize the surgical treatment planning with regard to the use of intraoperative frozen section examination of sN. Eighty-eight patients with clinically node-negative cutaneous melanoma pT1b-T4 stage underwent preoperative lymphoscintigraphy for the lymphatic mapping of sN. A lymphoscintigraphic 'score' (from L1 to L5) was developed based on the ratio of radiotracer concentration within sN nodes as compared with the injection site. Our score allowed us to foresee that sN of patients with thick melanomas (T3 and T4) and a low preoperative score (L1-L2-L3) had a 90% expected likelihood (P<0.001) of harboring metastasis, whereas sN in patients with thin melanomas (T1b-T2) and high preoperative score (from L4 to L5) showed a 100% likelihood of being metastasis free. In conclusion, the sN is a reliable predictor of regional lymph node status in patients with cutaneous malignant melanoma. Moreover, we suggest that a low score (L1-L2-L3) associated with a thick melanoma is a good predictive factor of the positive sN involvement. This information could be useful in scheduling the intraoperative frozen-section examination with an expected benefit of a positive test in almost 90% of patients. Such patients might be selected for a 'one-stage' procedure with a more effective cost/benefit ratio and decreased hospitalization costs. PMID:19584766

  6. Emerging targets for combination therapy in melanomas.

    PubMed

    Saito, Renata de Freitas; Tortelli, Tharcísio Citrângulo; Jacomassi, Mayara D'Auria; Otake, Andréia Hanada; Chammas, Roger

    2015-11-14

    Cutaneous melanomas are often difficult to treat when diagnosed in advanced stages. Melanoma cells adapt to survive in extreme environmental conditions and are among the tumors with larger genomic instability. Here we discuss some intrinsic and extrinsic mechanisms of resistance of melanoma cells to both conventional and target therapies, such as autophagy, adaptation to endoplasmic reticulum stress, metabolic reprogramming, mechanisms of tumor repopulation and the role of extracellular vesicles in this later phenomenon. These biological processes are potentially targetable and thus provide a platform for research and discovery of new drugs for combination therapy to manage melanoma patient treatment. PMID:26450371

  7. Pump-probe imaging of pigmented cutaneous melanoma primary lesions gives insight into metastatic potential

    PubMed Central

    Robles, Francisco E.; Deb, Sanghamitra; Wilson, Jesse W.; Gainey, Christina S.; Selim, M. Angelica; Mosca, Paul J.; Tyler, Douglas S.; Fischer, Martin C.; Warren, Warren S.

    2015-01-01

    Metastatic melanoma is associated with a poor prognosis, but no method reliably predicts which melanomas of a given stage will ultimately metastasize and which will not. While sentinel lymph node biopsy (SLNB) has emerged as the most powerful predictor of metastatic disease, the majority of people dying from metastatic melanoma still have a negative SLNB. Here we analyze pump-probe microscopy images of thin biopsy slides of primary melanomas to assess their metastatic potential. Pump-probe microscopy reveals detailed chemical information of melanin with subcellular spatial resolution. Quantification of the molecular signatures without reference standards is achieved using a geometrical representation of principal component analysis. Melanin structure is analyzed in unison with the chemical information by applying principles of mathematical morphology. Results show that melanin in metastatic primary lesions has lower chemical diversity than non-metastatic primary lesions, and contains two distinct phenotypes that are indicative of aggressive disease. Further, the mathematical morphology analysis reveals melanin in metastatic primary lesions has a distinct “dusty” quality. Finally, a statistical analysis shows that the combination of the chemical information with spatial structures predicts metastatic potential with much better sensitivity than SLNB and high specificity, suggesting pump-probe microscopy can be an important tool to help predict the metastatic potential of melanomas. PMID:26417529

  8. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.

    PubMed

    Shi, Jianxin; Yang, Xiaohong R; Ballew, Bari; Rotunno, Melissa; Calista, Donato; Fargnoli, Maria Concetta; Ghiorzo, Paola; Bressac-de Paillerets, Brigitte; Nagore, Eduardo; Avril, Marie Francoise; Caporaso, Neil E; McMaster, Mary L; Cullen, Michael; Wang, Zhaoming; Zhang, Xijun; Bruno, William; Pastorino, Lorenza; Queirolo, Paola; Banuls-Roca, Jose; Garcia-Casado, Zaida; Vaysse, Amaury; Mohamdi, Hamida; Riazalhosseini, Yasser; Foglio, Mario; Jouenne, Fanélie; Hua, Xing; Hyland, Paula L; Yin, Jinhu; Vallabhaneni, Haritha; Chai, Weihang; Minghetti, Paola; Pellegrini, Cristina; Ravichandran, Sarangan; Eggermont, Alexander; Lathrop, Mark; Peris, Ketty; Scarra, Giovanna Bianchi; Landi, Giorgio; Savage, Sharon A; Sampson, Joshua N; He, Ji; Yeager, Meredith; Goldin, Lynn R; Demenais, Florence; Chanock, Stephen J; Tucker, Margaret A; Goldstein, Alisa M; Liu, Yie; Landi, Maria Teresa

    2014-05-01

    Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations. PMID:24686846

  9. Extraordinary Lymph Drainage in Cutaneous Malignant Melanoma and the Value of Hybrid Imaging: A Case Report.

    PubMed

    Brammen, Lindsay; Nedomansky, Jakob; Haslik, Werner; Staudenherz, Anton

    2014-12-01

    In melanoma patients, preoperative lymphoscintigraphy has become a gold standard. The role of single-photon emission computed tomography (SPECT) or its combination with computed tomography (SPECT-CT) as part of the standard sentinel scintigraphy protocol has yet to be determined. A 46-year-old female patient with melanoma of the trunk received preoperative lymphoscintigraphy and subsequent surgical excision. Planar imaging displayed two hot spots in the region of the primary lesion. No other lymphatic flow pathways could be appreciated. Two focal hot spots, one dorsal to the primary lesion near the left latissimus dorsi muscle and one just lateral to the primary lesion in the subcutaneous tissue, were appreciated with SPECT-CT imaging. The primary melanoma lesion, as well as the two additional lesions, which were detected by SPECT-CT, were excised and sent for histopathological examination. While the primary lesion was a superficial spreading melanoma, the lesions appreciated in SPECT-CT revealed four sentinel lymph nodes, each of which was negative for tumor cells. Melanomas, especially of the trunk, can demonstrate multiple lymphatic drain basins in a large percentage of patients. Given that without the detailed anatomical information provided by SPECT-CT it would be very difficult to locate the diverse lymphatic drain basins and their lymph nodes, we would suggest routinely implementing SPECT-CT in the standard planar sentinel imaging protocol. PMID:26396636

  10. Mutation Scanning of D1705 and D1709 in the RNAse IIIb Domain of MicroRNA Processing Enzyme Dicer in Cutaneous Melanoma.

    PubMed

    Sand, Michael; Bechara, Falk G; Skrygan, Marina; Sand, Daniel; Gambichler, Thilo; Bromba, Michael; Stockfleth, Eggert; Hessam, Schapoor

    2016-07-01

    Since the discovery of microRNAs (miRNAs) there have been performed several studies showing perturbations in the expression of miRNAs and the miRNA expression machinery in cutaneous melanoma. Dicer, a pivotal cytosolic enzyme of miRNA maturation has shown to be affected by both somatic and germline mutations in a variety of cancers. Recent studies have shown that recurrent somatic mutations of Dicer frequently affect the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain, therefore called hot spot mutations. The present study investigates metal-ion-binding sites D1709 and D1705 of the Dicer RNase IIIb domain in cutaneous melanomas and melanoma metastasis by Sanger sequencing. All investigated samples showed wildtype sequence and no single mutation was detected. The miRNA processing enzyme Dicer of melanoma and melanoma metastasis does not appear to be affected by mutation in the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain. PMID:26683837

  11. Evaluating cost benefits of combination therapies for advanced melanoma

    PubMed Central

    Jensen, Ivar S.; Zacherle, Emily; Blanchette, Christopher M.; Zhang, Jie; Yin, Wes

    2016-01-01

    Background: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22–53% with progression-free survival (PFS) in the range of 4.8–8.8 months. Recently, combination targeted therapies have improved response rates to about 66–69%, PFS to 11.0–12.6 months and overall survival (OS) to 25.1–25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19–29% with monotherapies and improved PFS of 11.7 compared with 4.4–5.8 months with monotherapies, the OS benefit is yet to be established in phase 3 trials. As healthcare costs continue to rise, US payers have a predominant interest in assessing the value of available treatments. Therefore, a cost-benefit model was developed to evaluate the value of treating BRAF+ advanced melanoma with two combination therapies: nivolumab + ipilimumab (N+I) and dabrafenib + trametinib (D+T). Scope: The model was used to estimate total costs, total costs by expenditure category, cost per month of PFS and cost per responder for the payer, and societal perspectives of treating advanced melanoma patients with the BRAF V600 mutation using combination targeted therapy (D+T) or combination immunotherapy (N+I). The model followed patients from initiation of treatment to the point of progression or death. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results and to understand the dispersion of simulated results. Findings: Based on a hypothetical payer with one million covered lives, it was expected that fourteen metastatic melanoma patients with the BRAF V600 mutation would be treated each year. Cost-benefit with N+I and D+T was simulated from the payer perspective. The cost per month of PFS for N+I was $22,162, while that for D+T was $17,716 (−$4,446 cost difference); the cost per responder for N+I was $388,746 and that for D+T was

  12. [Vulvar melanoma].

    PubMed

    Chokoeva, A; Tchernev, G; Wollina, U

    2015-01-01

    Malignant melanoma of the vulva is a rare disease with aggressive behavior and poor prognosis. It consist < 5% of all cases of melanoma in females, as the ratio of its manifestation, compared with the cutaneous melanoma is 1:71. Higher risk of developing melanoma of the vulva is established in white women, as the peak of the incidence is between 60 and 70 years of age. Clinically, MM of the vulva manifests as asymptomatic pigmented, rarely a pigmented lesion, as the usual clinical form is superficial spreading MM and much less common nodular MM, which is associated with a poorer prognosis in. general. The diagnosis is confirmed by histological examination. Conduction of PCR and DNA analysis for detection of BRAF mutations, NRAS mutations and KIT amplification is also appropriate. Advanced age, black race, tumor size, tumor thickness, ulceration, presence of satellite lesions, involvement of adjacent organs (vagina, urethra), and the presence of regional or distant metastases are identified as the most important prognostic markers. Radical wide excision followed by bilateral lymphadenectomy id considered as the optimal therapeutic approach. PMID:25909143

  13. Recent advances in sunlight-induced carcinogenesis using the Xiphophorus melanoma model✰

    PubMed Central

    Fernandez, André A.; Paniker, Lakshmi; Garcia, Rachel; Mitchell, David L.

    2011-01-01

    Unlike breast and prostate cancers, the nature and sequence of critical genetic and epigenetic events involved in the initiation and progression of melanoma is not well understood. A contributing factor to this dilemma, especially given our current understanding of the importance of UV light in melanoma etiology, is the lack of quality UV-inducible melanoma animal models. In this study we elaborate on the capability of UV light to induce cutaneous malignant melanomas (CMM) in Xiphophorus fishes, which were previously found to develop melanomas after acute neonatal UVB irradiation. In two separate tumorigenesis experiments, we exposed adult Xiphophorus hybrids to either acute UVB irradiations (5 consecutive daily treatments) or chronic solar irradiations (continuous UVA/UVB treatment for 9 months). Acute adult UVB irradiation resulted in the significant induction of melanomas, and moreover, this induction rate is equivalent to that of animals exposed to acute neonatal UVB irradiation. This study represents the first evidence that acute adult UVB irradiation, in the absence of any early life exposures, induces CMM. Similar to the findings conducted on other divergent melanoma models, including HGF/SF transgenic mice and Monodelphis domestica, prolonged chronic solar UV was not a factor in melanomagenesis. PMID:21457786

  14. Seasonal variation in cutaneous melanoma incidence, link with recent UV levels: a population-based study in Belgium (2006-2011).

    PubMed

    Rommens, Kristine; Jegou, David; De Backer, Hugo; Weyler, Joost

    2016-04-01

    Our objective was to test the hypothesis of a short-term late-promoting effect of ultraviolet (UV) exposure on the development of cutaneous melanoma as an explanation for the summer peak in melanoma incidence. Therefore, we studied seasonal variation in melanoma incidence in relation to recent UV levels by direct UV measurements. Data from the Belgian Cancer Registry on invasive cutaneous melanoma diagnosed during 2006-2011 were used for analysis. Daily data on UV measurements in Belgium were obtained from the Royal Meteorological Institute. Simple and multiple negative binomial regression models were used to investigate the influence of recent UV levels on melanoma incidence. The sum of the mean UV doses in the 2 months before diagnosis was used as a proxy for recent UV exposure in the population. To include variable sunburn risks during the year, the categorical variable 'semester' was created. The incidence of melanoma in Belgium shows a distinct seasonal variation, with peaks in June or July. We found that part of this variation could be explained by the variation in dermatologic activity and, therefore, used this as an offset in our models. We found a linear relationship between melanoma incidence and UV dose in the 2 months preceding the diagnosis. UV levels had more impact in the first semester. The effect of UV levels was not modified by sex nor age. The interaction between anatomical site and UV levels was significant (P=0.002) and showed a higher effect on the upper and lower limbs compared with the head and neck and trunk. PMID:26930049

  15. Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis.

    PubMed

    Heppt, Markus V; Eigentler, Thomas K; Kähler, Katharina C; Herbst, Rudolf A; Göppner, Daniela; Gambichler, Thilo; Ulrich, Jens; Dippel, Edgar; Loquai, Carmen; Schell, Beatrice; Schilling, Bastian; Schäd, Susanne G; Schultz, Erwin S; Matheis, Fanny; Tietze, Julia K; Berking, Carola

    2016-08-01

    Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate. PMID:27294607

  16. Natural and orthogonal model for estimating gene-gene interactions applied to cutaneous melanoma.

    PubMed

    Xiao, Feifei; Ma, Jianzhong; Cai, Guoshuai; Fang, Shenying; Lee, Jeffrey E; Wei, Qingyi; Amos, Christopher I

    2014-05-01

    Epistasis, or gene-gene interaction, results from joint effects of genes on a trait; thus, the same alleles of one gene may display different genetic effects in different genetic backgrounds. In this study, we generalized the coding technique of a natural and orthogonal interaction (NOIA) model for association studies along with gene-gene interactions for dichotomous traits and human complex diseases. The NOIA model which has non-correlated estimators for genetic effects is important for estimating influence from multiple loci. We conducted simulations and data analyses to evaluate the performance of the NOIA model. Both simulation and real data analyses revealed that the NOIA statistical model had higher power for detecting main genetic effects and usually had higher power for some interaction effects than the usual model. Although associated genes have been identified for predisposing people to melanoma risk: HERC2 at 15q13.1, MC1R at 16q24.3 and CDKN2A at 9p21.3, no gene-gene interaction study has been fully explored for melanoma. By applying the NOIA statistical model to a genome-wide melanoma dataset, we confirmed the previously identified significantly associated genes and found potential regions at chromosomes 5 and 4 that may interact with the HERC2 and MC1R genes, respectively. Our study not only generalized the orthogonal NOIA model but also provided useful insights for understanding the influence of interactions on melanoma risk. PMID:24241239

  17. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.

    PubMed

    Amos, Christopher I; Wang, Li-E; Lee, Jeffrey E; Gershenwald, Jeffrey E; Chen, Wei V; Fang, Shenying; Kosoy, Roman; Zhang, Mingfeng; Qureshi, Abrar A; Vattathil, Selina; Schacherer, Christopher W; Gardner, Julie M; Wang, Yuling; Bishop, D Tim; Barrett, Jennifer H; MacGregor, Stuart; Hayward, Nicholas K; Martin, Nicholas G; Duffy, David L; Mann, Graham J; Cust, Anne; Hopper, John; Brown, Kevin M; Grimm, Elizabeth A; Xu, Yaji; Han, Younghun; Jing, Kaiyan; McHugh, Caitlin; Laurie, Cathy C; Doheny, Kim F; Pugh, Elizabeth W; Seldin, Michael F; Han, Jiali; Wei, Qingyi

    2011-12-15

    We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma. PMID:21926416

  18. Analysis and significance of the malignant 'eclipse' during the progression of primary cutaneous human melanomas.

    PubMed

    Kerbel, R S; Kobayashi, H; Graham, C H; Lu, C

    1996-04-01

    Why is it that primary melanomas which are less than 0.76 mm in thickness are almost always curable by surgery whereas thicker lesions are associated with a worse prognosis? Put in another way, why is it that such small increases in tumor thickness beyond 0.76 mm are often associated with the eventual formation of distant metastases and death? Part of the answer lies in the dramatic qualitative changes which can accompany small increases in the size of primary human melanomas. Thus, primary melanomas less than 0.76 mm in thickness usually contain very low proportions of metastatically competent tumor cells, whereas slightly thicker lesions can contain very high proportions of such cells, resulting from a selective growth advantage of the latter in the dermal mesenchyme. This overgrowth process is akin to a 'malignant eclipse' phenomenon (by analogy with a solar eclipse). We have been studying the causes of the malignant eclipse in melanoma, for which there are at least four possibilities: 1) an increase in autocrine, mitogenic growth factors by melanoma cells; 2) a decreased rate of apoptosis in the same population; 3) an acquired resistance to paracrine growth inhibitory factors; and 4) an increased ability to induce an angiogenic response. Evidence exists for all four possibilities. Our experimental approach to studying this problem has relied heavily on the use of cell lines obtained from early stage radial growth phase or vertical growth phase lesions which have a clinical-like inability to grow progressively in nude mice, and variants obtained from such lines which are aggressively tumorigenic. Using such paired lines, and other experimental systems, we have obtained evidence that shows early stage melanoma cell lines may be deficient in inducing angiogenesis, are highly sensitive to the growth inhibitory effects of a plethora of cytokines, including transforming growth factor beta, interleukin-6, and oncostatin M, and are more sensitive to undergoing

  19. A Pooled Analysis of Melanocytic Naevus Phenotype and the Risk of Cutaneous Melanoma at Different Latitudes

    PubMed Central

    Chang, Yu-mei; Newton-Bishop, Julia A; Bishop, D Timothy; Armstrong, Bruce K; Bataille, Veronique; Bergman, Wilma; Berwick, Marianne; Bracci, Paige M; Elwood, J Mark; Ernstoff, Marc S; Green, Adèle C; Gruis, Nelleke A; Holly, Elizabeth A; Ingvar, Christian; Kanetsky, Peter A; Karagas, Margaret R; Le Marchand, Loïc; Mackie, Rona M; Olsson, Håkan; Østerlind, Anne; Rebbeck, Timothy R; Reich, Kristian; Sasieni, Peter; Siskind, Victor; Swerdlow, Anthony J; Titus-Ernstoff, Linda; Zens, Michael S; Ziegler, Andreas; Barrett, Jennifer H

    2008-01-01

    An abnormal naevus phenotype is associated with an increased risk of melanoma. We report a pooled analysis conducted using individual naevus data from 15 case-control studies (5,421 melanoma cases and 6,966 controls). The aims were to quantify better the risk, and to determine whether relative risk varied by latitude. Bayesian unconditional logistic random coefficients models were employed to study the risk associated with naevus characteristics. Participants with whole body naevus counts in the highest of four population-based categories had a greatly increased risk of melanoma compared with those in the lowest category (pooled odds ratio (pOR) 6.9 (95% confidence interval (CI): 4.4, 11.2) for those aged <50 years and pOR 5.1 (95% CI: 3.6, 7.5) for those aged ≥50). The pOR for presence compared with absence of any clinically atypical naevi was 4.0 (95% CI: 2.8, 5.8). The pORs for 1–2 and ≥3 large naevi on the body compared with none were 2.9 (95% CI: 1.9, 4.3) and 7.1 (95% CI: 4.7, 11.6), respectively. The relative heterogeneities among studies were small for most measures of naevus phenotype, except for the analysis of naevus counts on the arms, which may have been due to methodological differences among studies. The pooled analysis also suggested that an abnormal naevus phenotype is associated most with melanomas on intermittently sun-exposed sites. The presence of increased numbers of naevi, large naevi and clinically atypical naevi on the body are robust risk factors for melanoma showing little variation in relative risk among studies performed at different latitudes. PMID:18792098

  20. Lymphoscintigraphy in cutaneous melanoma: a total body atlas of sentinel node mapping.

    PubMed

    Intenzo, Charles M; Kim, Sung M; Patel, Jayant I; Lin, Henry C; Kairys, John C

    2002-01-01

    Lymphoscintigraphy of malignant melanoma has been a reliable method of identifying regional lymph nodes at risk for metastases and is now considered part of the standard of care in patients with melanoma. The status of the sentinel lymph node (SLN) is predictive of the metastatic status of the corresponding regional lymph node group. Lymphatic channel mapping allows identification of the SLN, thereby making selective lymph node sampling possible. Consequently, SLN identification with lymphoscintigraphy results in both less extensive surgery and more efficient pathologic examination of the lymph node specimens. Therefore, it is imperative that radiologists and nuclear medicine physicians know which radiopharmaceuticals to use, recognize different lymphatic drainage patterns from various primary tumor sites throughout the body, use proper imaging techniques, and recognize potential pitfalls in image interpretation. PMID:12006683

  1. Superficial and deep lymph node dissection for stage III cutaneous melanoma: clinical outcome and prognostic factors

    PubMed Central

    2013-01-01

    Background The aims of this retrospective analysis were to evaluate the effect of combined superficial and deep groin dissection on disease-free and melanoma-specific survival, and to identify the most important factors for predicting the involvement of deep nodes according to clinically or microscopically detected nodal metastases. Methods Between January 1996 and December 2005, 133 consecutive patients with groin lymph node metastases underwent superficial and deep dissection at the National Cancer Institute, Naples. Lymph node involvement was clinically evident in 84 patients and detected by sentinel node biopsy in 49 cases. Results The 5-year disease-free survival was significantly better for patients with superficial lymph node metastases than for patients with involvement of both superficial and deep lymph nodes (34.9% vs. 19.0%; P = 0.001). The 5-year melanoma-specific survival was also significantly better for patients with superficial node metastases only (55.6% vs. 33.3%; P = 0.001). Conclusions Metastasis in the deep nodes is the strongest predictor of both disease-free and melanoma-specific survival. Deep groin dissection should be considered for all patients with groin clinical nodal involvement, but might be spared in patients with a positive sentinel node. Prospective studies will clarify the issue further. PMID:23379355

  2. Cutaneous amelanotic signet-ring cell malignant melanoma with interspersed myofibroblastic differentiation in a young cat.

    PubMed

    Hirz, Manuela; Herden, Christiane

    2016-07-01

    The diagnosis of malignant melanoma can be difficult because these tumors can be amelanotic and may contain diverse variants and divergent differentiations, of which the signet-ring cell subtype is very rare and has only been described in humans, dogs, cats, and a hamster. We describe herein histopathologic and immunohistochemical approaches taken to diagnose a case of signet-ring cell malignant melanoma with myofibroblastic differentiation in a cat. A tumor within the abdominal skin of a 2-year-old cat was composed of signet-ring cells and irregularly interwoven streams of spindle cells. Both neoplastic cell types were periodic-acid-Schiff, Fontana, and Sudan black B negative. Signet-ring cells strongly expressed vimentin and S100 protein. Spindle cells strongly expressed vimentin and smooth muscle actin; some cells expressed S100, moderately neuron-specific enolase, and others variably actin and desmin. A few round cells expressed melan A, and a few plump spindle cells expressed melan A and PNL2, confirming the diagnosis of amelanotic signet-ring cell malignant melanoma with myofibroblastic differentiation in a cat. Differential diagnoses were excluded, including signet-ring cell forms of adenocarcinomas, lymphomas, liposarcomas, leiomyosarcomas, squamous cell carcinomas, basal cell carcinomas, and adnexal tumors. PMID:27154314

  3. Diagnostic imaging in dermatology: utility of PET-CT in cutaneous melanoma.

    PubMed

    Sánchez-Sánchez, R; Serrano-Falcón, C; Rebollo Aguirre, A C

    2015-01-01

    Malignant melanoma accounts for 5% of all malignant skin tumors and its incidence is increasing. In the natural course of melanoma, tumors grow locally and can spread via the lymph system or the blood. Because survival is directly related to the stage of the disease at diagnosis, early detection (secondary prevention) has an impact on prognosis. Positron emission tomography (PET) is a nuclear medicine technique that generates images using molecules labeled with positron-emitting isotopes. The most widely used molecule is fluorodeoxyglucose (FDG). Because of the elevated glycolytic rate in tumor cells, which results in increased FDG uptake, greater quantities of FDG become trapped in tumor cells, enabling external detection. Today, most PET scanners are multimodal PET-computed tomography (CT) scanners, which provide more detailed information by combining morphological information with functional PET findings. The possible utility of PET-CT in patients with malignant melanoma is a subject of debate. Various questions have been raised: when the scan should be performed, whether PET-CT has advantages over conventional diagnostic methods, and whether PET-CT provides a real benefit to patients. In this review of the literature, we will analyze each of these questions. PMID:24661948

  4. High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

    ClinicalTrials.gov

    2016-09-14

    Metastatic Non-Cutaneous Melanoma; Non-Cutaneous Melanoma; Recurrent Melanoma of the Skin; Recurrent Non-Cutaneous Melanoma; Stage III Mucosal Melanoma of the Head and Neck; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Stage IVA Mucosal Melanoma of the Head and Neck; Stage IVB Mucosal Melanoma of the Head and Neck; Stage IVC Mucosal Melanoma of the Head and Neck

  5. Efficacy of Skin-Directed Therapy for Cutaneous Metastases From Advanced Cancer: A Meta-Analysis

    PubMed Central

    Spratt, Daniel E.; Gordon Spratt, Elizabeth A.; Wu, Shenhong; DeRosa, Antonio; Lee, Nancy Y.; Lacouture, Mario E.; Barker, Christopher A.

    2014-01-01

    Purpose To perform the first meta-analysis of the efficacy of skin-directed therapies for cutaneous metastases. Methods MEDLINE, EMBASE, The Cochrane Library, and ClinicalTrials.gov databases were searched for reports of prospective clinical studies published between 1960 and 2013 that assessed the response of skin-directed therapy for cutaneous metastases (47 of 2,955 unique studies were selected). Primary end points of the study were complete and objective response rates. Secondary analyses were preplanned and included subgroup analyses by skin-directed therapy, histology, and recurrence rates. Meta-analyses were performed with random-effect modeling, and extent of heterogeneity between studies was determined with the Cochran Q and I2 tests. Results After applying exclusion criteria, 47 prospective studies of 4,313 cutaneous metastases were assessed. Five skin-directed therapies were identified: electrochemotherapy, photodynamic therapy, radiotherapy, intralesional therapy, and topical therapy. Among all cutaneous metastases, complete response rate was 35.5% (95% CI, 27.6% to 44.3%) and objective response rate was 60.2% (95% CI, 50.6% to 69.0%). Overall recurrence rate was estimated to be 9.2% (95% CI, 3.7% to 21.2%). Melanoma and breast carcinoma comprised 96.8% of all cutaneous metastases studied and had similar objective response rates (54.5% [95% CI, 48.3% to 60.7%] and 54.0% [95% CI, 48.3% to 59.7%], respectively). Grade ≥ 3 toxicity was reported in less than 6% of patients. Conclusion Response to skin-directed therapy for cutaneous metastases is high but heterogeneous across treatment modalities, with low rates of recurrence post-treatment. Treatment was generally well tolerated and conferred improvements in quality of life. Standardization of response criteria for cutaneous metastases and treatment algorithms to optimally use the available skin-directed therapies are needed. PMID:25154827

  6. Desmoplastic melanoma--challenges in the diagnosis and management of a rare cutaneous tumor.

    PubMed

    Mărgăritescu, Irina; Chiriţă, Aurel Doru

    2014-01-01

    Desmoplastic melanoma (DM) represents a distinctive rare variant of spindle cell melanoma with a predilection for chronically sun-exposed skin of the elderly. This neoplasm is notoriously difficult to diagnose, both clinically and histopathologically. Therefore, DM is deeply infiltrative at the time of presentation. Histologically, the tumor presents as a proliferation consisting of non-pigmented spindle cells arranged in poorly formed fascicles. The neoplastic cells have a deceptively bland appearance with slightly pleomorphic and hyperchromatic nuclei, inconspicuous nucleoli and low mitotic activity. DM can mimic a whole range of benign and malignant neoplasms with spindle cell and fibrous appearance. Even though S100 remains the first-choice marker for DM, currently, there is no reliable marker with both high sensitivity and specificity for its detection. However, emerging melanoma markers, such as SOX10, have shown promising results in the diagnosis of DM. An accurate diagnosis of DM should always be based on the integration of all the clinical, histological and immunohistochemical features. Once diagnosed, DM should be aggressively excised with at least 2 cm lateral margins and down to the fascia. We present a case of DM that appeared on a non sun-exposed site. The tumor recurred multiple times in spite of repeated surgery involving wide local excisions and histologically reported negative margins. Recurrences are almost always associated with the presence of neurotropism. In our case, the neurotropism was obvious only in the second recurrence. We highlight the difficulties encountered in the diagnosis and management of both the initial tumor and its recurrence. PMID:25329125

  7. Lymphoscintigraphy in cutaneous melanoma: an updated total body atlas of sentinel node mapping.

    PubMed

    Intenzo, Charles M; Truluck, Christina A; Kushen, Medina C; Kim, Sung M; Berger, Adam; Kairys, John C

    2009-01-01

    Lymphoscintigraphy has become part of the standard of care for patients with a new or recurrent diagnosis of melanoma, in helping determine the status of regional lymph nodes. Correct identification of sentinel lymph nodes enables the surgeon to further delineate the extent of malignancy by allowing sampling of the appropriate nodal group. Performing the lymphoscintigraphy prior to the planned operation allows limited surgery with less extensive postoperative morbidity. For this reason, a thorough knowledge of the lymph node drainage patterns from the different primary tumor locations, as well as of proper lymphoscintigraphic techniques and radiopharmaceuticals, constitutes an important armamentarium in the hands of surgeons, radiologists, and nuclear medicine physicians. PMID:19605661

  8. Genetic and environmental melanoma models in fish

    PubMed Central

    Patton, E Elizabeth; Mitchell, David L; Nairn, Rodney S

    2010-01-01

    Experimental animal models are extremely valuable for the study of human diseases, especially those with underlying genetic components. The exploitation of various animal models, from fruitflies to mice, has led to major advances in our understanding of the etiologies of many diseases, including cancer. Cutaneous malignant melanoma is a form of cancer for which both environmental insult (i.e., UV) and hereditary predisposition are major causative factors. Fish melanoma models have been used in studies of both spontaneous and induced melanoma formation. Genetic hybrids between platyfish and swordtails, different species of the genus Xiphophorus, have been studied since the 1920s to identify genetic determinants of pigmentation and melanoma formation. Recently, transgenesis has been used to develop zebrafish and medaka models for melanoma research. This review will provide a historical perspective on the use of fish models in melanoma research, and an updated summary of current and prospective studies using these unique experimental systems. PMID:20230482

  9. HOXC11–SRC-1 regulation of S100beta in cutaneous melanoma: new targets for the kinase inhibitor dasatinib

    PubMed Central

    deBlacam, C; Byrne, C; Hughes, E; McIlroy, M; Bane, F; Hill, A D K; Young, L S

    2011-01-01

    Background: Cutaneous melanoma is an aggressive disease. S100beta is an established biomarker of disease progression; however, the mechanism of its regulation in melanoma is undefined. Methods: Expression of HOXC11 and SRC-1 was examined by immunohistochemistry and immunofluorescence. Molecular and cellular techniques were used to investigate regulation of S100beta, including, western blot, qPCR, ChIP and migration assays. Results: Expression levels of the transcription factor HOXC11 and its coactivator SRC-1 were significantly elevated in malignant melanoma in comparison with benign nevi (P<0.001 and P=0.017, respectively, n=80), and expression of HOXC11 and SRC-1 in the malignant tissue associated with each other (P<0.001). HOXC11 recruitment to the promoter of S100beta was observed in the primary melanoma cell line SKMel28. S100beta expression was found to be dependant on both HOXC11 and SRC-1. Treatment with the Src/Abl inhibitor, dasatinib, reduced HOXC11–SRC-1 interaction and prevented recruitment of HOXC11 to the S100beta promoter. Dasatinib inhibited both mRNA and protein levels of S100beta and reduced migration of the metastatic cell line MeWo. Conclusion: We have defined a signalling mechanism regulating S100beta in melanoma, which can be modulated by dasatinib. Profiling patients for expression of key markers of this network has the potential to increase the efficacy of dasatinib treatment. PMID:21654685

  10. Melanoma

    MedlinePlus

    ... have melanoma that has spread. Help the patient’s immune system fight the cancer Ipilimumab (Yervoy®), which was FDA ... How ipilimumab works : This drug helps the patient’s immune system to recognize, target, and attack cancer cells. Healthy ...

  11. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial

    PubMed Central

    Hayes, Andrew J; Maynard, Lauren; Coombes, Gillian; Newton-Bishop, Julia; Timmons, Michael; Cook, Martin; Theaker, Jeffrey; Bliss, Judith M; Thomas, J Meirion

    2016-01-01

    Summary Background The necessary margin of excision for cutaneous melanomas greater than 2 mm in thickness is controversial. At a median follow-up of 5 years, findings from our previously published randomised trial of narrow (1 cm) versus wide (3 cm) excision margins in patients with thick cutaneous melanomas showed that narrow margins were associated with an increased frequency of locoregional relapse, but no significant difference in overall survival was apparent. We now report a long-term survival analysis of that trial. Methods We did a randomised, open-label multicentre trial in 59 hospitals—57 in the UK, one in Poland, and one in South Africa. Patients with one primary localised cutaneous melanoma greater than 2 mm in Breslow thickness on the trunk or limbs (excluding palms or soles) were randomly assigned (1:1) centrally to receive surgery with either a 1 cm or 3 cm excision margin following an initial surgery. The randomisation lists were generated with random permuted blocks and stratified by centre and extent of initial surgery. The endpoints of this analysis were overall survival and melanoma-specific survival. Analyses were done in the intention-to-treat population. This trial was not registered because it predated mandatory trial registration. Findings Between Dec 16, 1992, and May 22, 2001, we randomly assigned 900 patients to surgery with either a 1 cm excision margin (n=453) or a 3 cm excision margin (n=447). At a median follow-up of 8·8 years (106 months [IQR 76–135], 494 patients had died, with 359 of these deaths attributed to melanoma. 194 deaths were attributed to melanoma in the 1 cm group compared with 165 in the 3 cm group (unadjusted hazard ratio [HR] 1·24 [95% CI 1·01–1·53]; p=0·041). Although a higher number of deaths overall occurred in the 1 cm group compared with the 3 cm group (253 vs 241), the difference was not significant (unadjusted HR 1·14 [95% CI 0·96–1·36]; p=0·14). Surgical complications were reported in 35 (8

  12. P16 protein expression in primary cutaneous melanoma with positive and negative lymph node biopsies: Particular aspects of a study performed at the Hospital de Clinicas de Porto Alegre, Brazil

    PubMed Central

    Fauri, JAC; Ricardi, F; Diehl, ES; Cartell, A; Furian, R; Bakos, L; Edelweiss, MI

    2011-01-01

    BACKGROUND: Cutaneous melanoma dermal invasion, identified through measurement of maximum tumour thickness and sentinel lymph node (SLN) biopsy, is important to establish melanoma prognosis and progression. P16 protein expression has been shown to be a predictive factor for melanoma evolution and prognosis. OBJECTIVE: To investigate p16 protein expression in cutaneous melanomas with and without SLN metastasis. PATIENTS AND METHODS: Sixty-seven paraffin-embedded cutaneous melanoma specimens of patients who had undergone SLN investigation were evaluated from 1995 to 2007. SLN biopsy was negative for metastasis in 34 of these patients (controls); in the remaining 33 patients, SLN biopsy was positive (cases). The expression of p16 protein in the primary tumour was measured using an immunohistochemical assay. The samples were classified according to their nuclear expression. RESULTS: P16 nuclear expression was absent in 14 cases and in 15 controls; P=0.812. There was no statistically significant difference in p16 nuclear expression between cases and controls. CONCLUSIONS: The present study does not support the findings of other studies that suggest p16 protein expression is important in the prognosis of cutaneous melanoma. PMID:22942654

  13. Aetiological factors in cutaneous malignant melanomas seen at a UK skin clinic.

    PubMed Central

    Bell, C M; Jenkinson, C M; Murrells, T J; Skeet, R G; Everall, J D

    1987-01-01

    A clinic-based case-control study was set up in 1961 to examine a variety of aetiological factors in malignant melanoma cases compared with controls with other non-malignant skin conditions. The 268 cases and 1577 controls showed odds ratios of 1.9 for red hair, 2.0 for skin that burns in the sun, and no difference between indoor and outdoor workers or between Celts and other Europeans, consistent with the results of more recent studies. Exposure to 16 specific chemicals was recorded in the study and, among these, men exposed to cutting oils were found to have a significantly raised odds ratio of 1.91. Other statistically significant findings were an elevated risk among women diabetics, particularly in the postmenopausal age group, and a reduced risk of 0.7 among cigarette smokers. PMID:3455424

  14. Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety

    PubMed Central

    Malvehy, J; Hauschild, A; Curiel-Lewandrowski, C; Mohr, P; Hofmann-Wellenhof, R; Motley, R; Berking, C; Grossman, D; Paoli, J; Loquai, C; Olah, J; Reinhold, U; Wenger, H; Dirschka, T; Davis, S; Henderson, C; Rabinovitz, H; Welzel, J; Schadendorf, D; Birgersson, U

    2014-01-01

    Summary Background Even though progress has been made, the detection of melanoma still poses a challenge. In light of this situation, the Nevisense electrical impedance spectroscopy (EIS) system (SciBase AB, Stockholm, Sweden) was designed and shown to have the potential to be used as an adjunct diagnostic tool for melanoma detection. Objectives To assess the effectiveness and safety of the Nevisense system in the distinction of benign lesions of the skin from melanoma with electrical impedance spectroscopy. Methods This multicentre, prospective, and blinded clinical study was conducted at five American and 17 European investigational sites. All eligible skin lesions in the study were examined with the EIS-based Nevisense system, photographed, removed by excisional biopsy and subjected to histopathological evaluation. A postprocedure clinical follow-up was conducted at 7 ± 3 days from the initial measurement. A total of 1951 patients with 2416 lesions were enrolled into the study; 1943 lesions were eligible and evaluable for the primary efficacy end point, including 265 melanomas – 112 in situ and 153 invasive melanomas with a median Breslow thickness of 0·57 mm [48 basal cell carcinomas (BCCs) and seven squamous cell carcinomas (SCCs)]. Results The observed sensitivity of Nevisense was 96·6% (256 of 265 melanomas) with an exact one-sided 95% lower confidence bound estimated at 94·2% and an observed specificity of 34·4%, and an exact two-sided 95% confidence bound estimated at 32·0–36·9%. The positive and negative predictive values of Nevisense were 21·1% and 98·2%, respectively. The observed sensitivity for nonmelanoma skin cancer was 100% (55 of 48 BCCs and seven SCCs) with an exact two-sided 95% confidence bound estimated at 93·5–100·0%. Conclusions Nevisense is an accurate and safe device to support clinicians in the detection of cutaneous melanoma. What's already known about this topic? Although progress has been made in the detection of

  15. Latest Advances in Chemotherapeutic, Targeted and Immune Approaches in the Treatment of Metastatic Melanoma

    PubMed Central

    Shah, Darshil J.; Dronca, Roxana S.

    2014-01-01

    Melanoma is the most dangerous form of skin cancer due to its metastatic potential and is an important public health concern. Melanoma incidence has been increasing worldwide. While potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/ Programmed cell death 1 ligand 1 (PD-L1) pathway blocking antibodies, as well as combinatorial strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review is to summarize the evolution of and recent advances in the treatment of metastatic melanoma. The present review is based on a comprehensive PubMed search between the dates of January 1, 1960, to November 15, 2013, using the search term melanoma or metastatic melanoma combined with terms, such as chemotherapy, immunotherapy, CTLA-4, PD-1, PDL-1, adoptive T cell, targeted therapy, MAPK, molecular biology and survival. PMID:24684873

  16. Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin Cancer Collaborative (ITSCC).

    PubMed

    Zwald, F; Leitenberger, J; Zeitouni, N; Soon, S; Brewer, J; Arron, S; Bordeaux, J; Chung, C; Abdelmalek, M; Billingsley, E; Vidimos, A; Stasko, T

    2016-02-01

    Advancements in solid organ transplantation successfully extend the lives of thousands of patients annually. The tenet of organ stewardship aims to prevent the futile expenditure of scarce donor organs in patient populations with high mortality risk, to the detriment of potential recipients with greater predicted life expectancy. The development of skin cancer posttransplantation portends tremendous morbidity, adversely affecting quality of life for many transplant recipients. This special article, provided by of members of the International Transplant Skin Cancer Collaborative (ITSCC), will provide the transplant professional with a consensus opinion and recommendations as to an appropriate wait period pretransplantation for transplant candidates with a history of either cutaneous squamous cell carcinoma, malignant melanoma, or Merkel cell carcinoma. PMID:26820755

  17. [External ear melanoma].

    PubMed

    Amando García, L; Suárez Nieto, C; Madrigal Rubiales, B; García García, J

    2003-02-01

    Cutaneous melanomas are the tumours that have increased more their incidence in the last fifty years. Melanomas arising from the external auditory canal are extraordinariously unfrequent. These tumours show an aggressive and silent behaviour, and due to this the diagnosis is frequently made in an advanced stage. A male with a malignant melanoma arising from his left external auditory canal was attended in our department, suspecting an epidermoid carcinoma. The clinical findings and the extension of the lesion required a lateral temporal bone resection, parotidectomy and neck dissection to achieve a total resection. We present a review of the literature about this entity and an analysis of the incidence, significance of the lymph node metastases and value of the elective neck dissection. PMID:12802982

  18. A Case of Pediatric Melanoma: Treatment Considerations in Advanced Disease.

    PubMed

    Albino, Frank P; Wood, Benjamin C; Oh, Albert; Rogers, Gary F; Sauerhammer, Tina

    2015-05-01

    We document a 3-year-old healthy African American girl who developed malignant melanoma on her lower extremity. The clinical appearance offered little indication of the lesion's severity (T4), and only the history of de novo presentation and disproportionate growth raised clinical suspicion. This case report highlights the subtle clinical findings of this condition and presents controversies related to surgical management of pediatric melanoma. PMID:26090292

  19. Analysis of the miR-34a locus in 62 patients with familial cutaneous melanoma negative for CDKN2A/CDK4 screening.

    PubMed

    Cozzolino, Angela M; Pedace, Lucia; Castori, Marco; De Simone, Paola; Preziosi, Nicoletta; Sperduti, Isabella; Panetta, Chiara; Mogini, Valerio; De Bernardo, Carmelilia; Morrone, Aldo; Catricalà, Caterina; Grammatico, Paola

    2012-06-01

    MicroRNAs are small non-coding RNAs, which inhibit expression of specific target genes at the post-transcriptional level and are often misregulated in human cancer. Among them, miR-34a is considered a tumor suppressor with a hypothetical role in melanoma tumorigenesis. In this work, 62 Italian index patients with familial melanoma and negative for CDKN2A/CDK4 screening were investigated for miR-34a germline mutations. Eight novel miR-34a sequence variants were identified at both the heterozygous (c.+259G>A, c.+424G>A, c.+1465C>T, c.+1769C>T, c.+2456T>G, c.+2603C>T, c.+2972T>A, c.+3069T>C) and homozygous (c.+424G>A, c.+1465C>T, c.+1769C>T) states. Molecular screening identified all nucleotide changes in a healthy population of 150 controls and demonstrated that they are common polymorphisms. However, statistically significant differences of allele and genotype frequencies were detected for c.+1465C>T and c.+1769C>T, and borderline values for c.+2456T>G. By stratifying patients by relevant clinical features (presence/absence of multiple primary melanoma, Breslow's thickness, phototype and number of nevi), no significant findings were noted except for an association between the c.+424G>A (heterozygous individual GA) and multiple primary melanoma and phototype III-IV. Our preliminary study suggests that miR-34a, although having a role in late tumorigenesis, does not contribute to the inherited susceptibility to cutaneous melanoma. A function as phenotypic modulator in familial melanoma cannot be excluded. PMID:22198089

  20. High frequencies of circulating melanoma-reactive CD8+ T cells in patients with advanced melanoma.

    PubMed

    Letsch, A; Keilholz, U; Schadendorf, D; Nagorsen, D; Schmittel, A; Thiel, E; Scheibenbogen, C

    2000-09-01

    To determine whether circulating tumor-reactive T cells are present in melanoma patients, unstimulated T cells from peripheral blood were tested for recognition of HLA-A2- or HLA-A1-matched melanoma cell lines using the ELISPOT assay. Eleven out of 19 patients with metastatic melanoma had a T-cell response with up to 0.81%, 0.78%, 0. 53%, 0.12%, 0.10%, 0.09%, 0.07%, 0.06%, 0.06%, 0.04%, and 0.04% of peripheral blood mononuclear cells (PBMC) secreting IFNgamma upon exposure to various HLA-A2- or HLA-A1-matched melanoma cell lines. These T-cell responses were mediated by CD8+ T cells and could specifically be blocked by an anti-HLA-A2 antibody in HLA-A2-positive patients. Separation experiments performed in one melanoma patient showed tumor-reactive T cells in both the CD8+ effector T cell (CD45RA+/IFNgamma+) as well as the CD8+ memory T-cell compartment (CD45RO+/IFNgamma+). In 3 out of 5 patients, in whom autologous cell lines were available, similar frequencies of T cells in response to HLA-A1- or HLA-A2-matched allogeneic and autologous tumor cells were observed, while 2 patients had a T-cell response restricted to either the autologous or the allogeneic cell lines. These results give evidence for the presence of tumor-reactive CD8+ T cells in more than half of melanoma patients tested. Although some of these patients have clinical evidence for an immunological-mediated tumor control, several patients have growing tumors suggesting presence of escape mechanisms. PMID:10925359

  1. Quantitative assessment of the association between XRCC1 Arg399Gln and Arg194Trp polymorphisms and risk of cutaneous melanoma.

    PubMed

    Jiang, Huayong; Xu, Weidong; Zhang, Fuli; Wei, Li; Wang, Yajie; Wang, Yadi; Liu, Chuan

    2016-06-01

    Accumulating evidence has suggested that the XRCC1 Arg399Gln and Arg194Trp polymorphisms might be related to cutaneous melanoma susceptibility. However, epidemiologic findings have been inconsistent. We have assessed reported studies by meta-analysis to perform a more precise estimation of the association between the XRCC1 two polymorphisms (Arg399Gln, Arg194Trp) and risk of cutaneous melanoma. A total of seven eligible articles were selected for this meta-analysis, including 3454 cases and 3811 controls for the XRCC1 Arg399Gln polymorphism and 1256 cases and 1575 controls for the XRCC1 Arg194Trp polymorphism. Overall, no significant associations were found in all genetic models when the studies were pooled into the meta-analysis for the Arg399Gln and Arg194Trp polymorphisms. When stratified by source of control, significant associations were found for the Arg399Gln polymorphism in the population-based subgroup under AA versus GG [odds ratio (OR)=1.43, 95% confidence interval (CI)=1.08-1.88]; the dominant model AA/GA versus GG (OR=1.25, 95% CI=1.04-1.51); and the recessive model AA versus GA/GG (OR=1.31, 95% CI=1.01-1.68). No significant associations were found for the Arg194Trp polymorphism in the subgroup analysis. This meta-analysis suggested that the XRCC1 Arg399Gln polymorphism was a risk factor for cutaneous melanoma in population-based subgroup. PMID:26967970

  2. A new understanding in the epidemiology of melanoma

    PubMed Central

    Erdei, Esther; Torres, Salina M

    2011-01-01

    The incidence of melanoma is continuing to increase worldwide. UV exposure is a known risk factor for melanoma. Geographic location is known to influence UV exposure and the distribution of the incidence of melanoma. Furthermore, epidemiologic data suggest that gender and genetics may influence the distribution of melanoma on the body surface and histopathologic characteristics of the lesion. This article describes what is known about the impact of gender, ethnicity and geography on the progression of melanoma. Advanced-stage cutaneous melanoma has a median survival time of less than 1 year. Surgical removal, radiotherapy, chemotherapy, targeted therapies and a variety of immunotherapies have been utilized in the treatment of melanoma. Current treatment strategies and the results of recent clinical trials are also discussed in this article. PMID:21080806

  3. Recommendations for managing cutaneous disorders associated with advancing age

    PubMed Central

    Humbert, Philippe; Dréno, Brigitte; Krutmann, Jean; Luger, Thomas Anton; Triller, Raoul; Meaume, Sylvie; Seité, Sophie

    2016-01-01

    The increasingly aged population worldwide means more people are living with chronic diseases, reduced autonomy, and taking various medications. Health professionals should take these into consideration when managing dermatological problems in elderly patients. Accordingly, current research is investigating the dermatological problems associated with the loss of cutaneous function with age. As cell renewal slows, the physical and chemical barrier function declines, cutaneous permeability increases, and the skin becomes increasingly vulnerable to external factors. In geriatric dermatology, the consequences of cutaneous aging lead to xerosis, skin folding, moisture-associated skin damage, and impaired wound healing. These problems pose significant challenges for both the elderly and their carers. Most often, nurses manage skin care in the elderly. However, until recently, little attention has been paid to developing appropriate, evidence-based, skincare protocols. The objective of this paper is to highlight common clinical problems with aging skin and provide some appropriate advice on cosmetic protocols for managing them. A review of the literature from 2004 to 2014 using PubMed was performed by a working group of six European dermatologists with clinical and research experience in dermatology. Basic topical therapy can restore and protect skin barrier function, which relieves problems associated with xerosis, prevents aggravating moisture-associated skin damage, and enhances quality of life. In conclusion, the authors provide physicians with practical recommendations to assist them in implementing basic skin care for the elderly in an integrated care approach. PMID:26929610

  4. Recommendations for managing cutaneous disorders associated with advancing age.

    PubMed

    Humbert, Philippe; Dréno, Brigitte; Krutmann, Jean; Luger, Thomas Anton; Triller, Raoul; Meaume, Sylvie; Seité, Sophie

    2016-01-01

    The increasingly aged population worldwide means more people are living with chronic diseases, reduced autonomy, and taking various medications. Health professionals should take these into consideration when managing dermatological problems in elderly patients. Accordingly, current research is investigating the dermatological problems associated with the loss of cutaneous function with age. As cell renewal slows, the physical and chemical barrier function declines, cutaneous permeability increases, and the skin becomes increasingly vulnerable to external factors. In geriatric dermatology, the consequences of cutaneous aging lead to xerosis, skin folding, moisture-associated skin damage, and impaired wound healing. These problems pose significant challenges for both the elderly and their carers. Most often, nurses manage skin care in the elderly. However, until recently, little attention has been paid to developing appropriate, evidence-based, skincare protocols. The objective of this paper is to highlight common clinical problems with aging skin and provide some appropriate advice on cosmetic protocols for managing them. A review of the literature from 2004 to 2014 using PubMed was performed by a working group of six European dermatologists with clinical and research experience in dermatology. Basic topical therapy can restore and protect skin barrier function, which relieves problems associated with xerosis, prevents aggravating moisture-associated skin damage, and enhances quality of life. In conclusion, the authors provide physicians with practical recommendations to assist them in implementing basic skin care for the elderly in an integrated care approach. PMID:26929610

  5. 4-Nitroquinoline-1-oxide-induced mutagen sensitivity and risk of cutaneous melanoma: a case–control analysis

    PubMed Central

    Wang, Li-E; Li, Chunying; Xiong, Ping; Gershenwald, Jeffrey E.; Prieto, Victor G.; Duvic, Madeleine; Lee, Jeffrey E.; Grimm, Elizabeth A.; Hsu, T.C.; Wei, Qingyi

    2016-01-01

    Mutagen sensitivity assay, which measures the enhanced cellular response to DNA damage induced in vitro by mutagens/carcinogens, has been used in the study of cancer susceptibility. 4-Nitroquinoline-1-oxide (4-NQO), an ultraviolet (UV) radiation-mimetic chemical, can produce chromosomal breaks in mammalian cells and induce cancer. Given the potential role of 4-NQO as the experimental mutagen substituting for UV as the etiological carcinogen of cutaneous melanoma (CM), we tested the hypothesis that cellular sensitivity to 4-NQO is associated with the risk of developing CM in a case–control study of 133 patients with primary CM and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 µmol/l for 24 h and scored chromatid breaks in 50 well-spread metaphases. Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals. We found that the log-transformed frequency of chromatid breaks was significantly higher in 133 patients than in 176 controls (P = 0.004) and was associated with an increased risk for CM (adjusted odds ratio = 1.78, 95% confidence interval: 1.12–2.84) after adjustment for age and sex. Moreover, as the chromatid break values increased, the risk for CM increased in a dose-dependent manner (Ptrend = 0.003). Further analysis explored a multiplicative interaction between the sensitivity to 4-NQO and a family history of skin cancer (Pinteraction = 0.004) on the risk of CM. Therefore, our findings suggest that sensitivity to 4-NQO may be a risk factor for the risk of CM, which is more sensitive than UV-induced chromosome breaks. PMID:24977319

  6. Influence of having a home garden on personal UVR exposure behavior and risk of cutaneous malignant melanoma in Denmark.

    PubMed

    Idorn, Luise Winkel; Thieden, Elisabeth; Philipsen, Peter Alshede; Wulf, Hans Christian

    2013-03-15

    There is a need for more knowledge concerning the association of higher socioeconomic status (SES) with cutaneous malignant melanoma (CMM). Having a home garden is associated with a higher SES. We aimed to study the influence of having a home garden on UVR exposure behavior and risk of CMM. Register study: We collected information from Danish national registers about gender, age, type of home and CMM among persons aged 16-75 in 2002-2006. A total of 5,118 CMM cases were identified. Risk of CMM of the trunk was increased by 46% (p < 0.001, 95% confidence interval (CI): 31-63) and risk of CMM of the extremities by 34% (p < 0.001, 95% CI: 20-49) among people with home gardens. Dosimeter study: During a summer season 194 participants living in the Capital area, Denmark, equally distributed in homes with and without a garden, wore personal electronic UVR dosimeters measuring time-stamped UVR doses continuously and filled in sun exposure diaries. While no difference was found in estimated yearly UVR dose between groups, participants with a home garden had more days exposing shoulders or upper body, and upper extremities outdoors than those without a garden (p = 0.026, age adjusted). People with a home garden are at increased risk of CMM of the trunk and extremities-body sites that seems to be exposed to a higher extent among people with home gardens. People with a higher SES are more likely to have a home garden. This may partly explain the well-known association of higher SES with CMM incidence. PMID:22821769

  7. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells

    PubMed Central

    Gopal, Y.N. Vashisht; Deng, Wanleng; Woodman, Scott E.; Komurov, Kakajan; Ram, Prahlad; Smith, Paul D.; Davies, Michael A.

    2014-01-01

    The majority of melanomas demonstrate constitutive activation of the RAS-RAF-MEK-MAPK pathway. AZD6244 is a selective MEK1/2 inhibitor which markedly reduces tumor P-MAPK levels, but it produced few clinical responses in melanoma patients. An improved understanding of the determinants of resistance to AZD6244 may lead to improved patient selection and effective combinatorial approaches. The effects of AZD6244 on cell growth and survival were tested in a total of 14 Braf-mutant and 3 wild-type human cutaneous melanoma cell lines. Quantitative assessment of phospho-protein levels in the Braf-mutant cell lines by reverse phase protein array (RPPA) analysis showed no significant association between P-MEK or P-MAPK levels and AZD6244 sensitivity, but activation-specific markers in the PI3K-AKT pathway correlated with resistance. We also identified resistant cell lines without basal activation of the PI3K-AKT pathway. RPPA characterization of the time-dependent changes in signaling pathways revealed that AZD6244 produced durable and potent inhibition of P-MAPK in sensitive and resistant Braf-mutant cell lines, but several resistant lines demonstrated AZD6244-induced activation of AKT. In contrast, sensitive cell lines demonstrated AZD6244 treatment-induced upregulation of PTEN protein and mRNA expression. Inhibition of AKT, TORC1/2, or IGF1R blocked AZD6244-induced activation of AKT and resulted in synergistic cell killing with AZD6244. These findings identify basal and treatment-induced regulation of the PI3K-AKT pathway as a critical regulator of AZD6244 sensitivity in Braf-mutant cutaneous melanoma cells, the novel regulation of PTEN expression by AZD6244 in sensitive cells, and suggest new combinatorial approaches for patients. PMID:20959481

  8. [Melanoma].

    PubMed

    Uhara, Hisashi

    2016-04-01

    Since 2011, several effective drugs for patients with metastatic melanoma, including BRAF inhibitors, MEK inhibitors, and immune checkpoint inhibitors, have been approved. The combination of BRAF and MEK inhibitors achieve response rates of 70% and a median progression-free survival of >11 months in patients. The combination of ipilimumab and nivolumab has shown response rates of up to 60-70% and a median progression-free survival of 11-14 months, despite increased toxicities. Moreover, many clinical trials for new combination therapies are still ongoing. PMID:27220785

  9. Skin toxicity in BRAF(V600) mutated metastatic cutaneous melanoma patients treated with vemurafenib

    PubMed Central

    Huszno, Joanna; Slomian, Grzegorz; Nieckula, Jaroslaw

    2016-01-01

    Introduction The use of orally available BRAF kinase inhibitor – vemurafenib is associated with numerous adverse skin reactions. Aim To assess the safety and early side effects of vemurafenib treatment in the unselected group of patients treated at the outpatient clinic, in particular the assessment of the incidence of skin cancer. Material and methods We carried out a systematic study of patients (pts) treated with vemurafenib. Skin toxicity during vemurafenib therapy was analyzed. Toxicity was determined on the basis of the toxicity scale CTCAE, version 4.0. Results The most common cutaneous side effects were hyperkeratotic perifollicular rash (69%) and photosensitivity (15%). Skin rash developed more frequently in the first month of treatment. Squamous cell carcinoma occurred in 38% of patients. Patients with skin cancer development during vemurafenib therapy had non-significantly longer overall survival (OS) than patients without skin cancer, p = 0.4. Skin cancer developed more often in women than in men (60% vs. 25%), p = 0.249. It was detected only in patients with normal weight compared to overweight patients (55% vs. 0), p = 0.09. The median OS was 26 months and median OS from the time of distant metastases diagnosis was 9.8 months. In patients with a low body mass index, shorter OS was observed, p = 0.09. Conclusions The incidence of squamous cell carcinoma was high (38%). This study has many limitations mostly due to a small group of patients. That is why the results should be taken into consideration with caution. The proper symptomatic treatment in cooperation with dermatologists allows to continue the vemurafenib therapy. PMID:26985180

  10. Histologic and Phenotypic Factors and MC1R Status Associated with BRAF(V600E), BRAF(V600K), and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas.

    PubMed

    Hacker, Elke; Olsen, Catherine M; Kvaskoff, Marina; Pandeya, Nirmala; Yeo, Abrey; Green, Adèle C; Williamson, Richard M; Triscott, Joe; Wood, Dominic; Mortimore, Rohan; Hayward, Nicholas K; Whiteman, David C

    2016-04-01

    Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF(V600E) (26%), BRAF(V600K) (8%), BRAF(other) (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF(V600E) mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF(V600K) mutations were also associated with high nevus counts. Both BRAF(V600K) and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports. PMID:26807515

  11. Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma?

    PubMed

    Carlino, Matteo S; Long, Georgina V

    2016-08-15

    Ipilimumab, an inhibitor of CTLA-4 on T cells, was the first drug to improve overall survival in patients with advanced melanoma. Subsequently, inhibitors of PD-1, including nivolumab and pembrolizumab, were shown to be superior to ipilimumab with a more favorable safety profile. The combination of ipilimumab and nivolumab is associated with a further improvement in response rate and progression-free survival; however, the combination is associated with an increased rate of immune-related toxicities. In 2015, the FDA approved the combination for the treatment of BRAF wild-type advanced melanoma. This review examines the preclinical rationale for the combination of ipilimumab and nivolumab as well as the efficacy and toxicity data from clinical trials in patients with advanced melanoma. Finally, alternative treatment options are discussed with a focus on patient selection. Clin Cancer Res; 22(16); 3992-8. ©2016 AACR. PMID:27340279

  12. Advances in the treatment of cutaneous lupus erythematosus.

    PubMed

    Kuhn, A; Landmann, A; Wenzel, J

    2016-07-01

    Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity which may present with skin manifestations as primary sign of the disease (cutaneous lupus erythematosus, CLE) or as part of a disease spectrum (systemic lupus erythematosus, SLE). To date, no drugs are approved specifically for the treatment of CLE and only single agents have been applied in randomized controlled trials. Therefore, topical and systemic agents are used "off-label", primarily based on open-label studies, case series, retrospective analyses, and expert opinions. In contrast, several agents, such as hydroxychloroquine, chloroquine, cyclophosphamide, azathioprine, and belimumab, are approved for the treatment of SLE. Recent approaches in the understanding of the molecular pathogenesis of LE enabled the development of further new agents, which target molecules such as interleukin 6 (IL-6) and interferon (IFN). Only single trials, however, applied these new agents in patients with cutaneous involvement of the disease and/or included endpoints which evaluated the efficacy of these agents on skin manifestations. This article provides an updated review on new and recent approaches in the treatment of CLE. PMID:27252259

  13. Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor

    PubMed Central

    Kim, Kevin B.; Kefford, Richard; Pavlick, Anna C.; Infante, Jeffrey R.; Ribas, Antoni; Sosman, Jeffrey A.; Fecher, Leslie A.; Millward, Michael; McArthur, Grant A.; Hwu, Patrick; Gonzalez, Rene; Ott, Patrick A.; Long, Georgina V.; Gardner, Olivia S.; Ouellet, Daniele; Xu, Yanmei; DeMarini, Douglas J.; Le, Ngocdiep T.; Patel, Kiran; Lewis, Karl D.

    2013-01-01

    Purpose BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. Patients and Methods This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. Results In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. Conclusion Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor–naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma. PMID:23248257

  14. MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project

    PubMed Central

    Pasquali, Elena; García-Borrón, José C.; Fargnoli, Maria Concetta; Gandini, Sara; Maisonneuve, Patrick; Bagnardi, Vincenzo; Specchia, Claudia; Liu, Fan; Kayser, Manfred; Nijsten, Tamar; Nagore, Eduardo; Kumar, Rajiv; Hansson, Johan; Kanetsky, Peter A.; Ghiorzo, Paola; Debniak, Tadeusz; Branicki, Wojciech; Gruis, Nelleke A.; Han, Jiali; Dwyer, Terry; Blizzard, Leigh; Landi, Maria Teresa; Palmieri, Giuseppe; Ribas, Gloria; Stratigos, Alexander; Council, M.Laurin; Autier, Philippe; Little, Julian; Newton-Bishop, Julia; Sera, Francesco; Raimondi, Sara

    2015-01-01

    The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a Summary Odds Ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17–1.84) for V60L to 2.74 (1.53–4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared to wild-type subjects (SOR; 95%CI: 1.66; 1.41–1.96), and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R–associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06–4.80) for subjects with no freckles, no red hair and skin type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly-pigmented, fair-skinned subjects. PMID:24917043

  15. Advances in Personalized Targeted Treatment of Metastatic Melanoma and Non-Invasive Tumor Monitoring

    PubMed Central

    Klinac, Dragana; Gray, Elin S.; Millward, Michael; Ziman, Mel

    2013-01-01

    Despite extensive scientific progress in the melanoma field, treatment of advanced stage melanoma with chemotherapeutics and biotherapeutics has rarely provided response rates higher than 20%. In the past decade, targeted inhibitors have been developed for metastatic melanoma, leading to the advent of more personalized therapies of genetically characterized tumors. Here we review current melanoma treatments and emerging targeted molecular therapies. In particular we discuss the mutant BRAF inhibitors Vemurafenib and Dabrafenib, which markedly inhibit tumor growth and advance patients’ overall survival. However this response is almost inevitably followed by complete tumor relapse due to drug resistance hampering the encouraging initial responses. Several mechanisms of resistance within and outside the MAPK pathway have now been uncovered and have paved the way for clinical trials of combination therapies to try and overcome tumor relapse. It is apparent that personalized treatment management will be required in this new era of targeted treatment. Circulating tumor cells (CTCs) provide an easily accessible means of monitoring patient relapse and several new approaches are available for the molecular characterization of CTCs. Thus CTCs provide a monitoring tool to evaluate treatment efficacy and early detection of drug resistance in real time. We detail here how advances in the molecular analysis of CTCs may provide insight into new avenues of approaching therapeutic options that would benefit personalized melanoma management. PMID:23515890

  16. Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects.

    PubMed

    Kosiniak-Kamysz, Agnieszka; Marczakiewicz-Lustig, Anna; Marcińska, Magdalena; Skowron, Małgorzata; Wojas-Pelc, Anna; Pośpiech, Ewelina; Branicki, Wojciech

    2014-08-01

    Cutaneous malignant melanoma (CMM) is a malicious human skin cancer that primarily affects individuals with light pigmentation and heavy sun exposure, but also has a known familial association. Multiple genes and polymorphisms have been reported as low-penetrance susceptibility loci for CMM. Here, we examined 33 candidate polymorphisms located in 11 pigmentation genes and the vitamin D receptor gene (VDR) in a population of 130 cutaneous melanoma patients and 707 healthy controls. The genotypes obtained were evaluated for main association effects and potential gene-gene interactions. MC1R, TYR, VDR and SLC45A2 genes were found to be associated with CMM in our population. The results obtained for major function MC1R mutations were the most significant [with odds ratio (OR)=1.787, confidence interval (CI)=1.320-2.419 and P=1.715(-4)], followed by TYR (rs1393350) (with OR=1.569, CI=1.162-2.118, P=0.003), VDR (GCCC haplotype in rs2238136-rs4516035-rs7139166-rs11568820 block) (with OR=5.653, CI=1.794-17.811, P=0.003) and SLC45A2 (rs16891982) (with OR=0.238, CI=0.057-0.987, P=0.048). The study also detected significant intermolecular epistatic effects between MC1R and TYR, SLC45A2 and VDR, HERC2 and VDR, OCA2 and TPCN2, as well as intramolecular interactions between variants within the genes MC1R and VDR. In the final multivariate logistic regression model for CMM development, only the gene-gene interactions discovered remained significant, showing that epistasis may be an important factor in the risk of melanoma. PMID:24926819

  17. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies

    PubMed Central

    Flavin, Marisa; Panageas, Katherine S.; Ayers, Gregory D.; Zhao, Zhiguo; Iams, Wade T.; Colgan, Marta; DeNoble, Sarah; Terry, Charles R.; Berry, Elizabeth G.; Iafrate, A. John; Sullivan, Ryan J.; Carvajal, Richard D.; Sosman, Jeffrey A.

    2015-01-01

    Activating NRAS mutations are found in 15-20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g. NRAS mutations) correlate with benefit from immune therapy in melanoma. We identified 229 melanoma patients treated with immune therapies (interleukin-2, ipilimumab, or anti-programmed cell-death-1/ligand-1 (PD-1/PD-L1)) at three centers, and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 melanoma patients, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF WT. The NRAS-mutant cohort had superior or a trend to superior outcomes compared to the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, p=0.04), response to any line of immune therapy (32% vs. 20%, p=0.07), clinical benefit (response + stable disease lasting ≥24 weeks; 50% vs. 31%, p<0.01), and progression-free survival (median 4.1 vs. 2.9 months, p=0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared to other genotypes (8/12 vs. 9/20 samples with ≥1% expression; 6/12 vs 6/20 samples with ≥5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared to other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression. PMID:25736262

  18. Talimogene Laherparepvec for the Treatment of Advanced Melanoma.

    PubMed

    Ott, Patrick A; Hodi, F Stephen

    2016-07-01

    Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus that mediates local and systemic antitumor activity by direct cancer cell lysis and an "in situ vaccine" effect. Based on an increased durable response rate compared with granulocyte macrophage-colony stimulating factor in a randomized phase III trial, it was approved by the FDA for the treatment of melanoma metastatic to skin or lymph nodes. The drug is currently in clinical trials as monotherapy and in combination with immune-checkpoint inhibitors and radiotherapy in melanoma and other cancers. The mechanism of action, toxicity, and efficacy as well as its role in current clinical practice and potential future applications are reviewed. Clin Cancer Res; 22(13); 3127-31. ©2016 AACR. PMID:27146699

  19. The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells.

    PubMed

    Whipple, Chery A; Boni, Andrea; Fisher, Jan L; Hampton, Thomas H; Tsongalis, Gregory J; Mellinger, Diane L; Yan, Shaofeng; Tafe, Laura J; Brinckerhoff, Constance E; Turk, Mary J; Mullins, David W; Fadul, Camilo E; Ernstoff, Marc S

    2016-06-01

    The advent of drugs targeting the mitogen-activated protein kinase (MAPK) pathway has markedly changed the treatment of advanced-stage melanoma harboring BRAF mutations. However, drug resistance, through mechanisms not well elucidated, often occurs. A better understanding of how melanoma-derived immunologically active molecules change in response to MAPK inhibition of BRAF mutated (BRAF) and BRAF wild type (BRAF) melanomas could help identify promising treatment combinations of small molecule inhibitors and immunotherapy. To this aim, we treated 13 BRAF and 13 BRAF mutated human melanoma cell lines with either a specific BRAF inhibitor or an MEK1/2 inhibitor and analyzed changes in the secretion of 42 selected cytokines, chemokines, and growth factors. We also measured changes in the expression levels of immunologically relevant melanoma cell surface markers. The BRAF melanomas showed minimal changes in response to the inhibitors, whereas the BRAF cell lines showed, on average, a significant decrease in IFNα2, interleukin-7, Fractalkine, GCSF, GRO, TGFα2, interleukin-8, and VEGF, as well as a reduction in pERK and pMEK protein levels, upon MAPK pathway blockade. BRAF inhibition in BRAF cell lines also resulted in significant changes in the expression of several surface markers including upregulation of β2-microglobulin as well as a decrease in MIC A/B and TRAIL-R2. These results indicate that MAPK pathway inhibition leads to changes in the immunological properties of mutant BRAF melanoma cells and lends support for future studies aimed at designing effective treatment strategies that combine BRAF and MEK inhibition with immunotherapy. PMID:26974965

  20. Cutaneous wound healing: Current concepts and advances in wound care

    PubMed Central

    Klein, Kenneth C; Guha, Somes Chandra

    2014-01-01

    A non-healing wound is defined as showing no measurable signs of healing for at least 30 consecutive treatments with standard wound care.[1] It is a snapshot of a patient's total health as well as the ongoing battle between noxious factors and the restoration of optimal macro and micro circulation, oxygenation and nutrition. In practice, standard therapies for non-healing cutaneous wounds include application of appropriate dressings, periodic debridement and eliminating causative factors.[2] The vast majority of wounds would heal by such approach with variable degrees of residual morbidity, disability and even mortality. Globally, beyond the above therapies, newer tools of healing are selectively accessible to caregivers, for various logistical or financial reasons. Our review will focus on the use of hyperbaric oxygen therapy (HBOT), as used at our institution (CAMC), and some other modalities that are relatively accessible to patients. HBOT is a relatively safe and technologically simpler way to deliver care worldwide. However, the expense for including HBOT as standard of care for recognized indications per UHMS(Undersea and Hyperbaric Medical Society) may vary widely from country to country and payment system.[3] In the USA, CMS (Centers for Medicare and Medicaid Services) approved indications for HBOT vary from that of the UHMS for logistical reasons.[1] We shall also briefly look into other newer therapies per current clinical usage and general acceptance by the medical community. Admittedly, there would be other novel tools with variable success in wound healing worldwide, but it would be difficult to include all in this treatise. PMID:25593414

  1. Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D; Green, Myke R; Wahner Hendrickson, Andrea E; Abraham, Ivo

    2016-07-01

    Anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta-analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti-CTLA-4 or anti-PD-1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression-free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76-0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59-0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76-0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune-related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65-9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti-PD-1 treatment compared to anti-CTLA-4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti-PD-1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients. PMID:27167347

  2. Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

    PubMed Central

    Pécuchet, N; Lebbe, C; Mir, O; Billemont, B; Blanchet, B; Franck, N; Viguier, M; Coriat, R; Tod, M; Avril, M-F; Goldwasser, F

    2012-01-01

    Background: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. Patients and methods: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. Results: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6–78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11–0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13–0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand–foot skin reaction were correlated with drug exposure. Conclusions: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications. PMID:22767146

  3. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

    PubMed Central

    Tran, Khiem A; Cheng, Michelle Y; Mitra, Anupam; Ogawa, Hiromi; Shi, Vivian Y; Olney, Laura P; Kloxin, April M; Maverakis, Emanual

    2016-01-01

    The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy. PMID:26730180

  4. Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

    PubMed Central

    Viola, Joana R.; Rafael, Diana F.; Wagner, Ernst; Besch, Robert; Ogris, Manfred

    2013-01-01

    Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed. PMID:23634303

  5. Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma

    PubMed Central

    2013-01-01

    Background Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. Methods Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening. Results Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients’ geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases. Conclusions Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease. PMID:23987572

  6. Phase 1 Study of Erlotinib Plus Radiation Therapy in Patients With Advanced Cutaneous Squamous Cell Carcinoma

    SciTech Connect

    Heath, C. Hope; Deep, Nicholas L.; Nabell, Lisle; Carroll, William R.; Desmond, Renee; Clemons, Lisa; Spencer, Sharon; Magnuson, J. Scott; Rosenthal, Eben L.

    2013-04-01

    Purpose: To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Methods and Materials: This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method. Results: The majority of patients were male (87%) and presented with T4 disease (93%). The most common toxicity attributed to erlotinib was a grade 2-3 dermatologic reaction occurring in 100% of the patients, followed by mucositis (87%). Diarrhea occurred in 20% of the patients. The 2-year recurrence rate was 26.7%, and mean time to cancer recurrence was 10.5 months. Two-year overall survival was 65%, and disease-free survival was 60%. Conclusions: Erlotinib and radiation therapy had an acceptable toxicity profile in patients with advanced cutaneous squamous cell carcinoma. The disease-free survival in this cohort was comparable to that in historical controls.

  7. Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy.

    PubMed

    Niezgoda, Anna; Niezgoda, Piotr; Czajkowski, Rafał

    2015-01-01

    The incidence of malignant melanoma is increasing. The majority of patients are diagnosed in early stages when the disease is highly curable. However, the more advanced or metastatic cases have always been a challenge for clinicians. The poor prognosis for patients with melanoma is now changing as numerous of promising approaches have appeared recently. The discovery of aberrations of pathways responsible for intracellular signal transduction allowed us to introduce agents specifically targeting the mutated cascades. Numerous clinical studies have been conducted to improve effectiveness of melanoma treatment. From 2011 until now, the U.S. FDA has approved seven novel agents, such as BRAF-inhibitors (vemurafenib 2011, dabrafenib 2013), MEK-inhibitors (trametinib 2013), anti-PD1 antibodies (nivolumab 2014, pembrolizumab 2014), anti-CTLA-4 antibody (ipilimumab 2011), or peginterferon-alfa-2b (2011) intended to be used in most advanced cases of melanoma. Nevertheless, clinicians continue working on new possible methods of treatment as resistance to the novel drugs is a commonly observed problem. This paper is based on latest data published until the end of January 2015. PMID:26171394

  8. Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy

    PubMed Central

    Niezgoda, Anna; Niezgoda, Piotr; Czajkowski, Rafał

    2015-01-01

    The incidence of malignant melanoma is increasing. The majority of patients are diagnosed in early stages when the disease is highly curable. However, the more advanced or metastatic cases have always been a challenge for clinicians. The poor prognosis for patients with melanoma is now changing as numerous of promising approaches have appeared recently. The discovery of aberrations of pathways responsible for intracellular signal transduction allowed us to introduce agents specifically targeting the mutated cascades. Numerous clinical studies have been conducted to improve effectiveness of melanoma treatment. From 2011 until now, the U.S. FDA has approved seven novel agents, such as BRAF-inhibitors (vemurafenib 2011, dabrafenib 2013), MEK-inhibitors (trametinib 2013), anti-PD1 antibodies (nivolumab 2014, pembrolizumab 2014), anti-CTLA-4 antibody (ipilimumab 2011), or peginterferon-alfa-2b (2011) intended to be used in most advanced cases of melanoma. Nevertheless, clinicians continue working on new possible methods of treatment as resistance to the novel drugs is a commonly observed problem. This paper is based on latest data published until the end of January 2015. PMID:26171394

  9. Nursing the patient with malignant melanoma: early intervention.

    PubMed

    Wheeler, Tracey

    This article summarizes the key facts about cutaneous melanoma, including its causative factors, incidence, classification, diagnosis and management guidelines. The role of the nurse is then discussed, in particular health education post-diagnosis, the specific information required to improve safety in the sun, the teaching of self-examination techniques, and the provision of psychological support throughout diagnosis and follow-up. Since most melanomas have an excellent prognosis, the majority of nursing care is at the educational and supportive level, however, melanoma can be an aggressive disease, and some aspects of nursing the patient with advanced disease are also considered. PMID:19273989

  10. Deconstructing the role of the ECM microenvironment on drug efficacy targeting MAPK signaling in a pre-clinical platform for cutaneous melanoma

    PubMed Central

    Blehm, Benjamin H.; Jiang, Nancy; Kotobuki, Yorihisa; Tanner, Kandice

    2015-01-01

    Therapeutics targeting the BRAF kinase in cutaneous melanoma have significantly improved patient survival. However, durable responses in the face of metastatic disease are rarely realized where the problem of brain metastases is generally growing in magnitude. Tumor and stromal cells dynamically remodel the extracellular matrix (ECM) during the establishment of a metastatic lesion. We reasoned that ECM composition strongly determines drug efficacy on cell motility, adhesion and viability rendering one drug more potent and another less so. To test this hypothesis, we constructed platforms recreating the ECM composition due to the stroma and tumor cells, mimicking the brain’s perivascular niche and hyaluronic acid (HA) rich parenchyma. Using human melanoma cell lines, we observed that cell adhesion was minimally affected by BRAF inhibition but ablated by ERK inhibition. Cell motility was impaired for both drugs. We determined that the composition and architecture of the ECM niche modulated drug efficacy. In one series, potency of BRAF inhibition was blunted in 3D Fibronectin-HA hydrogels whereas Laminin-HA hydrogels protected against ERK inhibition. In the other series, Laminin blunted drug efficacy, despite both series sharing the same BRAF mutation. These data reinforce the importance of contextual drug assessment in designing future therapeutics. PMID:25934286

  11. Prevalence of Germline BAP1, CDKN2A, and CDK4 Mutations in an Australian Population-Based Sample of Cutaneous Melanoma Cases.

    PubMed

    Aoude, Lauren G; Gartside, Michael; Johansson, Peter; Palmer, Jane M; Symmons, Judith; Martin, Nicholas G; Montgomery, Grant W; Hayward, Nicholas K

    2015-04-01

    Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the sample. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence. PMID:25787093

  12. Intratumoral expression of cyclooxygenase-2 (COX-2) is a negative prognostic marker for patients with cutaneous melanoma.

    PubMed

    Kuźbicki, Łukasz; Lange, Dariusz; Stanek-Widera, Agata; Chwirot, Barbara W

    2016-10-01

    Because of the well-known heterogeneity of melanomas, prognosis of the disease is often difficult to assess even for lesions classified in similar stages. The aim of this study was to assess the usefulness of COX-2 as a melanoma prognostic marker and to establish an optimum algorithm for analysis of COX-2 expression levels in lesions of interest. Expression of COX-2 was detected immunohistochemically in standard sections of formalin-fixed paraffin-embedded tissue samples of 85 primary melanomas, 36 lymph node metastases, and five skin metastases including 39 cases of paired primary and metastatic lesions obtained from the same patient. Enhanced expression of COX-2 in primary melanomas is an indicator of poorer prognosis. A significant correlation was found between high expression of COX-2 in primary lesions and shorter survival. The enhancement of COX-2 expression is also positively correlated with other prognostic factors such as tumor thickness and infiltration level, ulceration, high mitotic index, more invasive histologic type, vertical growth phase, and lymph node metastasis. On the whole, the results suggest that intratumoral expression of COX-2 is a strong negative prognostic marker for patients with melanoma. Moreover, our work shows that a simple and objective immunohistochemical scoring algorithm involving the determination of only a percentage fraction of positively stained cells is sufficient to obtain the prognostic information. PMID:27391144

  13. Adjuvant Therapy: Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad; Kirkwood, John M.

    2011-01-01

    With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway. PMID:22220281

  14. Unmet clinical needs in the management of advanced melanoma: findings from a survey of oncologists.

    PubMed

    Jones, C; Clapton, G; Zhao, Z; Barber, B; Saltman, D; Corrie, P

    2015-11-01

    Advanced melanoma is a life-threatening cancer with limited life expectancy. The recent introduction of new targeted systemic therapies has provided clinicians with the means to potentially extend survival for the first time. However, the chance of cure remains very low and treatment-induced toxicity is well described. This qualitative study was undertaken to evaluate clinicians' assessment regarding the key concerns in managing advanced melanoma following the introduction of these new treatments. Three hundred and forty-three oncologists were surveyed online between August and November 2012 (in 11 countries) and March and April 2013 (in an additional country). Analysis of free-text responses identified 23 clinical issues of concern across all countries. Of these, the most common clinical concerns were drug toxicity and tolerability, followed by limited treatment effectiveness and limited treatment options. These results suggest that despite the promise of the two new agents in the field, clinicians are still concerned about the limitations of current treatment options, recognising that there remains a significant unmet need in the treatment of advanced melanoma. PMID:26222136

  15. High expression of immunotherapy candidate proteins gp100, MART-1, tyrosinase and TRP-1 in uveal melanoma.

    PubMed Central

    de Vries, T. J.; Trancikova, D.; Ruiter, D. J.; van Muijen, G. N.

    1998-01-01

    In the treatment of cutaneous melanoma, provisional therapeutic strategies have been designed to combat tumour load using T cells that are sensitized with peptides derived from melanoma autoantigens, such as glycoprotein 100 (gp100), melanoma antigen recognized by T cells 1 (MART-1 or MelanA), tyrosinase and tyrosinase-related protein 1 (TRP-1). We recently found that gp100, MART-1 and tyrosinase are heterogeneously expressed in human cutaneous melanoma (De Vries et al (1997) Cancer Res 57: 3223-3229). Here, we extended our investigations on expression of these immunotherapy candidate proteins to uveal melanoma lesions. Cryostat sections from 11 spindle-type, 21 mixed and epithelioid tumours and four metastasis lesions were stained with antibodies specifically recognizing gp100, MART-1, tyrosinase and TRP-1. In addition, we used the DOPA reaction to detect tyrosinase enzyme activity as a confirmation of the tyrosinase immunohistochemical results. High expression of gp100, MART-1 and tyrosinase was found in the uveal melanoma lesions: 80% of the lesions displayed 75-100% positive tumour cells. TRP-1 positivity was slightly less: approximately 65% of the lesions stained in the 75-100% positive tumour cell category. All uveal melanoma lesions were positive for the four markers studied, this being in contrast to cutaneous melanoma where 17% of the advanced primary lesions and metastases were negative. The presence of these antigens was a little lower in metastases. We conclude that uveal melanomas and their metastases express melanocyte-lineage immunotherapy candidate proteins very abundantly. Uveal melanomas differ in this respect from cutaneous melanoma, in which the expression of these immunotherapy antigens was much more heterogeneous. This makes uveal melanoma a suitable candidate tumour for immunotherapeutic approaches. Images Figure 1 Figure 3 PMID:9820172

  16. Limited genomic heterogeneity of circulating melanoma cells in advanced stage patients

    NASA Astrophysics Data System (ADS)

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Edward; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-02-01

    Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml-1). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.

  17. Biomarkers in melanoma.

    PubMed

    Griewank, Klaus G

    2016-01-01

    Malignant melanoma remains the skin cancer with the highest number of mortalities worldwide. While early diagnosis and complete surgical excision remain the best possibility for curing disease, prognosis at the stage of metastasis is still poor. Recent years have brought about considerable advances in terms of understanding the pathogenesis of melanoma and treating advanced disease. The discovery of activating BRAF mutations in around 50% of tumors has led to the introduction of targeted therapies downregulating BRAF signaling output. These have been further refined as combination therapies, which by targeting multiple targets have further improved the clinical outcome. A comparable, potentially even superior therapeutic alternative has been the introduction of immunotherapeutic approaches, including PD-1 and CTLA-4 checkpoint blockade therapies. Despite all genetic knowledge acquired in recent years, a clearly applicable prognostic signature of clinical value has not been established. General prognostic assessment of cutaneous melanoma remains based on clinical and pathological criteria (most importantly tumor thickness). The main challenges lying ahead are to establish a reliable prognostic test effectively determining which tumors will metastasize. Additionally establishing biomarkers which will allow patients to be stratified according to the most promising systemic therapy (immunotherapies and/or BRAF inhibitor therapies) is of utmost importance for patients with metastasized disease. Identifying serum biomarkers enabling disease to be monitored as well as determining tumor properties (i.e. resistance) would also be of great value. While initial results have proven promising, there remains much work to be done. PMID:27467728

  18. The evolution of combined molecular targeted therapies to advance the therapeutic efficacy in melanoma: a highlight of vemurafenib and cobimetinib

    PubMed Central

    Medina, Theresa M; Lewis, Karl D

    2016-01-01

    Metastatic melanoma is an aggressive, rapidly progressive disease which historically had very few effective treatment options. However, since 2011, the therapeutic landscape of melanoma has undergone a dramatic transformation with two distinct approaches and has catalyzed the successful advancement in the clinical field of immuno-oncology. In addition, the recognition of a key oncogenic driver mutation in melanoma, BRAF, stimulated the development of multiple potent kinase inhibitors which has also influenced the expansion and use of targeted agents in the practice of oncology. Vemurafenib, the initial BRAF inhibitor approved for the treatment of melanoma, was the first agent to demonstrate rapid clinical responses and significantly improved survival which was a clinical breakthrough in the treatment of melanoma. Although exciting and practice changing, the unparalleled responses with vemurafenib are usually not sustained. Further investigations delineated several mechanisms of acquired resistance which are most often mediated by the upregulation of the MAPK pathway. MEK inhibitors, another class of small-molecule inhibitors, were developed as an alternative agent to suppress the MAPK pathway downstream, independent from BRAF activation. Multiple studies have demonstrated the improvement in antitumor activity when MEK inhibitors are used in combination with BRAF inhibitors in the treatment of metastatic melanoma. This is a review of the investigations that led to the US Food and Drug Administration approval in 2015 of the combination of vemurafenib and cobimetinib, adding to the quickly growing armament for the treatment of advanced or metastatic melanoma with a BRAF V600 mutation. PMID:27382311

  19. Melanoma with gastric metastases.

    PubMed

    Wong, Katherine; Serafi, Sam W; Bhatia, Abhijit S; Ibarra, Irene; Allen, Elizabeth A

    2016-01-01

    An 81-year-old woman with a history of malignant melanoma who presented with dyspnea and fatigue was found to have metastases to the stomach detected on endoscopy. Primary cutaneous malignant melanoma with gastric metastases is a rare occurrence, and it is often not detected until autopsy because of its non-specific manifestations. PMID:27609722

  20. Basic and clinical aspects of malignant melanoma

    SciTech Connect

    Nathanson, L. )

    1987-01-01

    This book contains the following 10 chapters: The role of oncogenes in the pathogenesis of malignant melanoma; Laminin and fibronectin modulate the metastatic activity of melanoma cells; Structure, function and biosynthesis of ganglioside antigens associated with human tumors derived from the neuroectoderm; Epidemiology of ocular melanoma; Malignant melanoma: Prognostic factors; Endocrine influences on the natural history of human malignant melanoma; Psychosocial factors associated with prognostic indicators, progression, psychophysiology, and tumor-host response in cutaneous malignant melanoma; Central nervous system metastases in malignant melanoma; Interferon trials in the management of malignant melanoma and other neoplasms: an overview; and The treatment of malignant melanoma by fast neutrons.

  1. New developments in the management of advanced melanoma – role of pembrolizumab

    PubMed Central

    Improta, Giuseppina; Leone, Isabella; Donia, Marco; Gieri, Stefania; Pelosi, Giuseppe; Fraggetta, Filippo

    2015-01-01

    Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma. PMID:26396529

  2. Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations

    PubMed Central

    Stei, Marta M.; Loeffler, Karin U.; Holz, Frank G.; Herwig, Martina C.

    2016-01-01

    Animal models serve as powerful tools for investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic agents. They have facilitated rapid scientific progress in many tumor entities. However, for establishing a powerful animal model of uveal melanoma fundamental challenges remain. To date, no animal model offers specific genetic attributes as well as histologic, immunologic, and metastatic features of uveal melanoma. Syngeneic models with intraocular injection of cutaneous melanoma cells may suit best for investigating immunologic/tumor biology aspects. However, differences between cutaneous and uveal melanoma regarding genetics and metastasis remain problematic. Human xenograft models are widely used for evaluating novel therapeutics but require immunosuppression to allow tumor growth. New approaches aim to establish transgenic mouse models of spontaneous uveal melanoma which recently provided preliminary promising results. Each model provides certain benefits and may render them suitable for answering a respective scientific question. However, all existing models also exhibit relevant limitations which may have led to delayed research progress. Despite refined therapeutic options for the primary ocular tumor, patients' prognosis has not improved since the 1970s. Basic research needs to further focus on a refinement of a potent animal model which mimics uveal melanoma specific mechanisms of progression and metastasis. This review will summarise and interpret existing animal models of uveal melanoma including recent advances in the field. PMID:27366747

  3. Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas.

    PubMed

    de Masson, Adèle; Beylot-Barry, Marie; Bouaziz, Jean-David; Peffault de Latour, Régis; Aubin, François; Garciaz, Sylvain; d'Incan, Michel; Dereure, Olivier; Dalle, Stéphane; Dompmartin, Anne; Suarez, Felipe; Battistella, Maxime; Vignon-Pennamen, Marie-Dominique; Rivet, Jacqueline; Adamski, Henri; Brice, Pauline; François, Sylvie; Lissandre, Séverine; Turlure, Pascal; Wierzbicka-Hainaut, Ewa; Brissot, Eolia; Dulery, Rémy; Servais, Sophie; Ravinet, Aurélie; Tabrizi, Reza; Ingen-Housz-Oro, Saskia; Joly, Pascal; Socié, Gérard; Bagot, Martine

    2014-03-01

    The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides. PMID:24213148

  4. The proportion cured of patients diagnosed with Stage III-IV cutaneous malignant melanoma in Sweden 1990-2007: A population-based study.

    PubMed

    Eriksson, Hanna; Lyth, Johan; Andersson, Therese M-L

    2016-06-15

    The survival in cutaneous malignant melanoma (CMM) is highly dependent on the stage of the disease. Stage III-IV CMM patients are at high risk of relapse with a heterogeneous outcome, but not all experience excess mortality due to their disease. This group is referred to as the cure proportion representing the proportion of patients who experience the same mortality rate as the general population. The aim of this study was to estimate the cure proportion of patients diagnosed with Stage III-IV CMM in Sweden. From the population-based Swedish Melanoma Register, we included 856 patients diagnosed with primary Stage III-IV CMM, 1990-2007, followed-up through 2013. We used flexible parametric cure models to estimate cure proportions and median survival times (MSTs) of uncured by sex, age, tumor site, ulceration status (in Stage III patients) and disease stage. The standardized (over sex, age and site) cure proportion was lower in Stage IV CMMs (0.15, 95% CI 0.09-0.22) than non-ulcerated Stage III CMMs (0.48, 95% CI 0.41-0.55) with a statistically significant difference of 0.33 (95% CI = 0.24-0.41). Ulcerated Stage III CMMs had a cure proportion of 0.27 (95% CI 0.21-0.32) with a statistically significant difference compared to non-ulcerated Stage III CMMs (difference 0.21; 95% CI = 0.13-0.30). The standardized MST of uncured was approximately 9-10 months longer for non-ulcerated versus ulcerated Stage III CMMs. We could demonstrate a significantly better outcome in patients diagnosed with non-ulcerated Stage III CMMs compared to ulcerated Stage III CMMs and Stage IV disease after adjusting for age, sex and tumor site. PMID:26815934

  5. The new seventh edition American Joint Committee on Cancer staging of cutaneous non-melanoma skin cancer: a critical review.

    PubMed

    Warner, Christina L; Cockerell, Clay J

    2011-06-01

    The seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual includes a major revision of the staging protocol for cutaneous carcinomas. There are several significant improvements to the Tumor, Nodes, and Metastases (TNM) staging system, including consideration of high-risk factors within the primary T grade, a decrease in the tumor size threshold from 5 cm to 2 cm, improved stratification of patient lymph node status, as well as exclusion of Merkel cell carcinomas from the staging system for squamous cell carcinoma (SCC) and other cutaneous carcinomas. However, some important variables in cutaneous SCC were excluded from consideration. In addition, the AJCC Cancer Staging Manual makes some recommendations that will likely prove difficult to apply in clinical practice, particularly that Clark level, depth of invasion, and presence or absence of perineural invasion should be recorded for each peripheral SCC. In this review, we examine the new recommendations with an emphasis on their utility and practicality. PMID:21469759

  6. Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

    PubMed Central

    Merrill, Stephen J; Ashrafi, Samira; Subramanian, Madhan; Godar, Dianne E

    2015-01-01

    For several decades the incidence of cutaneous malignant melanoma (CMM) steadily increased in fair-skinned, indoor-working people around the world. Scientists think poor tanning ability resulting in sunburns initiate CMM, but they do not understand why the incidence continues to increase despite the increased use of sunscreens and formulations offering more protection. This paradox, along with lower incidences of CMM in outdoor workers, although they have significantly higher annual UV doses than indoor workers have, perplexes scientists. We found a temporal exponential increase in the CMM incidence indicating second-order reaction kinetics revealing the existence of 2 major risk factors. From epidemiology studies, we know one major risk factor for getting CMM is poor tanning ability and we now propose the other major risk factor may be the Human Papilloma Virus (HPV) because clinicians find β HPVs in over half the biopsies. Moreover, we uncovered yet another paradox; the increasing CMM incidences significantly correlate with decreasing personal annual UV dose, a proxy for low vitamin D3 levels. We also discovered the incidence of CMM significantly increased with decreasing personal annual UV dose from 1960, when it was almost insignificant, to 2000. UV and other DNA-damaging agents can activate viruses, and UV-induced cytokines can hide HPV from immune surveillance, which may explain why CMM also occurs in anatomical locations where the sun does not shine. Thus, we propose the 2 major risk factors for getting CMM are intermittent UV exposures that result in low cutaneous levels of vitamin D3 and possibly viral infection. PMID:26413188

  7. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.

    PubMed

    Eisen, T; Ahmad, T; Flaherty, K T; Gore, M; Kaye, S; Marais, R; Gibbens, I; Hackett, S; James, M; Schuchter, L M; Nathanson, K L; Xia, C; Simantov, R; Schwartz, B; Poulin-Costello, M; O'Dwyer, P J; Ratain, M J

    2006-09-01

    The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease

  8. MERTK receptor tyrosine kinase is a therapeutic target in melanoma

    PubMed Central

    Schlegel, Jennifer; Sambade, Maria J.; Sather, Susan; Moschos, Stergios J.; Tan, Aik-Choon; Winges, Amanda; DeRyckere, Deborah; Carson, Craig C.; Trembath, Dimitri G.; Tentler, John J.; Eckhardt, S. Gail; Kuan, Pei-Fen; Hamilton, Ronald L.; Duncan, Lyn M.; Miller, C. Ryan; Nikolaishvili-Feinberg, Nana; Midkiff, Bentley R.; Liu, Jing; Zhang, Weihe; Yang, Chao; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton; Shields, Janiel M.; Graham, Douglas K.

    2013-01-01

    Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. Additionally, over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. This work establishes MERTK as a therapeutic target in melanoma and provides a rationale for the continued development of MERTK-targeted therapies. PMID:23585477

  9. Clinical utilities and biological characteristics of melanoma sentinel lymph nodes

    PubMed Central

    Han, Dale; Thomas, Daniel C; Zager, Jonathan S; Pockaj, Barbara; White, Richard L; Leong, Stanley PL

    2016-01-01

    An estimated 73870 people will be diagnosed with melanoma in the United States in 2015, resulting in 9940 deaths. The majority of patients with cutaneous melanomas are cured with wide local excision. However, current evidence supports the use of sentinel lymph node biopsy (SLNB) given the 15%-20% of patients who harbor regional node metastasis. More importantly, the presence or absence of nodal micrometastases has been found to be the most important prognostic factor in early-stage melanoma, particularly in intermediate thickness melanoma. This review examines the development of SLNB for melanoma as a means to determine a patient’s nodal status, the efficacy of SLNB in patients with melanoma, and the biology of melanoma metastatic to sentinel lymph nodes. Prospective randomized trials have guided the development of practice guidelines for use of SLNB for melanoma and have shown the prognostic value of SLNB. Given the rapidly advancing molecular and surgical technologies, the technical aspects of diagnosis, identification, and management of regional lymph nodes in melanoma continues to evolve and to improve. Additionally, there is ongoing research examining both the role of SLNB for specific clinical scenarios and the ways to identify patients who may benefit from completion lymphadenectomy for a positive SLN. Until further data provides sufficient evidence to alter national consensus-based guidelines, SLNB with completion lymphadenectomy remains the standard of care for clinically node-negative patients found to have a positive SLN. PMID:27081640

  10. Clinicopathological features, vitamin D serological levels and prognosis in cutaneous melanoma of shield-sites: an update.

    PubMed

    Paolino, Giovanni; Moliterni, Elisa; Didona, Dario; Garelli, Valentina; Corsetti, Paola; Lopez, Teresa; Richetta, Antonio Giovanni; Cantisani, Carmen; Bottoni, Ugo; Calvieri, Stefano

    2015-01-01

    Intermittent sun exposure and sunburns are strongly related to the development of melanoma (MM); however, MM can also arise in non-sun exposed areas, where other biological pathways may cause the disease, with different outcomes. At the same time, evidences of serum levels of vitamin D in melanoma patients according to sun-exposed or not-sun-exposed areas are still lacking, especially if compared with the percentage of BRAF mutation. We performed a retrospective analysis with patients registered in our electronic database and an observational study in patients with a recent diagnosis of MM. Performing Kaplan-Meier product and log-rank test, median disease-free survival was 78 months in non-shield-sites (NST-MM) patients and 20.5 months in shield-sites (ST-MM) patients (p < 0.0001); also in the long term, a better behavior was observed for NST-MM (80 vs. 42 months; p < 0.0001). Among 87 melanoma patients with a recent history of MM (≤30 days), we found that ST-MM patients showed lower values of vitamin D compared with NST-MM patients. Regarding BRAF status, a BRAF mutation was present in 13 % of ST-MM and in 41 % of NST-MM. Performing Mc-Nemar test, we found a statistical significant correlation between low serum levels of vitamin D in ST-MM and low percentage of BRAF mutation (p = 0.03), as well as between serum levels of vitamin D and high percentage of BRAF mutation in NST-MM (p < 0.001). All these aspects confirm that in ST-MM, other pathways play pivotal points, if compared with NST-MM. PMID:25516505

  11. Limited Genomic Heterogeneity of Circulating Melanoma Cells in Advanced Stage Patients

    PubMed Central

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Ed; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-01-01

    Purpose Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design Blood samples from 40 metastatic melanoma patients and 10 normal blood donors (NBD) were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAb) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification (WGA) and copy number variation (CNV) analysis. Results Based on CSPG4 expression and nuclear size, 1 to 250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5 to 371.5 CMCs/ml). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this population may contribute to develop effective therapeutic strategies. PMID:25574741

  12. Population exposure to ultraviolet radiation in Finland 1920-1995: Exposure trends and a time-series analysis of exposure and cutaneous melanoma incidence

    SciTech Connect

    Kojo, Katja . E-mail: katja.kojo@uta.fi; Jansen, Christer T.; Nybom, Pia; Huurto, Laura; Laihia, Jarmo; Ilus, Taina; Auvinen, Anssi

    2006-05-15

    Ultraviolet radiation (UVR) is the principal cause of cutaneous malignant melanoma (CMM). However, the relation between CMM and UVR exposure is not clear. We present the trends of population exposure to UVR and conduct a time-series analysis of the relation between UVR exposure and incidence of CMM. Data on CMM incidence were obtained from the Finnish Cancer Registry. Clothing coverage of the body was scored from archival photographs and the proportion of uncovered skin was used as a measure of solar exposure. Information on the number of sunny resort holidays, duration of annual holidays, and sunscreen sales were obtained from various sources. Exposed skin area doubled from 1920 to 1985. The average duration of annual holidays increased 30-fold. The number of sunny resort holidays and the sales of sunscreens increased rapidly from 1980. CMM was most strongly associated with solar exposure of 5-19 years earlier. There is a considerable decrease in clothing coverage during the 20th century. UVR exposure preceding CMM occurrence 4 years or less does not appear relevant, whereas the period 5-19 years prior to CMM occurrence might be the most relevant period. However, findings of ecological studies may not be applicable at the individual level.

  13. The metastatic microenvironment: Claudin-1 suppresses the malignant phenotype of melanoma brain metastasis.

    PubMed

    Izraely, Sivan; Sagi-Assif, Orit; Klein, Anat; Meshel, Tsipi; Ben-Menachem, Shlomit; Zaritsky, Assaf; Ehrlich, Marcelo; Prieto, Victor G; Bar-Eli, Menashe; Pirker, Christine; Berger, Walter; Nahmias, Clara; Couraud, Pierre-Olivier; Hoon, Dave S B; Witz, Isaac P

    2015-03-15

    Brain metastases occur frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. Identification of molecular determinants regulating melanoma brain metastasis would advance the development of prevention and therapy strategies for this disease. Gene expression profiles of cutaneous and brain-metastasizing melanoma variants from three xenograft tumor models established in our laboratory revealed that expression of tight junction component CLDN1 was lower in the brain-metastasizing variants than in cutaneous variants from the same melanoma. The objective of our study was to determine the significance of CLDN1 downregulation/loss in metastatic melanoma and its role in melanoma brain metastasis. An immunohistochemical analysis of human cells of the melanocyte lineage indicated a significant CLDN1 downregulation in metastatic melanomas. Transduction of melanoma brain metastatic cells expressing low levels of CLDN1 with a CLDN1 retrovirus suppressed their metastatic phenotype. CLDN1-overexpressing melanoma cells expressed a lower ability to migrate and adhere to extracellular matrix, reduced tumor aggressiveness in nude mice and, most importantly, eliminated the formation of micrometastases in the brain. In sharp contrast, the ability of the CLDN1-overexpressing cells to form lung micrometastases was not impaired. CLDN1-mediated interactions between these cells and brain endothelial cells constitute the mechanism underlying these results. Taken together, we demonstrated that downregulation or loss of CLDN1 supports the formation of melanoma brain metastasis, and that CLDN1 expression could be a useful prognostic predictor for melanoma patients with a high risk of brain metastasis. PMID:25046141

  14. An unusual case of desmoplastic malignant melanoma.

    PubMed

    Javabal, Pandiaraja; Subramanian, Viswanathan

    2015-01-01

    Desmoplastic malignant melanoma is a rare variant of spindle cell melanoma, commonly seen in older adults, on sun-exposed areas. It accounts for 1-4% of all cases of cutaneous melanoma. The common location of the desmoplastic melanoma is the head and neck region, whereas, other sites are less common. Regional lymph node involvement is reported in 0 to 13.7% of the cases, which is less frequent than other cutaneous melanomas. A 75-year-old male presented with an ulceroproliferative growth on the left foot that was diagnosed as desmoplastic melanoma with regional lymph node metastasis and in transit metastasis, with extensive pulmonary metastasis. PMID:25949027

  15. BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma: a potential neoadjuvant strategy.

    PubMed

    Sloot, Sarah; Zager, Jonathan S; Kudchadkar, Ragini R; Messina, Jane L; Benedict, Jacob J; Gonzalez, Ricardo J; DeConti, Ronald; Turner, Leslie M; McCardle, Timothy; Smalley, Keiran S M; Weber, Jeffrey S; Sondak, Vernon K; Gibney, Geoffrey T

    2016-02-01

    Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival. PMID:26731560

  16. Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors

    PubMed Central

    ZURAC, SABINA; NEAGU, MONICA; CONSTANTIN, CAROLINA; CIOPLEA, MIRELA; NEDELCU, ROXANA; BASTIAN, ALEXANDRA; POPP, CRISTIANA; NICHITA, LUCIANA; ANDREI, RAZVAN; TEBEICA, TIBERIU; TANASE, CRISTIANA; CHITU, VIRGINIA; CARUNTU, CONSTANTIN; GHITA, MIHAELA; POPESCU, CATALIN; BODA, DANIEL; MASTALIER, BOGDAN; MARU, NICOLETA; DAHA, CLAUDIU; ANDREESCU, BOGDAN; MARINESCU, IOAN; REBOSAPCA, ADRIAN; STANICEANU, FLORICA; NEGROIU, GABRIELA; ION, DANIELA A.; NIKITOVIC, DRAGANA; TZANAKAKIS, GEORGE N.; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

    2016-01-01

    Regression in melanoma is a frequent biological event of uncertain prognostic value as the lesion exhibits heterogeneous phenotypical features, both at the morphological and immunohistochemical level. In the present study, we examined the expression of tissue inhibitors of metalloproteinases (TIMP1, TIMP2 and TIMP3) in melanoma with regression. We specifically examined the expression levels of these TIMPs in regressed components (RC) and non-regressed components (NRC) of the tumor and compared their expression levels with those in non-regressed melanomas. We found that TIMP1 was overexpressed in the NRC of melanomas with partial regression (PR) compared with the NRC in melanomas with segmental regression (SR) (P=0.011). TIMP2 was overexpressed in the NRC of melanomas with PR compared with the NRC in melanomas with SR (PR/SR, P=0.009); or compared with the NRC in melanomas with simultaneous SR-PR (P=0.002); or compared with melanomas without regression (absence of regression) (P=0.037). Moreover, TIMP3 was overexpressed in the NRC of all melanomas with SR as compared to the RC component (P=0.007). Our findings on the differential expression of TIMP1, TIMP2 and TIMP3 in melanomas with regression support the hypothesis that the morphological differences identified in the melanoma regression spectrum may have a correlation with prognosis. This may explain the controversial findings within the literature concerning the biological and prognostic role of regression in melanoma. PMID:27123116

  17. Systematic review of the use of granulocyte-macrophage colony-stimulating factor in patients with advanced melanoma.

    PubMed

    Hoeller, Christoph; Michielin, Olivier; Ascierto, Paolo A; Szabo, Zsolt; Blank, Christian U

    2016-09-01

    Several immunomodulatory checkpoint inhibitors have been approved for the treatment of patients with advanced melanoma, including ipilimumab, nivolumab and pembrolizumab. Talimogene laherparepvec is the first oncolytic virus to gain regulatory approval in the USA; it is also approved in Europe. Talimogene laherparepvec expresses granulocyte-macrophage colony-stimulating factor (GM-CSF), and with other GM-CSF-expressing oncolytic viruses in development, understanding the clinical relevance of this cytokine in treating advanced melanoma is important. Results of trials of GM-CSF in melanoma have been mixed, and while GM-CSF has the potential to promote anti-tumor responses, some preclinical data suggest that GM-CSF may sometimes promote tumor growth. GM-CSF has not been approved as a melanoma treatment. We undertook a systematic literature review of studies of GM-CSF in patients with advanced melanoma (stage IIIB-IV). Of the 503 articles identified, 26 studies met the eligibility criteria. Most studies investigated the use of GM-CSF in combination with another treatment, such as peptide vaccines or chemotherapy, or as an adjuvant to surgery. Some clinical benefit was reported in patients who received GM-CSF as an adjuvant to surgery, or in combination with other treatments. In general, outcomes for patients receiving peptide vaccines were not improved with the addition of GM-CSF. GM-CSF may be a valuable therapeutic adjuvant; however, further studies are needed, particularly head-to-head comparisons, to confirm the optimal dosing regimen and clinical effectiveness in patients with advanced melanoma. PMID:27372293

  18. Survival of patients with advanced metastatic melanoma: The impact of novel therapies.

    PubMed

    Ugurel, Selma; Röhmel, Joachim; Ascierto, Paolo A; Flaherty, Keith T; Grob, Jean Jacques; Hauschild, Axel; Larkin, James; Long, Georgina V; Lorigan, Paul; McArthur, Grant A; Ribas, Antoni; Robert, Caroline; Schadendorf, Dirk; Garbe, Claus

    2016-01-01

    The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited. PMID:26707829

  19. Worldwide cutaneous malignant melanoma incidences analyzed by sex, age, and skin type over time (1955–2007): Is HPV infection of androgenic hair follicular melanocytes a risk factor for developing melanoma exclusively in people of European-ancestry?

    PubMed Central

    Merrill, Stephen J.; Subramanian, Madhan; Godar, Dianne E.

    2016-01-01

    ABSTRACT The cutaneous malignant melanoma (CMM) incidence has been increasing in an exponential manner in certain populations around the world for over 7 decades. To help illuminate the etiology, we performed worldwide temporal (1955–2007) CMM incidence analysis by sex, age (0–14, 15–29, 30–49, 50–69, 70–85+), and skin type on 6 continents using data from the International Agency for Research on Cancer. We observe an exponential increase in the CMM incidence over time and an increase of about 2 orders of magnitude between age groups 0–14 and 15–29 exclusively in European-ancestry populations around the world independent of skin type (I–III or III–IV). Other populations like the Chinese (III-IV) had much lower CMM incidences that either remained stable or temporally decreased but did not display a dramatic increase between the youngest age groups. The dramatic increase in the incidence between the youngest age groups found only in European-ancestry populations suggests one of the most important risk factors for CMM may be developing androgenic hair, the occurrence of which appears to correlate with the distribution of CMM over male and female body sites. Besides that potential new risk factor, the increasing CMM incidence with increasing age, known not to be from cumulative UV doses, may be associated with age-related changes to skin, i.e., thinning epidermis causing lower vitamin D3 levels, and hair, i.e., whitening from higher reactive oxygen species. The temporal exponential increasing CMM incidence in European-ancestry populations may be due to Human Papilloma Virus infection of follicular hair melanocytes, found in CMM biopsies. PMID:27588159

  20. Worldwide cutaneous malignant melanoma incidences analyzed by sex, age, and skin type over time (1955-2007): Is HPV infection of androgenic hair follicular melanocytes a risk factor for developing melanoma exclusively in people of European-ancestry?

    PubMed

    Merrill, Stephen J; Subramanian, Madhan; Godar, Dianne E

    2016-01-01

    The cutaneous malignant melanoma (CMM) incidence has been increasing in an exponential manner in certain populations around the world for over 7 decades. To help illuminate the etiology, we performed worldwide temporal (1955-2007) CMM incidence analysis by sex, age (0-14, 15-29, 30-49, 50-69, 70-85+), and skin type on 6 continents using data from the International Agency for Research on Cancer. We observe an exponential increase in the CMM incidence over time and an increase of about 2 orders of magnitude between age groups 0-14 and 15-29 exclusively in European-ancestry populations around the world independent of skin type (I-III or III-IV). Other populations like the Chinese (III-IV) had much lower CMM incidences that either remained stable or temporally decreased but did not display a dramatic increase between the youngest age groups. The dramatic increase in the incidence between the youngest age groups found only in European-ancestry populations suggests one of the most important risk factors for CMM may be developing androgenic hair, the occurrence of which appears to correlate with the distribution of CMM over male and female body sites. Besides that potential new risk factor, the increasing CMM incidence with increasing age, known not to be from cumulative UV doses, may be associated with age-related changes to skin, i.e., thinning epidermis causing lower vitamin D3 levels, and hair, i.e., whitening from higher reactive oxygen species. The temporal exponential increasing CMM incidence in European-ancestry populations may be due to Human Papilloma Virus infection of follicular hair melanocytes, found in CMM biopsies. PMID:27588159

  1. [Strategies for the noninvasive diagnosis of melanoma].

    PubMed

    Fink, C; Haenssle, H A

    2016-07-01

    The diagnosis of advanced cutaneous melanoma may easily be made by the unaided eye, followed by excisional biopsy and histopathological examination. However, in the setting of melanoma screening examinations in high-risk patients with many nevi, dermatologists are challenged with the differentiation of atypical but benign nevi and early invasive or in situ melanomas. In this situation, there is a real need for additional, noninvasive examination techniques that may serve as an aide to decide for or against an excisional biopsy. Conventional dermoscopy is a well-established examination procedure and an increase in sensitivity was confirmed by two independent meta-analyses. Moreover, dynamic changes or newly developed pigmented lesions may be detected by sequential digital dermoscopy or (automated) total body photography, respectively. Over the past years, a number of medicinal products gained market access after licensing by American and European agencies for the noninvasive diagnosis of cutaneous neoplasms. These devices are based on technologies including in vivo reflectance confocal microscopy, multispectral analysis, electrical impedance spectroscopy, or Raman spectroscopy. Other technologies are still on the verge of becoming less experimental but more clinically applicable for diagnosing melanoma (in vivo multiphoton tomography, stepwise two-photon laser spectroscopy, infrared thermal image analysis, epidermal genetic information retrieval). This review provides a concise overview of general principles and sheds light on indication and added value for dermatologists. PMID:27193101

  2. Black light visualized solar lentigines on the shoulders and upper back are associated with objectively measured UVR exposure and cutaneous malignant melanoma.

    PubMed

    Idorn, Luise Winkel; Datta, Pameli; Heydenreich, Jakob; Philipsen, Peter Alshede; Wulf, Hans Christian

    2015-02-01

    Previous studies on the association of solar lentigines with ultraviolet radiation (UVR) exposure have been based on retrospective questionnaires about UVR exposure. We aimed to investigate the association between solar lentigines and UVR exposure in healthy individuals using objective measurements, and to investigate the association between solar lentigines and cutaneous malignant melanoma (CMM). Forty-eight patients with CMM and 48 controls that matched the patients individually by age, sex, constitutive skin type and occupation participated. Solar lentigines on the shoulders and upper back were counted and graded into 3 categories using black light photographs to show sun damage. Current UVR exposure in healthy controls was assessed by personal electronic UVR dosimeters that measured time-related UVR and by corresponding exposure diaries during a summer season. Sunburn history was assessed by interviews. Among controls, the number of solar lentigines was positively associated with daily hours spent outdoors between noon and 3 pm on holidays (P = 0.027), days at the beach (P = 0.048) and reported number of life sunburns (P < 0.001). Compared with matched controls CMM patients had a higher number of solar lentigines (P = 0.044). There was a positive association between CMM and higher solar lentigines grade; Category III versus Category I (P = 0.002) and Category II versus Category I (P = 0.014). Our findings indicate that solar lentigines in healthy individuals are associated with number of life sunburns, as well as time spent outdoors around noon on holidays and beach trips during a summer season, most likely reflecting past UVR exposure, and that solar lentigines are a risk factor for CMM. PMID:25410723

  3. Real-world treatment practice in patients with advanced melanoma in the era before ipilimumab: results from the IMAGE study.

    PubMed

    Middleton, Mark R; Dalle, Stéphane; Claveau, Joel; Mut, Pilar; Hallmeyer, Sigrun; Plantin, Patrice; Highley, Martin; Kotapati, Srividya; Le, Trong Kim; Brokaw, Jane; Abernethy, Amy P

    2016-07-01

    The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies. PMID:27118102

  4. Stem cell properties in cell cultures from different stage of melanoma progression.

    PubMed

    Magnoni, Cristina; Giudice, Stefania; Pellacani, Giovanni; Bertazzoni, Giorgia; Longo, Caterina; Veratti, Eugenia; Morini, Daria; Benassi, Luisa; Vaschieri, Cristina; Azzoni, Paola; De Pol, Anto; Seidenari, Stefania; Tomasi, Aldo; Pollio, Annamaria; Ponti, Giovanni

    2014-03-01

    Cutaneous melanoma is an extremely heterogenous human cancer. The most aggressive melanoma may contain deregulated cells with undifferentiated/stem cell-like phenotype. A critical mechanism by which melanoma cells enhance their invasive capacity is the dissolution of the intercellular adhesion and the acquisition of mesenchymal features as a part of an epithelial-to-mesenchymal transition. The aim of this study was to clarify the role of a stem cell-like population in human melanomas by means of melanocytic cell culture analysis obtained from distinct histotypes of primary and metastatic malignant melanoma. Patients with advanced melanoma >2 cm in diameter and/or >300 mm surface were enrolled. The melanoma cells were isolated from skin biopsies of lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, and metastatic melanoma. The colony forming unit assay and alkaline phosphatase stain were evaluated. Cells were subsequently cultured and maintained in different media to evaluate their ability to differentiate into osteogenic and adipogenic lineages. Immunohistochemistry and flow cytometry analysis were performed to evaluate antigenic markers CD90, CD73, CD105, CD146, CD20, CD166, and Nestin. This study confirms that melanoma can include heterogenous cell populations with the ability both to self-renew and to a give rise to differentiated progeny. Melanoma cells displayed intratumoral heterogeneity and dynamic antigen phenotypes. Histologically, transitions from normal skin to melanoma were associated with a gradual increase in the expression of CD146, CD20, CD133, Nestin, and CD73. These molecular profiles could be further analyzed and, in the future, used for the development of novel biomolecular targeted-therapy approaches. PMID:23702651

  5. Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma

    PubMed Central

    Hurabielle, Charlotte; Pillebout, Evangéline; Stehlé, Thomas; Pagès, Cécile; Roux, Jennifer; Schneider, Pierre; Chevret, Sylvie; Chaffaut, Cendrine; Boutten, Anne; Mourah, Samia; Basset-Seguin, Nicole; Vidal-Petiot, Emmanuelle; Lebbé, Céleste; Flamant, Martin

    2016-01-01

    Context Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known. Objective We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma. Methods We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients. Results 70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion. Conclusion Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective. PMID:26930506

  6. Limb Preservation With Isolated Limb Infusion for Locally Advanced Nonmelanoma Cutaneous and Soft-Tissue Malignant Neoplasms

    PubMed Central

    Turaga, Kiran K.; Beasley, Georgia M.; Kane, John M.; Delman, Keith A.; Grobmyer, Stephen R.; Gonzalez, Ricardo J.; Letson, G. Douglas; Cheong, David; Tyler, Douglas S.; Zager, Jonathan S.

    2015-01-01

    Objective To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms. Background Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including soft-tissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms. Methods We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and actinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Toxicity was measured using the Wieberdink scale and serum creatinine phosphokinase levels. Results The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months. Conclusions Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet

  7. Desmoplastic Melanoma: Clinical Behavior and Management Implications

    PubMed Central

    Kapil, Jyoti P.; Wolfe, Luke G.; Kaplan, Brian J.; Neifeld, James P.

    2016-01-01

    Introduction: Desmoplastic melanoma is a rare variant of melanoma that has been reported to demonstrate unique clinical behavior when compared with other histological subtypes. In this study, we present the clinical course of patients with this unusual diagnosis. We hypothesized that desmoplastic melanoma would differ from nondesmoplastic melanoma with regard to its presentation, rate of regional metastasis, and recurrence pattern. Methods: After institutional review board approval, a retrospective chart review was performed on all patients with a diagnosis of desmoplastic melanoma since 1998. The following data were collected: patient demographics, histopathological details of the lesion, initial treatment, and clinical course. In addition, the available slides were reviewed by a dermatopathologist. Results: Twenty-eight patient charts were reviewed. Mean age at diagnosis was 65 years. Fifty-seven percent of patients were men, and 67% of the lesions originated from the head and neck. Of the 28 patients, 11 had pathology slides that were adequate for evaluation. Pure desmoplastic melanoma, defined by more than 90% of the specimen demonstrating desmoplastic features, was found in only 3 patients. Taking into account all cases, the mean Breslow thickness was 5.09 mm and ulceration was present in 12.5% of lesions. Regional disease was discovered in 18% of patients. The mean follow-up time was 43 months, and the overall recurrence rate was 32%. 66.7% of first recurrences were local. Two of 3 patients with pure desmoplastic melanoma developed regional metastasis. Conclusions: Our data largely support previous studies that suggest desmoplastic melanoma behaves differently compared with other histological subtypes. However, the incidence of regional disease among patients with pure desmoplastic melanoma appears to be higher in our study than in previous reports. Although this rare variant typically presents with advanced local disease, the rate of regional metastasis is

  8. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  9. The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial

    PubMed Central

    Algazi, A P; Cha, E; Ortiz-Urda, S M; McCalmont, T; Bastian, B C; Hwang, J; Pampaloni, M H; Behr, S; Chong, K; Cortez, B; Quiroz, A; Coakley, F; Liu, S; Daud, A I

    2015-01-01

    Background: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. Methods: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0–1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1–14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m−2) was administered on day 1 starting with cycle 2. 3′-Deoxy-3′-18F-fluorothymidine (18F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. Results: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing 18F-FLT-PET scans showed increases (23–92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAFV600E/K patients had significantly worse PFS than patients without these mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3′-Deoxy-3′-18F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal. PMID:25867272

  10. Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma

    PubMed Central

    Ito, Mitsugu; Abe, Fumito; Nara, Miho; Watanabe, Atsushi; Takahashi, Naoto; Miyagaki, Tomomitsu; Sugaya, Makoto; Tagawa, Hiroyuki

    2016-01-01

    We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with neutralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL. PMID:26789110

  11. XPC (A2920C), XPF (T30028C), TP53 (Arg72Pro), and GSTP1 (Ile105Val) polymorphisms in prognosis of cutaneous melanoma.

    PubMed

    Gomez, Gabriela Vilas Bôas; de Oliveira, Cristiane; Rinck-Junior, José Augusto; de Moraes, Aparecida Machado; Lourenço, Gustavo Jacob; Lima, Carmen Silvia Passos

    2016-03-01

    This study aimed to evaluate whether XPC A2920C, XPF T30028C, TP53 Arg72Pro, and GSTP1 Ile105Val polymorphisms alter outcomes of cutaneous melanoma (CM) patients. DNA from 237 CM patients seen at the University of Campinas Teaching Hospital from April 2000 to February 2014 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival (PFS) and overall survival (OS) of CM patients were examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox regression analyses. At 60 months of follow-up, shorter PFS and OS were seen in patients with XPF CC genotype (48.9 vs. 66.7 %, P = 0.002; 77.9 vs. 83.5 %, P = 0.006, respectively) and XPF CC + TP53 ArgArg (43.6 vs. 65.9 %, P = 0.007; 71.6 vs. 84.8 %, P = 0.006, respectively) compared with those with remaining genotypes (Kaplan-Meier estimates). Patients with XPF CC (hazard ratio (HR) 2.45, P = 0.002; HR 3.77, P = 0.005) and XPF CC + TP53 ArgArg (HR 2.67, P = 0.009; HR 4.04, P = 0.03) genotypes had more chance to present tumor progression in univariate and multivariate analyses, whereas patients with XPF CC (HR 2.78, P = 0.009) and XPF CC + TP53 ArgArg (HR 3.84, P = 0.01) genotypes were under greater risk of progressing to death in univariate analysis, compared with those with the remaining genotypes. The data suggest, for the first time, that inherited abnormalities in DNA repair pathway related to XPF 30028C and TP53 Arg72Pro polymorphisms act as prognostic factors for PFS and OS of CM patients. PMID:26427666

  12. Stage-specific survival and recurrence in patients with cutaneous malignant melanoma in Europe – a systematic review of the literature

    PubMed Central

    Svedman, Fernanda Costa; Pillas, Demetris; Taylor, Aliki; Kaur, Moninder; Linder, Ragnar; Hansson, Johan

    2016-01-01

    Background Given the increasing incidence in cutaneous malignant melanoma (CMM) and the recent changes in the treatment landscape, it is important to understand stage-specific overall and recurrence-free survival patterns in Europe. Despite publications such as EUROCARE-5, there is limited information on stage-specific survival for CMM in Europe. Method We carried out a systematic literature review to provide an up-to-date summary of stage-specific survival and recurrence-free survival patterns in patients with CMM in Europe. Studies were included if they were published in Medline during the past 12 years and included information on stage-specific survival and/or recurrence in CMM. Results Of the 8,749 studies identified, 26 studies were included, representing nine countries. Collectively, the studies covered a population of 152,422 patients and included data from 1978 to 2011. Randomized clinical trials and single-center observational studies comprised the most common study designs, including five large registry-based studies. Stage-specific information for survival and recurrence varied: 5-year overall survival: 95%–100% (stage I), 65%–92.8% (stage II), 41%–71% (stage III), and 9%–28% (stage IV); 5-year relapse-free survival was reported less frequently: 56% (stage II), and 28%–44% (stage III). Studies reporting survival by sentinel node (SN) status reported 5-year overall survival as 80%–95% for negative SN (stage I/II) and 35%–75% for positive SN (stage III) status; recurrence-free survival at 5 years: 76%–90% for negative and 35%–58% for positive SN status. Some studies included comparisons of survival by key patient sociodemographic characteristics, suggesting that these have a substantial influence on survival and recurrence estimates. Conclusion The studies identified in this review show large variations in stage-specific overall and recurrence-free survival by study type and by country. Owing to differing study designs and populations, it

  13. The CASC15 Long Intergenic Noncoding RNA Locus Is Involved in Melanoma Progression and Phenotype Switching.

    PubMed

    Lessard, Laurent; Liu, Michelle; Marzese, Diego M; Wang, Hongwei; Chong, Kelly; Kawas, Neal; Donovan, Nicholas C; Kiyohara, Eiji; Hsu, Sandy; Nelson, Nellie; Izraely, Sivan; Sagi-Assif, Orit; Witz, Isaac P; Ma, Xiao-Jun; Luo, Yuling; Hoon, Dave S B

    2015-10-01

    In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma. PMID:26016895

  14. The efficacy and safety of nivolumab in the treatment of advanced melanoma: a meta-analysis of clinical trials

    PubMed Central

    Jin, Conghui; Zhang, Xunlei; Zhao, Kuiling; Xu, Jun; Zhao, Min; Xu, Xiaohong

    2016-01-01

    Background Nivolumab has become a therapeutic regimen for the treatment of patients with advanced melanoma. The goal of this study was to assess the efficacy and safety of nivolumab in patients with advanced melanoma. Methods A systematic search from January 2008 to August 2015 with “nivolumab” and “advanced melanoma” as search terms was performed for possible clinical trials. According to the hazard ratio and the 95% confidence interval (CI) for progression-free survival (PFS), rates of objective response, complete response, partial response, rates of toxic effects, and the efficacy and safety of nivolumab were assessed. Using the software Review Manager (version 5.3) a meta-analysis was performed. Results There were four trials with 1,910 patients included. Based on the four trials, the pooled hazard ratio of PFS was 0.53 (95% CI, 0.43–0.66; P<0.001). The pooled risk ratio for the objective response rate, complete response, and partial response was 2.98% (95% CI, 2.38%–3.73%; P<0.001), 3.71% (95% CI, 2.67%–5.14%; P<0.001), and 2.51% (95% CI, 2.12%–2.99%; P<0.001), respectively. Nivolumab plus ipilimumab therapy significantly increased the risk of grade 3/4 rash and fatigue. Conclusion Nivolumab-based therapy prolonged PFS in treatment of advanced melanoma, with less adverse effects. Nivolumab appears to be a favorable treatment option as a novel, targeted anticancer agent, for patients with advanced melanoma. PMID:27051297

  15. Serum proteomic profile of cutaneous malignant melanoma and relation to cancer progression: association to tumor derived alpha-N-acetylgalactosaminidase activity.

    PubMed

    Greco, Marilena; Mitri, Marianna De; Chiriacò, Fernanda; Leo, Giuseppe; Brienza, Ettore; Maffia, Michele

    2009-10-01

    Currently clinical outcome in melanoma is not predictable by known serum biomarkers. The only reliable tool for the diagnosis of this tumor is the histopathological assay after surgical removing. We used a proteomic approach in order to identify novel non-invasive serum biomarkers of melanoma. Serum proteomic maps showed different patterns in relation to the presence and progression of the tumor in five regions of the map. Differently expressed spots were identified by MALDI-TOF mass spectrometry. Significant increases of expression were found for transthyretin (TTR) and angiotensinogen (AGT) while vitamin D binding protein (DBP) expression was decreased in presence of melanoma. Interestingly, protein expression came back to control values in stages I and II of the disease after 1 month since surgical removal of suspected melanoma. We related the decrease of DBP spot to the impaired immune response of cancer patients. In fact cancer cells release the alpha-N-acetylgalactosaminidase that can deglycosylate DBP thus interfering with the immune cascade response in which DBP is involved, leading to immunosuppression in melanoma patients. Specific enzymatic activity of serum alpha-N-acetylgalactosaminidase was significantly increased in stage III melanoma patients, but not in early stages. This enzymatic assay may provide a non-invasive way of evaluation of melanoma severity. PMID:19394758

  16. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

    2014-08-01

    Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma. PMID:24991839

  17. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

    PubMed Central

    Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O’Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

    2014-01-01

    Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m2 daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma. PMID:24991839

  18. Malignant melanoma maxilla

    PubMed Central

    Devi, Seema; Sinha, Richi; Singh, Rakesh Kumar

    2015-01-01

    A malignant melanoma is a highly lethal melanocytic neoplasm. A neoplasm usually affects the skin. Malignant melanomas in the head and neck region are rare, accounting for less than 1% of all melanomas. Malignant melanoma of the nose and paranasal sinuses is an aggressive disease typically presenting at an advanced stage, with a 5-year survival rate ranging 20-30%. Melanomas are tumors arising from melanocytes, which are neuroectodermally derived cells located in the basal layers of the skin. This is a case report of a 35-year-old male, who presented with very aggressive disease and developed liver metastasis. PMID:26668467

  19. Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

    ClinicalTrials.gov

    2016-02-05

    Adult Solid Neoplasm; Hormone-Resistant Prostate Cancer; Recurrent Melanoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  20. Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma

    PubMed Central

    Ribas, Antoni; Kefford, Richard; Marshall, Margaret A.; Punt, Cornelis J.A.; Haanen, John B.; Marmol, Maribel; Garbe, Claus; Gogas, Helen; Schachter, Jacob; Linette, Gerald; Lorigan, Paul; Kendra, Kari L.; Maio, Michele; Trefzer, Uwe; Smylie, Michael; McArthur, Grant A.; Dreno, Brigitte; Nathan, Paul D.; Mackiewicz, Jacek; Kirkwood, John M.; Gomez-Navarro, Jesus; Huang, Bo; Pavlov, Dmitri; Hauschild, Axel

    2013-01-01

    Purpose In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. Patients and Methods Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). Results In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. Conclusion This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma. PMID:23295794

  1. Genetic epidemiology of melanoma.

    PubMed

    Ribero, Simone; Glass, Dan; Bataille, Veronique

    2016-08-01

    The field of melanoma genetics is moving at great pace with new platforms to investigate single nucleotide polymorphism, genome sequencing, gene expression, and methylation. Melanoma incidence is still rising mainly because of screening campaigns, which has increased the number of reported melanomas. However, mortality due to melanoma is not decreasing. Many cutaneous phenotypic risk factors have been linked to melanoma, but the association with UV radiation is very complex. The level of vitamin D affects both the risk of melanoma and prognosis, but more studies are needed. The genetics of melanoma involves genes involved in pigmentation and naevi, as well as genes involved in the cell cycle and senescence, which have been identified via genome-wide association studies over the last 10 years. One area of research highly relevant to melanoma is telomere biology with further links to reduced senescence. At the somatic level, new gene pathways are being explored with many new therapeutic targets, and boosting immune responses against the tumour appears to offer the best long-term outcome. PMID:27436815

  2. Polymorphisms in naevus-associated genes MTAP, PLA2G6, and IRF4 and the risk of invasive cutaneous melanoma

    PubMed Central

    Kvaskoff, Marina; Whiteman, David C.; Zhao, Zhen Z.; Montgomery, Grant W.; Martin, Nicholas G.; Hayward, Nicholas K.; Duffy, David L.

    2012-01-01

    An evolving hypothesis postulates that melanomas may arise through “naevus-associated” and “chronic sun exposure” pathways. We explored this hypothesis by examining associations between naevus-associated loci and melanoma risk across strata of body site and histological subtype. We genotyped 1028 invasive case patients and 1469 controls for variants in MTAP, PLA2G6, and IRF4, and compared allelic frequencies globally and by anatomical site and histological subtype of melanoma. Odds-ratios (ORs) and 95% confidence intervals (CIs) were calculated using classical and multinomial logistic regression models. Among controls, MTAP rs10757257, PLA2G6 rs132985 and IRF4 rs12203592 were the variants most significantly associated with number of naevi. In adjusted models, a significant association was found between MTAP rs10757257 and overall melanoma risk (OR=1.32, 95% CI=1.14–1.53), with no evidence of heterogeneity across sites (Phomogeneity=0.52). In contrast, MTAP rs10757257 was associated with superficial spreading/nodular melanoma (OR=1.34, 95% CI=1.15–1.57), but not with lentigo maligna melanoma (OR=0.79, 95% CI=0.46–1.35) (Phomogeneity=0.06), the subtype associated with chronic sun exposure. Melanoma was significantly inversely associated with rs12203592 in children (OR=0.35, 95% CI=0.16–0.77) and adolescents (OR=0.61, 95% CI=0.42–0.91), but not in adults (Phomogeneity=0.0008). Our results suggest that the relationship between MTAP and melanoma is subtype-specific, and that the association between IRF4 and melanoma is more evident for cases with a younger age at onset. These findings lend some support to the “divergent pathways” hypothesis and may provide at least one candidate gene underlying this model. Further studies are warranted to confirm these findings and improve our understanding of these relationships. PMID:21962134

  3. The CASC15 long intergenic non-coding RNA locus is involved in melanoma progression and phenotype-switching

    PubMed Central

    Lessard, Laurent; Liu, Michelle; Marzese, Diego M.; Wang, Hongwei; Chong, Kelly; Kawas, Neal; Donovan, Nicholas C; Kiyohara, Eiji; Hsu, Sandy; Nelson, Nellie; Izraely, Sivan; Sagi-Assif, Orit; Witz, Isaac P; Ma, Xiao-Jun; Luo, Yuling; Hoon, Dave SB

    2015-01-01

    In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long non-coding RNAs in melanoma progression. We hypothesized that copy number alterations of intergenic non-protein coding domains could help identify long intergenic non-coding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and up-regulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC stage III lymph node metastasis. Moreover, siRNA knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma. PMID:26016895

  4. Sunburn and malignant melanoma.

    PubMed Central

    Green, A.; Siskind, V.; Bain, C.; Alexander, J.

    1985-01-01

    We investigated the relationship between cutaneous malignant melanoma and multiple sunburns in the Queensland population. Interview data were gathered from 236 case-control pairs concerning their lifetime experience of severe sunburns, their occupational and recreational sun exposure, and their skin type. Excluding the lentigo maligna melanoma subtype, an association between multiple sunburns and melanoma was evident. After controlling for other major risk factors there was a significant dose-response relationship (P less than 0.05): the estimated relative risk associated with 2-5 sunburns in life was 1.5, and with 6 or more was 2.4. This observation extends the hitherto circumstantial evidence of a causal relationship between exposure to solar ultraviolet radiation and melanoma, and suggests that precautionary measures could prevent the development of this disease in a proportion of cases in fair-skinned populations. PMID:3970815

  5. Melanoma and Hawaii's youth.

    PubMed

    Williams, Laura

    2004-03-01

    Hawaii's sandy beaches, warm crystal waters, and mild climate attract tourists and residents alike to enjoy hours of outdoor activities under the sun. As frequent participants of these sun related activities, Hawaii's youth are exposed to high levels and duration of ultraviolet radiation throughout their early lives. This study aims to define occurrence trends of cutaneous malignant melanoma in Hawaii in correlation to increased childhood ultraviolet exposure. This paper addresses trends in melanoma incidence during 1979-2002 for Hawaii residents < 25 years of age. Data obtained from this review were analyzed by age group and ethnicity. Results show that although the incidence of melanoma is increasing for Hawaii residents over 25 years of age, the rate of melanoma occurrence in Hawaii's youth (< 25 years) is not increasing. PMID:15124743

  6. Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma.

    PubMed

    Theurich, Sebastian; Rothschild, Sacha I; Hoffmann, Michael; Fabri, Mario; Sommer, Andrea; Garcia-Marquez, Maria; Thelen, Martin; Schill, Catherine; Merki, Ramona; Schmid, Thomas; Koeberle, Dieter; Zippelius, Alfred; Baues, Christian; Mauch, Cornelia; Tigges, Christian; Kreuter, Alexander; Borggrefe, Jan; von Bergwelt-Baildon, Michael; Schlaak, Max

    2016-09-01

    Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune-related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31-1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744-54. ©2016 AACR. PMID:27466265

  7. Cross-presentation of cutaneous melanoma antigen by migratory XCR1+CD103− and XCR1+CD103+ dendritic cells

    PubMed Central

    Wylie, Ben; Seppanen, Elke; Xiao, Kun; Zemek, Rachael; Zanker, Damien; Prato, Sandro; Foley, Bree; Hart, Prue H; Kroczek, Richard A; Chen, Weisan; Waithman, Jason

    2015-01-01

    The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unanswered. We assessed the ability of multiple skin-derived and lymphoid resident DCs to perform this function in a novel orthotopic murine melanoma model where tumor establishment and expansion is within the skin. Two migratory populations defined as CD103−XCR1+ and CD103+XCR1+ efficiently cross-presented melanoma-derived antigen, with the CD103−XCR1+ DCs surprisingly dominating this process. These results are critical for understanding how antitumor CD8+ T cell immunity is coordinated to tumor antigens present within the skin. PMID:26405572

  8. Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential

    PubMed Central

    Duvic, Madeleine; Evans, Mark; Wang, Casey

    2016-01-01

    Mogamulizumab (KW-0761) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CC chemokine receptor 4 (CCR4). It has shown promising therapeutic potential in phase I and II clinical trials and is currently being investigated for efficacy in treating cutaneous T-cell lymphoma (CTCL). We review the mechanism of action of mogamulizumab and its role in treating CTCL. We also discuss the results of major clinical trials. PMID:27247757

  9. Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma.

    PubMed

    Danlos, François-Xavier; Pagès, Cécile; Baroudjian, Barouyr; Vercellino, Laetitia; Battistella, Maxime; Mimoun, Maurice; Jebali, Majdi; Bagot, Martine; Tazi, Abdellatif; Lebbé, Céleste

    2016-05-01

    To our knowledge, we report the first case of sarcoid-like granulomatous reaction induced by nivolumab, a fully human IgG4 anti-programmed death 1 (PD-1) immune checkpoint inhibitor antibody. A 57-year-old man was treated with nivolumab 3 mg/kg for 2 weeks for a desmoplastic melanoma stage III American Joint Commission on Cancer, with no BRAF, NRAS, and cKit mutations. At 10 months, although melanoma complete response was achieved, he developed sarcoid-like granulomatous reaction in the mediastinal lymph node and skin, which resumed after nivolumab arrest. Melanoma did not relapse after 12 months of follow-up. Considering the recently demonstrated role of activated PD-1/PDL-1 axis in sarcoidosis, granulomatous reaction in the patient seems to be a paradoxical reaction, but similar observations have been reported with ipilimumab, another immune checkpoint inhibitor. Sarcoid-like granulomatous reaction during immunotherapy treatment could be a manifestation of cell-mediated immunity induced by these drugs. Impact of granulomatous reaction induced by immune checkpoint inhibitor on melanoma progression is not known and requires further study. Melanoma patients treated by immunotherapy (anti-cytotoxic T-lymphocyte-associated protein-4/anti-PD-1) should be considered for developing sarcoid-like granulomatous reaction that must not be confused with tumor progression. PMID:27157227

  10. Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Advanced Melanoma

    PubMed Central

    Ott, Patrick A.; Hamid, Omid; Pavlick, Anna C.; Kluger, Harriet; Kim, Kevin B.; Boasberg, Peter D.; Simantov, Ronit; Crowley, Elizabeth; Green, Jennifer A.; Hawthorne, Thomas; Davis, Thomas A.; Sznol, Mario; Hwu, Patrick

    2014-01-01

    Purpose The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma. Patients and Methods Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity. Results One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival. Conclusion Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity. PMID:25267741

  11. A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma

    PubMed Central

    Ibrahim, Nageatte; Lawrence, Donald P.; Aldridge, Julie; Giobbie-Hurder, Anita; Hodi, F. Stephen; Flaherty, Keith T.; Conley, Christine; Mier, James W.; Atkins, Michael B.; McDermott, David F.

    2015-01-01

    Lessons Learned This study is a rare example of effective doses of both targeted agents being both administered and tolerated. This combination should not be used in melanoma. Background. Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. Methods. Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented. Results. Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m2 weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. Conclusion. The combination of sorafenib and bortezomib is safe but not active in patients with melanoma. PMID:25986244

  12. Cytogenetics of melanoma: a review.

    PubMed

    James, Aaron W; Chang, Le; Shrestha, Swati; Cochran, Alistair; Binder, Scott; Tirado, Carlos A

    2014-01-01

    Malignant melanoma is an aggressive cutaneous neoplasm whose incidence has continued to increase worldwide. Currently, histopathologic examination of specimens is the gold standard for the diagnosis and categorization of melanoma. Cytogenetic analysis represents a powerful, and currently underused, adjunct to traditional histologic examination in distinguishing nevi and melanomas. Chromosomal studies have shown that malignant melanomas often contain multiple chromosomal alterations, most commonly of chromosomes 1, 6, 7, 9, 10 and 11. These chromosomes often include genes within the MAPK molecular pathway, which is involved in the development and progression of melanoma. Fluorescence in situ hybridization (FISH) can detect a number of recurrent anomalies, and commercially available kits for melanoma detection have been devised. The utility of cytogenetics in melanocytic lesions at certain anatomic sites has been evaluated, including acral lesions, uveal lesions, and lymph node metastases. Recurring cytogenetic anomalies have been defined in various challenging histologic subtypes, such as desmoplastic melanomas and Spitzoid lesions. Cytogenetic analysis may also be used to provide supplementary information in prognostication, particularly in uveal melanomas. We provide a brief review of the molecular pathways found in melanoma and a summary of what is known and remains unknown regarding cytogenetic aberrations associated with malignant melanoma. PMID:26030295

  13. A phase I–II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma

    PubMed Central

    Rocca, A; Minucci, S; Tosti, G; Croci, D; Contegno, F; Ballarini, M; Nolè, F; Munzone, E; Salmaggi, A; Goldhirsch, A; Pelicci, P G; Testori, A

    2009-01-01

    We explored in a phase I/II clinical trial the combination of valproic acid (VPA), a clinically available histone deacetylase inhibitor, with standard chemoimmunotherapy in patients with advanced melanoma, to evaluate its clinical activity, to correlate the clinical response with the biological activity of VPA and to assess toxicity. Patients were treated initially with VPA alone for 6 weeks. The inhibition of the target in non-tumour peripheral blood cells (taken as a potential surrogate marker) was measured periodically, and valproate dosing adjusted with the attempt to reach a measurable inhibition. After the treatment with valproate alone, dacarbazine plus interferon-α was started in combination with valproate. Twenty-nine eligible patients started taking valproate and 18 received chemoimmunotherapy and are assessable for response. We observed one complete response, two partial remissions and three disease stabilisations lasting longer than 24 weeks. With the higher valproate dosages needed to reach a measurable inhibition of the target, we observed an increase of side effects in those patients who received chemoimmunotherapy. The combination of VPA and chemoimmunotherapy did not produce results overtly superior to standard therapy in patients with advanced melanoma and toxicity was not negligible, casting some doubts on the clinical use of VPA in this setting (at least in the administration schedule adopted). PMID:19127265

  14. Primary malignant melanoma of the esophagus

    PubMed Central

    Jora, Charu; Pankaj, Promila; Verma, Ritu; Jain, Anjali; Belho, Ethel S.

    2015-01-01

    Primary malignant melanoma most commonly originates from the skin; other less common extra cutaneous sites include squamous mucous membranes, uvea, retina, leptomeninges, genitourinary tract, digestive tract, biliary tract, and upper respiratory tract. Primary melanoma of the gastrointestinal tract is exceedingly rare. We are reporting a histo-pathologically proven rare case of primary malignant melanoma of the esophagus and its findings on fluorodeoxyglucose positron emission tomography and computed tomography. PMID:25829739

  15. Primary malignant melanoma of the esophagus.

    PubMed

    Jora, Charu; Pankaj, Promila; Verma, Ritu; Jain, Anjali; Belho, Ethel S

    2015-01-01

    Primary malignant melanoma most commonly originates from the skin; other less common extra cutaneous sites include squamous mucous membranes, uvea, retina, leptomeninges, genitourinary tract, digestive tract, biliary tract, and upper respiratory tract. Primary melanoma of the gastrointestinal tract is exceedingly rare. We are reporting a histo-pathologically proven rare case of primary malignant melanoma of the esophagus and its findings on fluorodeoxyglucose positron emission tomography and computed tomography. PMID:25829739

  16. In situ photoimmunotherapy for melanoma: preliminary clinical results

    NASA Astrophysics Data System (ADS)

    Naylor, Mark F.; Nordquist, Robert E.; Teauge, T. Kent; Perry, Lisa A.; Chen, Wei R.

    2006-02-01

    Although melanoma accounts for only 4% of skin cancer cases, it causes 79% of all skin cancer deaths. Patients with metastatic melanoma have a poor prognosis, and long term survival is only about 5% [1, 2]. Conventional therapies such as surgery and radiation therapy usually do not cure stage III or stage IV melanoma, while traditional chemotherapy is primarily palliative. Over the last decade we have been developing new methods for treating solid tumors like melanoma, first in animal models and now in humans. We present here preliminary results from a new technique that utilizes a combination of laser stimulation and drug therapy to stimulate brisk immunological responses in cases of advanced melanoma with cutaneous metastases. A high-power, near-infrared diode laser (805 nm) is used to kill tumors in situ and a topical toll-like receptor agonist (imiquimod cream, 5%) is used to intensify the resulting immunological response. This is essentially an in situ, tumor vaccine approach to treating solid tumors.

  17. [ Spectrum of oncogene mutations is different in melanoma subtypes].

    PubMed

    Mazurenko, N N; Tsyganova, I V; Lushnikova, A A; Ponkratova, D A; Anurova, O A; Cheremushkin, E A; Mikhailova, I N; Demidov, L V

    2015-01-01

    Melanoma is the most lethal malignancy of skin, which is comprised of clinically relevant molecular subsets defined by specific "driver" mutations in BRAF, NRAS, and KIT genes. Recently, the better results in melanoma treatment were obtained with the mutation-specific inhibitors that have been developed for clinical use and target only patients with particular tumor genotypes. The aim of the study was to characterize the spectrum of "driver" mutations in melanoma subtypes from 137 patients with skin melanoma and 14 patients with mucosal melanoma. In total 151 melanoma cases, the frequency of BRAF, NRAS, KIT, PDGFRA, and KRAS mutations was 55.0, 10.6, 4.0, 0.7, and 0.7%, respectively. BRAF mutations were found in 69% of cutaneous melanoma without UV exposure and in 43% of cutaneous melanoma with chronic UV exposure (p=0.045), rarely in acral and mucosal melanomas. Most of melanomas containing BRAF mutations, V600E (92%) and V600K (6.0%) were potentially sensitive to inhibitors vemurafenib and dabrafenib. NRAS mutations were more common in cutaneous melanoma with chronic UV exposure (26.0%), in acral and mucosal melanomas; the dominant mutations being Q61R/K/L (87.5%). KIT mutations were found in cutaneous melanoma with chronic UV exposure (8.7%) and mucosal one (28.6%), but not in acral melanoma. Most of KIT mutations were identified in exon 11; these tumors being sensitive to tyrosine kinase inhibitors. This is the first monitoring of BRAF, NRAS, KIT, PDGFRA, and KRAS hotspot mutations in different subtypes of melanoma for Russian population. On the base of data obtained, one can suppose that at the molecular level melanomas are heterogeneous tumors that should be tested for "driver" mutations in the each case for evaluation of the potential sensitivity to target therapy. The obtained results were used for treatment of melanoma patients. PMID:26710785

  18. Therapeutic advances in cutaneous T-cell lymphoma (CTCL): from retinoids to rexinoids.

    PubMed

    Stadler, Rudolf; Kremer, Almut

    2006-02-01

    Retinoids comprise a family of polyisoprenoid lipids that include vitamin A (retinol) and its various natural and synthetic analogues. Retinoids are compounds with multiple actions. They are involved in the control of cell proliferation, cell differentiation, and embryonic development. Each retinoid has its own profile of pharmacologic properties that determines its usefulness in clinical dermatology or oncology. Although numerous synthetic retinoids have been synthesized, their biological activities are usually associated with clinical disadvantages such as toxicity and teratogenicity. Retinoids that bind to both the retinoic acid receptor and retinoid X receptor subtypes have shown clinical activity in hematologic malignancies and can mediate genes associated with both growth and differentiation. Retinoid X receptor-specific rexinoids have also shown efficacy in the treatment of cutaneous T-cell lymphomas, but their exact mechanism of action is unclear. This article summarizes the clinical relevance of both groups of compounds in this important patient population. PMID:16516669

  19. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

    2014-08-01

    The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted. PMID:24991838

  20. BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs

    PubMed Central

    Wong, C W; Fan, Y S; Chan, T L; Chan, A S W; Ho, L C; Ma, T K F; Yuen, S T; Leung, S Y

    2005-01-01

    Background: Malignant melanoma arising from different body compartments may be associated with differing aetiological factors and clinical behaviour, and may manifest diverse molecular genetic profiles. Although many studies have focused on cutaneous melanoma, little is known of mucosal and other types of melanoma. In particular, malignant melanoma of soft parts is different from other melanomas in many respects, yet manifests a common melanocytic differentiation. Mutation of BRAF is now known to be common in cutaneous melanomas, and raises possible new therapeutic options of anti-RAF treatment for these patients. Few data are available for non-cutaneous melanomas. Aims: To study the incidence of BRAF and NRAS mutations in melanomas arising in diverse internal organs. Methods: Fifty one melanomas from various internal organs were investigated for BRAF and NRAS mutation by direct DNA sequencing. Results: BRAF and NRAS mutations were found in two and five mucosal melanomas arising from the aerodigestive and female genital tracts (n = 36). Their occurrence is mutually exclusive, giving a combined mutation incidence rate of 19.4% in mucosal melanomas. Both BRAF and NRAS mutations were absent in malignant melanoma of soft parts (n = 7). BRAF mutation was also absent in uveal melanoma (n = 6), but was seen in two of five cutaneous melanomas. The incidence of BRAF or combined BRAF/NRAS mutations in all non-cutaneous groups was significantly lower than published rates for cutaneous melanomas. Conclusion: Each melanoma subtype may have a unique oncogenetic pathway of tumour development, and only a small fraction of non-cutaneous melanomas may benefit from anti-RAF treatment. PMID:15917418

  1. Subverting the B7-H1/PD-1 Pathway in Advanced Melanoma and Kidney Cancer

    PubMed Central

    Harshman, Lauren C.; Choueiri, Toni K.; Drake, Charles; Hodi, F. Stephen

    2016-01-01

    Ligands for inhibitory immune receptors on T cells may be constitutively expressed on tumor cells or host cells in tumor microenvironment as a consequence of adaptive immunity. Programmed death 1 (PD-1) is 1 such receptor on T cells, which functions as a negative regulator of T cell activity. Tumors that up-regulate programmed death ligand 1 (PD-L1) (B7-H1) may abrogate the host’s effector T cell antitumor response. Higher tumoral PD-L1 expression has been linked with inferior clinical outcomes. Multiple cancers including renal cell cancers (RCCs) and melanomas have relatively high levels of PD-L1 on the cell surface. Early evaluations of antibodies that block the interaction of PD-1 and PD-L1 have shown efficacy and a favorable tolerability profile with notable inflammatory toxicities that are generally manageable. Upward of 30% of RCC patients and 50% of melanoma patients achieve objective responses. Durable responses can occur, even in some patients who have discontinued treatment. The developing investigation of PD-1/PD-L1 pathway–blocking agents in RCC and melanoma will likely alter our approaches to the treatment of these 2 deadly diseases. PMID:25098288

  2. Basal cell carcinoma, squamous cell carcinoma and melanoma of the head and face.

    PubMed

    Feller, L; Khammissa, R A G; Kramer, B; Altini, M; Lemmer, J

    2016-01-01

    Ultraviolet light (UV) is an important risk factor for cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma of the skin. These cancers most commonly affect persons with fair skin and blue eyes who sunburn rather than suntan. However, each of these cancers appears to be associated with a different pattern of UV exposure and to be mediated by different intracellular molecular pathways.Some melanocortin 1 receptor (MC1R) gene variants play a direct role in the pathogenesis of cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma apart from their role in determining a cancer-prone pigmentory phenotype (fair skin, red hair, blue eyes) through their interactions with other genes regulating immuno-inflammatory responses, DNA repair or apoptosis.In this short review we focus on the aetiological role of UV in cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma of the skin, and on some associated biopathological events. PMID:26850723

  3. Long-term outcome of patients with advanced-stage cutaneous T cell lymphoma treated with gemcitabine.

    PubMed

    Pellegrini, Cinzia; Stefoni, Vittorio; Casadei, Beatrice; Maglie, Roberto; Argnani, Lisa; Zinzani, Pier Luigi

    2014-11-01

    The choice of treatment for cutaneous T cell lymphoma (CTCL) is often determined by institutional experience, particularly as there is a paucity of data from phase III trials and a lack of consensus concerning treatment of the advanced stages. Among the several second-line and experimental drugs, gemcitabine could be considered one of the most suitable options for pretreated CTCL. Since it is difficult to find in literature the long-term outcome regarding the efficacy of a single-agent drug in pretreated patients and, in particular, in rare diseases such as CTCL, a retrospective observational study was conducted with the aim of evaluating the long-term outcome of CTCL patients treated with gemcitabine. Twenty-five patients with at least one therapy (range 1-8) performed prior to gemcitabine were found. After gemcitabine treatment, the overall response was 48 % with a 20 % of complete responses. At 15 years, the estimated overall survival is 47 %, progression-free survival 8.8 %, and disease-free survival 40 % (median reached at 2.9 years). All patients received at least three cycles and no grade 3-4 hematological adverse events occurred. At the latest follow-up, two patients are still in continuous complete response. This long-term update on the role of gemcitabine as a single agent in pretreated advanced-stage CTCL confirms this monotherapy as effective and safe. PMID:24908331

  4. Primary mucosal melanomas: a comprehensive review

    PubMed Central

    Mihajlovic, Marija; Vlajkovic, Slobodan; Jovanovic, Predrag; Stefanovic, Vladisav

    2012-01-01

    Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas. PMID:23071856

  5. Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

    PubMed Central

    Hamilton, Betty K.; Rosen, Mark A.; Amaravadi, Ravi K.; Schuchter, Lynn M.; Gallagher, Maryann; Chen, Helen; Sehgal, Chandra; O’Dwyer, Peter J.

    2015-01-01

    Background. Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. Patients and Methods. We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. Results. A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. Conclusion. Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients. Implications for Practice: Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a

  6. The Efficacy and Safety of Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors for Advanced Melanoma

    PubMed Central

    Guan, Xiuwen; Wang, Haijuan; Ma, Fei; Qian, Haili; Yi, Zongbi; Xu, Binghe

    2016-01-01

    Abstract The purpose of this study was to investigate the efficacy and safety of programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) inhibitors using a meta-analysis of present trials for advanced melanoma. A fully recursive literature search of the primary electronic databases for available trials was performed. The objective response rate (ORR) and the median progression-free survival (PFS) of clinical responses were considered the main endpoints to evaluate the efficacy, whereas Grade 3–4 adverse effects (AEs) were analyzed to evaluate safety. The ORR of PD-1 and PD-L1 inhibitors was 30% (95% CI: 25–35%). No significant difference in the ORR was observed after the comparisons of low-dose, median-dose, and high-dose cohorts. In addition, the rate of Grade 3–4 AEs was 9% (95% CI: 6–12%). According to the 3 randomized controlled trials that compared PD-1 inhibitors with chemotherapy, the difference between these 2 groups was found to be statistically significant with respect to the ORR, PFS and the incidence of Grade 3–4 AEs; that is, the relative risk (RR) of the ORR was 3.42 (95% CI: 2.49–4.69, P < 0.001), the hazard ratio (HR) of the PFS was 0.50 (95% CI: 0.44–0.58, P < 0.001), and the RR of Grade 3–4 AEs was 0.45 (95% CI: 0.31–0.65, P < 0.001). According to a meta-analysis of limited concurrent studies, PD-1 and PD-L1 inhibitors appear to be associated with improved response rates, superior response durability and tolerable toxicity in patients with advanced melanoma. PMID:26986169

  7. Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma.

    PubMed

    Kirchberger, Michael C; Hauschild, Axel; Schuler, Gerold; Heinzerling, Lucie

    2016-09-01

    With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single-agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment-related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity. PMID:27501507

  8. [Cutaneous neoplasms].

    PubMed

    Dummer, R; Beyeler, M; Morcinek, J; Burg, G

    2003-09-01

    The skin is the organ most commonly affected by malignancies. Various cancers of the skin show a dramatic increase in incidence over the last decades. Epithelial skin tumors are most frequently, e.g., basal cell carcinoma and the squamous cell carcinoma with its precursors, the actinic keratoses. Melanoma, which is extremely difficult to treat in advanced tumor stages, is dreaded. Besides that, there are other epithelial malignant diseases, e.g. Morbus Bowen and adnexal tumors originating from the skin appendices. Mesenchymal malignant neoplasias such as Morbus Kaposi, angiosarcomas and other dermal sarcomas, are rare. Since the majority of malignant neoplasms is removable and curable by a simple surgical intervention, the knowledge of the different skin tumors is essential for non-dermatologist. PMID:14526630

  9. Emerging phytochemicals for prevention of melanoma invasion

    PubMed Central

    Jones, Virginia; Katiyar, Santosh K.

    2013-01-01

    Cutaneous malignant melanoma is the leading cause of death from skin diseases due to its propensity to metastasize. Once diagnosed with metastatic melanoma, most patients will die of their disease within 2 years. As suppression of metastases requires long-term interventions, potential anti-metastatic agents must not only be efficacious but also have low toxicity. Many phytochemicals used in traditional medicine have low toxicity and recent studies suggest that some are promising candidates for the prevention or treatment of metastatic melanoma. Here, we review the recent literature regarding phytochemicals that have shown inhibitory effects on melanoma cell migration or invasion. PMID:23474498

  10. Vemurafenib: in unresectable or metastatic melanoma.

    PubMed

    Keating, Gillian M

    2012-10-01

    Vemurafenib is a first-in-class, small molecule BRAFV600E inhibitor. It is indicated in the US for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, and in the EU as monotherapy in adults with BRAFV600 mutation-positive unresectable or metastatic melanoma. Oral vemurafenib improved overall survival (OS) [co-primary endpoint] in patients with unresectable, previously untreated, BRAFV600E mutation-positive, stage IIIC or IV melanoma, according to the results of a randomized, open-label, multicenter, phase III trial (BRIM-3). With vemurafenib versus dacarbazine, the risk of death was significantly reduced by 63% in the interim OS analysis, and by 56%, 38%, and 30% in subsequent updated OS analyses. The median OS duration was 13.6 months in vemurafenib recipients and 9.7 months in dacarbazine recipients in the most recent OS analysis. In the phase III trial, progression-free survival (PFS) [co-primary endpoint] was also significantly improved in vemurafenib versus dacarbazine recipients (median PFS of 5.3 vs 1.6 months), with a significant reduction in the risk of death or disease progression of 74% in the final PFS analysis. Vemurafenib was also associated with a high overall response rate in patients with previously treated, BRAFV600 mutation-positive, stage IV melanoma, according to the results of a noncomparative, multicenter, phase II trial. Patients had received at least one prior systemic treatment for advanced disease (excluding BRAF inhibitors other than sorafenib or MEK inhibitors). The overall response rate (primary endpoint) was 53% (complete response rate of 6% and partial response rate of 47%), with a median duration of response of 6.7 months, and a median OS duration of 15.9 months. Oral vemurafenib was generally well tolerated in patients with metastatic melanoma, with cutaneous adverse events among the most commonly occurring adverse events. Cutaneous squamous cell carcinoma and/or keratoacanthoma were

  11. Immunobiology of primary murine melanomas.

    PubMed

    Donawho, C; Evans, R; Kripke, M L

    1992-10-01

    Primary cutaneous melanomas can be induced in inbred mice by applying a dose of dimethylbenz[a]anthracene to the skin of 4-day-old mice, and then applying repeated doses of a tumor promoter to the same site over a long period of time. Preliminary experiments suggest that the final incidence of melanomas is strongly influenced by the age at which the initiating dose of carcinogen is applied. Melanomas induced by this method in C3H mice are immunogenic and exhibit a high degree of cross-reactivity when tested by immunization and challenge in vivo. Exposing the mice to ultraviolet (UV) radiation during carcinogenesis dramatically accelerates the appearance of melanoma. We are attempting to determine how UV radiation potentiates melanoma induction by studying the growth of melanoma cells transplanted into UV-irradiated skin. Our studies suggest that UV irradiation accelerates the outgrowth of melanoma cells by means of a local, immunosuppressive effect on the skin. However, this effect is distinct from the ability of UV irradiation to alter epidermal Langerhans cells and interfere with the induction of contact hypersensitivity responses. We postulate that UV irradiation augments melanoma development by interfering with the efferent arm of the immune response in the UV-irradiated site. PMID:1445809

  12. Uveal melanoma: estimating prognosis.

    PubMed

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-02-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID:25827538

  13. Genetic testing for melanoma predisposition: current challenges.

    PubMed

    Gerstenblith, Meg R; Goldstein, Alisa M; Tucker, Margaret A; Fraser, Mary C

    2007-01-01

    A complex interaction of genetic, host, and environmental factors results in cutaneous malignant melanoma, the fifth most common cancer among men and the sixth among women in the United States. Mortality rates for cutaneous malignant melanoma depend on stage at diagnosis; thus, efforts are aimed at early detection and identification of risk factors for melanoma to distinguish those individuals requiring close surveillance. Melanoma susceptibility genes CDKN2A and CDK4 play a role in the development of melanoma, especially among some familial melanoma kindreds. The functions of CDKN2A and CDK4 in melanoma development, however, are currently incompletely understood. Therefore, at this time, predictive genetic testing for CDKN2A mutations outside of defined research protocols is not recommended because of the low likelihood of detecting mutations even in high-risk groups, the present inadequacy of interpreting a test result due to variations in penetrance and unclear associations with other cancers, and the minimal influence knowledge of mutation status currently has on medical management. Oncology nurses have an important role in identifying individuals at high risk for melanoma regardless of CDKN2A mutation status, encouraging enrollment in skin surveillance programs, and providing patient education regarding sun protection, prevention and early detection of melanoma. PMID:18025917

  14. A Multi-center Phase I Dose Escalation Trial to Evaluate Safety and Tolerability of Intra-arterial Temozolomide for Patients with Advanced Extremity Melanoma Using Normothermic Isolated Limb Infusion

    PubMed Central

    Beasley, Georgia M.; Speicher, Paul; Augustine, Christina K.; Dolber, Paul C.; Peterson, Bercedis L.; Sharma, Ketan; Mosca, Paul J.; Royal, Richard; Ross, Merrick; Zager, Jonathan S.; Tyler, Douglas S.

    2015-01-01

    Synopsis This phase I trial reports the first use of intra arterial temozolomide via isolated limb infusion for patients with advanced extremity melanoma. There was minimal toxicity and the maximum tolerated dose was determined. PMID:25145500

  15. Concomitant cetuximab and radiation therapy: A possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas

    PubMed Central

    DELLA VITTORIA SCARPATI, GIUSEPPINA; PERRI, FRANCESCO; PISCONTI, SALVATORE; COSTA, GIUSEPPE; RICCIARDIELLO, FILIPPO; DEL PRETE, SALVATORE; NAPOLITANO, ALBERTO; CARRATURO, MARCO; MAZZONE, SALVATORE; ADDEO, RAFFAELE

    2016-01-01

    Non-melanoma skin cancers (NMSCs) include a heterogeneous group of malignancies arising from the epidermis, comprising squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma and more rare entities, including malignant pilomatrixoma and sebaceous gland tumours. The treatment of early disease depends primarily on surgery. In addition, certain patients present with extensive local invasion or metastasis, which renders these tumours surgically unresectable. Improving the outcome of radiotherapy through the use of concurrent systemic therapy has been demonstrated in several locally advanced cancer-treatment paradigms. Recently, agents targeting the human epidermal growth factor receptor (EGFR) have exhibited a consolidated activity in phase II clinical trials and case series reports. Cetuximab is a monoclonal antibody that binds to and completely inhibits the EGFR, which has been revealed to be up-regulated in a variety of SCCs, including NMSCs. The present review aimed to summarize the role of anti-EGFR agents in the predominant types of NMSC, including SCC and BCC, and focuses on the cetuximab-based studies, highlighting the biological rationale of this therapeutic option. In addition, the importance of the association between cetuximab and radiotherapy for locally advanced NMSC is discussed. PMID:27073643

  16. Molecular Pathogenesis of Sporadic Melanoma and Melanoma-Initiating Cells

    PubMed Central

    Kong, Yunyi; Kumar, Suresh M.; Xu, Xiaowei

    2014-01-01

    Recent advances in molecular genetics and cancer stem cell biology have shed some light on the molecular basis of melanomagenesis. In this review, we will focus on major genetic alterations in the melanoma, particularly pathways involved in cell proliferation, apoptosis, and tumor suppression. The potential role of melanoma-initiating cells during melanomagenesis and progression will also be discussed. Understanding pathogenesis of melanoma may uncover new diagnostic clues and therapeutic targets for this increasingly prevalent disease. PMID:21128770

  17. Uveal melanoma: From diagnosis to treatment and the science in between.

    PubMed

    Chattopadhyay, Chandrani; Kim, Dae Won; Gombos, Dan S; Oba, Junna; Qin, Yong; Williams, Michelle D; Esmaeli, Bita; Grimm, Elizabeth A; Wargo, Jennifer A; Woodman, Scott E; Patel, Sapna P

    2016-08-01

    Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society. PMID:26991400

  18. [Cutaneous lymphoma].

    PubMed

    Beyeler, M; Burg, G; Dummer, R

    2004-10-01

    Cutaneous lymphomas are uncommon. They must be distinguished from secondary skin manifestations of primary nodal lymphomas. Primary cutaneous lymphomas are divided into B-cell- and T-cell cutaneous lymphoma and commonly have good prognosis. Therapy is based on the stage of the disease. Since cure is not possible, the aim of treatment is to control the disease and reduce symptoms. A variety of new and promising therapeutic modalities have been introduced in recent years. PMID:15349694

  19. Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study

    PubMed Central

    Board, R E; Ellison, G; Orr, M C M; Kemsley, K R; McWalter, G; Blockley, L Y; Dearden, S P; Morris, C; Ranson, M; Cantarini, M V; Dive, C; Hughes, A

    2009-01-01

    Background: This study investigated the potential clinical utility of circulating free DNA (cfDNA) as a source of BRAF mutation detection in patients enrolled into a phase II study of AZD6244, a specific MEK1/2 inhibitor, in patients with advanced melanoma. Methods: BRAF mutations were detected using Amplification Refractory Mutation System allele-specific PCR. BRAF mutation status was assessed in serum-derived cfDNA from 126 patients enrolled into the study and from 94 matched tumour samples. Results: Of 94 tumour samples, 45 (47.9%) were found to be BRAF mutation positive (BRAF+). Serum-derived cfDNA was BRAF+ in 33 of 126 (26.2%) samples, including in five samples for which tumour data were unavailable. Of BRAF+ tumours, 25 of 45 (55.6%) were BRAF+ in cfDNA. In three cases in which the tumour was negative, cfDNA was BRAF+. Progression-free survival (PFS) of patients with BRAF+ tumour and cfDNA was not significantly different compared with tumour BRAF+ but cfDNA BRAF-negative patients, indicating that cfDNA BRAF detection is not associated with poorer prognosis on PFS in stage III/IV advanced melanoma. Conclusions: These data demonstrate the feasibility of BRAF mutation detection in cfDNA of patients with advanced melanoma. Future studies should aim to incorporate BRAF mutation testing in cfDNA to further validate this biomarker for patient selection. PMID:19861964

  20. Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma.

    PubMed

    Klein, Oliver; Davis, Ian D; McArthur, Grant A; Chen, Li; Haydon, Andrew; Parente, Phillip; Dimopoulos, Nektaria; Jackson, Heather; Xiao, Kun; Maraskovsky, Eugene; Hopkins, Wendie; Stan, Rodica; Chen, Weisan; Cebon, Jonathan

    2015-04-01

    Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents. PMID:25662405

  1. New Diagnostic Aides for Melanoma

    PubMed Central

    Ferris, Laura K.; Harris, Ryan J.

    2012-01-01

    Synopsis Detection of melanoma at an early stage is crucial to improving survival rates in melanoma. Accurate diagnosis by current techniques including dermatoscopy remains difficult, and new tools are needed to improve our diagnostic abilities. This article discusses recent advances in diagnostic techniques including confocal scanning laser microscopy, MelaFind, Siascopy, noninvasive genomic detection, as well as other future possibilities to aid in diagnosing melanoma. Advantages and barriers to implementation of the various technologies are discussed as well. PMID:22800557

  2. Advanced Glycation End Products Evolution after Pancreas-Kidney Transplantation: Plasmatic and Cutaneous Assessments

    PubMed Central

    Oliveira, José C.; Vizcaíno, José Ramón; Gouveia, Carlos; Silva, Donzília; Henriques, António C.; Noronha, Irene L.; Rodrigues, Anabela

    2016-01-01

    Diabetes mellitus leads to increased Advanced Glycation End Products (AGE) production, which has been associated with secondary diabetic complications. Type 1 diabetic patients undergoing pancreas-kidney transplantation (SPKT) can restore normoglycemia and renal function, eventually decreasing AGE accumulation. We aimed to prospectively study AGE evolution after SPKT. Circulating AGE were assessed in 20 patients, at time 0 (T0), 3 months (T3), 6 months (T6), and 12 months (T12) after successful SPKT. Global AGE and carboxymethyllysine (CML) were analyzed, as well as advanced oxidation protein products (AOPP). Skin biopsies were obtained at T0 and T12. Immunohistochemistry with anti-AGE antibody evaluated skin AGE deposition. AGE mean values were 16.8 ± 6.4 μg/mL at T0; 17.1 ± 3.8 μg/mL at T3; 17.5 ± 5.6 μg/mL at T6; and 16.0 ± 5.2 μg/mL at T12. CML mean values were 0.94 ± 0.36 ng/mL at T0; 1.11 ± 0.48 ng/mL at T3; 0.99 ± 0.42 ng/mL at T6; and 0.78 ± 0.38 ng/mL at T12. AOPP mean values were 130.1 ± 76.8 μMol/L at T0; 137.3 ± 110.6 μMol/L at T3; 116.4 ± 51.2 μMol/L at T6; and 106.4 ± 57.9 μMol/L at T12. CML variation was significant (P = 0.022); AOPP variation was nearly significant (P = 0.076). Skin biopsies evolved mostly from a cytoplasmic diffuse to a peripheral interkeratinocytic immunoreaction pattern; in 7 cases, a reduction in AGE immunoreaction intensity was evident at T12. In conclusion, glycoxidation markers decrease, plasmatic and on tissues, may start early after SPKT. Studies with prolonged follow-up may confirm these data. PMID:26881017

  3. Melanoma-specific marker expression in skin biopsy tissues as a tool to facilitate melanoma diagnosis.

    PubMed

    Alexandrescu, Doru T; Kauffman, C Lisa; Jatkoe, Timothy A; Hartmann, Dan P; Vener, Tatiana; Wang, Haiying; Derecho, Carlo; Rajpurohit, Yashoda; Wang, Yixin; Palma, John F

    2010-07-01

    Diagnosis of cutaneous melanoma requires accurate differentiation of true malignant tumors from highly atypical lesions, which lack the capacity to develop uncontrolled proliferation and to metastasize. We used melanoma markers from previous work to differentiate benign and atypical lesions from melanoma using paraffin-embedded tissue. This critical step in diagnosis generates the most uncertainty and discrepancy between dermatopathologists. A total of 193 biopsy tissues were selected: 47 melanomas, 48 benign nevi, and 98 atypical/suspicious, including 48 atypical nevi and 50 melanomas as later assigned by expert dermatopathologists. Performance for SILV, GDF15, and L1CAM normalized to TYR in unequivocal melanoma versus benign nevi resulted in an area under the curve (AUC) of 0.94, 0.67, and 0.5, respectively. SILV also differentiated atypical cases classified as melanoma from atypical nevi with an AUC=0.74. Furthermore, SILV showed a significant difference between suspicious melanoma and each suspicious atypia group: melanoma versus severe atypia and melanoma versus moderate atypia had P-values of 0.0077 and 0.0009, respectively. SILV showed clear discrimination between melanoma and benign unequivocal cases as well as between different atypia subgroups in the group of suspicious samples. The role and potential utility of this molecular assay as an adjunct to the morphological diagnosis of melanoma are discussed. PMID:20357814

  4. Malignant Melanoma With Rhabdomyosarcomatous Differentiation: A Case Report.

    PubMed

    Antonov, Nina K; Niedt, George W

    2016-06-01

    Malignant melanoma may exhibit morphologic characteristics of nonmelanocytic cell or tissue components, a phenomenon termed divergent differentiation. Melanoma with rhabdomyosarcomatous differentiation is rare, with 6 definite cases in adults reported in the literature. The authors describe a 75-year-old man with a cutaneous lesion of the right ear initially diagnosed as malignant melanoma. Three months later, biopsy of a right cervical lymph node showed changes suggestive of rhabdomyosarcoma. Reexamination of the initial skin biopsy with muscle markers confirmed a diagnosis of malignant melanoma with rhabdomyosarcomatous differentiation. This case serves to highlight the diagnostic challenges associated with this rare subtype of melanoma. PMID:27205908

  5. Melanoma (image)

    MedlinePlus

    ... tumor that involves the skin cells that produce pigment (melanin). The risk of melanoma increases with age, but frequently effects young, otherwise healthy people. Melanoma is an aggressive type of cancer that can spread very rapidly.

  6. Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: A combination nanomedicine approach.

    PubMed

    Lu, Yao; Wang, Yuhua; Miao, Lei; Haynes, Matthew; Xiang, Guangya; Huang, Leaf

    2016-08-28

    Therapeutic anticancer vaccine development must address a number of barriers to achieve successful tumor specific killing, including effective antigen presentation and antigen-specific T-cell activation to mediate cytotoxic cellular effects, inhibition of an immune-suppressive tumor microenvironment in order to facilitate and enhance CTL activity, and induction of memory T-cells to prolong tumor rejection. While traditional as well as modern vaccines rely upon delivery of both antigen and adjuvant, a variety of clinically relevant cancers lack ideal immunogenic antigens. Building upon recent efforts, we instead chose to exploit chemotherapy-induced apoptosis to allow for in situ antigen generation in a combination, nanomedicine-based approach. Specifically, lipid-coated cisplatin nanoparticles (LPC) and CpG-encapsulated liposomes (CpG-Lipo) were prepared for the temporally-controlled and multifaceted treatment of an advanced in vivo model of melanoma. Such combination therapy established strong synergistic effects, both in apoptotic extent and subsequent abrogation of tumor growth, which were due largely to both an enhanced cytotoxic T-cell recruitment and a reduction of immune-suppressive mediators in the microenvironments of both spleens and tumor. These results underlie a prolonged host lifespan in the combination approach (45 days) as compared with control (25 days, p < 0.02), providing promise toward a personalized approach to nanomedicine by establishing effect synergy in host-specific immunotherapy following chemotherapy. PMID:27235608

  7. Melanoma and genetics.

    PubMed

    Nelson, Andrew A; Tsao, Hensin

    2009-01-01

    As the incidence of malignant melanoma continues to increase and with the completion of the sequencing of the human genome, there have been increasing efforts to identify the "melanoma gene(s)." Although some patients and families have significantly increased risks due to genetic predisposition, most melanoma cases are sporadic and likely result from low to moderate risk genetic factors. This review focuses on the genes that cover the greatest risk of developing melanoma. It is important to remember that many--if not most--cases of melanoma are the result of undiscovered variants. The strongest genetic risk for the development of melanoma results from heritable alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which encodes two separate but related proteins, p16/INK4a and p14/ARF. These proteins help regulate cell division and apoptosis, both of which are necessary to maintain cellular homeostasis. Other important genes include CDK4/6 and retinoblastoma (RB1), which encode downstream proteins in the same pathway as p16/INK4a and p14/ARF. Finally, we discuss the relative importance of the melanocortin 1 receptor (MC1R) gene as a moderate risk factor for melanoma. Although great advances have been made in understanding the molecular basis and genetic predisposition of melanoma, many questions still remain to be answered. Someday soon, it will be possible to predict a patient's risk of melanoma by DNA analysis; however, it is important to reconcile our tremendous technologic capabilities with documented clinical utility. PMID:19095153

  8. In situ photoimmunotherapy for melanoma: an ongoing phase I clinical trial

    NASA Astrophysics Data System (ADS)

    Naylor, Mark F.; Nordquist, Robert E.; Teague, T. Kent; Perry, Lisa A.; Chen, Wei R.

    2007-02-01

    In situ Photoimmunotherapy (ISPI) was developed to treat metastatic tumors using a combination of phototherapy and immunotherapy. It utilizes local intervention through photothermal destruction of existing solid tumors and through immune response modifier to elicit host anti-tumor responses. Such combination in pre-clinical studies has shown promise in cancer treatment by eradicating the primary tumors and also controlling metastases at distant sites. ISPI has been used in our preliminary clinical studies for melanoma patients and the outcome has been extremely encouraging. In 2006, we began enrolling patients in a new phase I immunotherapy trial for advanced cutaneous melanoma. This trial is based on our previous results which indicated that we had developed an effective treatment for advanced melanoma. Of the first six patients treated, (4 stage IV, and 2 surgically unresectable stage III), 2 of the stage IV patients are still alive, one tumor free, and one with a possible treatable recurrence after 2 1/2 years. We have also discovered that recurrences of the skin cancer can be retreated by the same technique and that treatment seems to blunt the virulence of the disease and make it more treatable. These initial results indicate that ISPI probably will have the ability to prolong survival in selected cases of advanced melanoma, and potentially cure a significant percentage of treated patients.

  9. Zebrafish Melanoma.

    PubMed

    Kaufman, Charles K

    2016-01-01

    Melanoma skin cancer is a potentially deadly disease in humans and has remained extremely difficult to treat once it has metastasized. In just the last 10 years, a number of models of melanoma have been developed in the zebrafish that are biologically faithful to the human disease and have already yielded important insights into the fundamental biology of melanoma and offered new potential avenues for treatment. With the diversity and breadth of the molecular genetic tools available in the zebrafish, these melanoma models will continue to be refined and expanded upon to keep pace with the rapidly evolving field of melanoma biology. PMID:27165365

  10. Melanoma: oncogenic drivers and the immune system

    PubMed Central

    Karachaliou, Niki; Pilotto, Sara; Teixidó, Cristina; Viteri, Santiago; González-Cao, María; Riso, Aldo; Morales-Espinosa, Daniela; Molina, Miguel Angel; Chaib, Imane; Santarpia, Mariacarmela; Richardet, Eduardo; Bria, Emilio

    2015-01-01

    Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches. PMID:26605311

  11. Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma.

    PubMed

    Taylor, Nicholas J; Thomas, Nancy E; Anton-Culver, Hoda; Armstrong, Bruce K; Begg, Colin B; Busam, Klaus J; Cust, Anne E; Dwyer, Terence; From, Lynn; Gallagher, Richard P; Gruber, Stephen B; Nishri, Diane E; Orlow, Irene; Rosso, Stefano; Venn, Alison J; Zanetti, Roberto; Berwick, Marianne; Kanetsky, Peter A

    2016-09-15

    Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. PMID:27101944

  12. Reduced Intensity Conditioning Before Partially Matched Donor Stem Cell Transplant in Treating Patients With Advanced Cutaneous T Cell Lymphoma

    ClinicalTrials.gov

    2016-04-11

    Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Stage IIB Mycosis Fungoides and Sezary Syndrome; Stage IIIA Mycosis Fungoides and Sezary Syndrome; Stage IIIB Mycosis Fungoides and Sezary Syndrome; Stage IVA Mycosis Fungoides and Sezary Syndrome; Stage IVB Mycosis Fungoides and Sezary Syndrome

  13. Melanoma of the Foot.

    PubMed

    Bristow, Ivan; Bower, Chris

    2016-07-01

    Melanoma is a rare form of skin cancer that is responsible for most skin cancer deaths globally. Tumors arising on the foot continue to be a particular challenge. Patients present later and lesions are frequently misdiagnosed, leading to more advanced disease with an overall poorer prognosis then melanoma elsewhere. In order to improve early recognition, this article reviews the clinical features of the disease along with published algorithms. Emerging assessment techniques such as dermoscopy are also discussed as tools to improve clinical decision making. Contemporary drug therapies in the treatment of advanced disease are also discussed. PMID:27215160

  14. Prognostic significance of hematological profiles in melanoma patients.

    PubMed

    Gandini, Sara; Ferrucci, Pier Francesco; Botteri, Edoardo; Tosti, Giulio; Barberis, Massimo; Pala, Laura; Battaglia, Angelo; Clerici, Alessandra; Spadola, Giuseppe; Cocorocchio, Emilia; Martinoli, Chiara

    2016-10-01

    Cancer-related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000-2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre-operative blood tests were analyzed. Survival was estimated with the Kaplan-Meier method, and analyzed using Log-rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I-III patients. Furthermore, at a single-patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p < 0.0001) and LMR (p = 0.005) were all significantly associated with survival, independently of other known prognostic factors. These results suggest that cellular components of peripheral blood do count for survival of patients with advanced melanoma. PMID:27252119

  15. Malignant melanoma metastatic to the ovary: presentation and radiological characteristics.

    PubMed

    Moselhi, M; Spencer, J; Lane, G

    1998-05-01

    Cutaneous melanomas rarely metastasize to the ovary; however, we have recently encountered three cases which have proved a diagnostic dilemma. All presented with a pelvic mass and a past history of cutaneous melanoma but both ultrasound examination and CT scanning proved inconclusive and neither was able to accurately characterize the lesions. Magnetic resonance imaging (MRI) was able to demonstrate the presence of melanin in one of the ovarian lesions as peripheral high signal change on T1-weighted images. The two lesions without melanin failed to show this feature. MRI may therefore be useful in the diagnosis of ovarian melanoma but only if melanin is present. PMID:9600825

  16. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma

    PubMed Central

    2013-01-01

    Background The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial. Methods A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D). Results Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events. Conclusions No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine. Trial registration ClinicalTrials.gov: NCT01359956 PMID:23402397

  17. Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma.

    PubMed

    Albertini, Mark R; Ranheim, Erik A; Zuleger, Cindy L; Sondel, Paul M; Hank, Jacquelyn A; Bridges, Alan; Newton, Michael A; McFarland, Thomas; Collins, Jennifer; Clements, Erin; Henry, Mary Beth; Neuman, Heather B; Weber, Sharon; Whalen, Giles; Galili, Uri

    2016-08-01

    Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥1:50 were eligible for two intratumoral α-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received two intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids. PMID:27207605

  18. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: A Phase I/II dose-escalation study

    SciTech Connect

    Tsuji, Hiroshi . E-mail: h_tsuji@nirs.go.jp; Ishikawa, Hitoshi; Yanagi, Takeshi; Hirasawa, Naoki; Kamada, Tadashi; Mizoe, Jun-Etsu; Kanai, Tatsuaki; Tsujii, Hirohiko; Ohnishi, Yoshitaka

    2007-03-01

    Purpose: To evaluate the applicability of carbon ion beams for the treatment of choroidal melanoma with regard to normal tissue morbidity and local tumor control. Methods and Materials: Between January 2001 and February 2006, 59 patients with locally advanced or unfavorably located choroidal melanoma were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy at the National Institute of Radiologic Sciences. The primary endpoint of this study was normal tissue morbidity, and secondary endpoints were local tumor control and patient survival. Of the 59 subjects enrolled, 57 were followed >6 months and analyzed. Results: Twenty-three patients (40%) developed neovascular glaucoma, and three underwent enucleation for eye pain due to elevated intraocular pressure. Incidence of neovascular glaucoma was dependent on tumor size and site. Five patients had died at analysis, three of distant metastasis and two of concurrent disease. All but one patient, who developed marginal recurrence, were controlled locally. Six patients developed distant metastasis, five in the liver and one in the lung. Three-year overall survival, disease-free survival, and local control rates were 88.2%, 84.8%, and 97.4%, respectively. No apparent dose-response relationship was observed in either tumor control or normal tissue morbidity at the dose range applied. Conclusion: Carbon-ion radiotherapy can be applied to choroidal melanoma with an acceptable morbidity and sufficient antitumor effect, even with tumors of unfavorable size or site.

  19. Combining Immunotherapy with Oncogene-Targeted Therapy: A New Road for Melanoma Treatment

    PubMed Central

    Aris, Mariana; Barrio, María Marcela

    2015-01-01

    Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50 years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field. PMID:25709607

  20. Genetics of melanoma

    PubMed Central

    Wangari-Talbot, Janet; Chen, Suzie

    2013-01-01

    Genomic variation is a trend observed in various human diseases including cancer. Genetic studies have set out to understand how and why these variations result in cancer, why some populations are pre-disposed to the disease, and also how genetics affect drug responses. The melanoma incidence has been increasing at an alarming rate worldwide. The burden posed by melanoma has made it a necessity to understand the fundamental signaling pathways involved in this deadly disease. Signaling cascades such as mitogen-activated protein kinase and PI3K/AKT have been shown to be crucial in the regulation of processes that are commonly dysregulated during cancer development such as aberrant proliferation, loss of cell cycle control, impaired apoptosis, and altered drug metabolism. Understanding how these and other oncogenic pathways are regulated has been integral in our challenge to develop potent anti-melanoma drugs. With advances in technology and especially in next generation sequencing, we have been able to explore melanoma genomes and exomes leading to the identification of previously unknown genes with functions in melanomagenesis such as GRIN2A and PREX2. The therapeutic potential of these novel candidate genes is actively being pursued with some presenting as druggable targets while others serve as indicators of therapeutic responses. In addition, the analysis of the mutational signatures of melanoma tumors continues to cement the causative role of UV exposure in melanoma pathogenesis. It has become distinctly clear that melanomas from sun-exposed skin areas have distinct mutational signatures including C to T transitions indicative of UV-induced damage. It is thus necessary to continue spreading awareness on how to decrease the risk factors of developing the disease while at the same time working for a cure. Given the large amount of information gained from these sequencing studies, it is likely that in the future, treatment of melanoma will follow a highly

  1. Immunotherapy in a rare case of primary pelvic retroperitoneal melanoma.

    PubMed

    Talag, Maria Monica; Alsharedi, Mohamed; Bou Zgheib, Nadim; Lebowicz, Yehuda

    2016-01-01

    Recent advances in novel immunotherapeutic and targeted therapeutic agents have increased treatment options in patients with advanced metastatic melanoma. However, evidence in the literature on whether or not extracutaneous melanoma will acquire an equivalent advantage from these therapies is very scarce. In general, extracutaneous melanomas are rare and aggressive melanomas, which are clinically and biologically unique, with higher incidence of metastatic disease and poor prognosis. In this case report, we present a very rare case of a 54-year-old woman with primary pelvic retroperitoneal melanoma treated with an anti-PD-1 antibody, pembrolizumab. Furthermore, we explore the role of novel immunotherapies in the treatment of advanced melanoma. PMID:27624447

  2. Metastatic melanoma - a review of current and future treatment options.

    PubMed

    Maverakis, Emanual; Cornelius, Lynn A; Bowen, Glen M; Phan, Tiffany; Patel, Falin B; Fitzmaurice, Sarah; He, Young; Burrall, Barbara; Duong, Christopher; Kloxin, April M; Sultani, Hawa; Wilken, Reason; Martinez, Steve R; Patel, Forum

    2015-05-01

    Despite advances in treatment and surveillance, melanoma continues to claim approximately 9,000 lives in the US annually (SEER 2013). The National Comprehensive Cancer Network currently recommends ipilumumab, vemurafenib, dabrafenib, and high-dose IL-2 as first line agents for Stage IV melanoma. Little data exists to guide management of cutaneous and subcutaneous metastases despite the fact that they are relatively common. Existing options include intralesional Bacillus Calmette-Guérin, isolated limb perfusion/infusion, interferon-α, topical imiquimod, cryotherapy, radiation therapy, interferon therapy, and intratumoral interleukin-2 injections. Newly emerging treatments include the anti-programmed cell death 1 receptor agents (nivolumab and pembrolizumab), anti-programmed death-ligand 1 agents, and oncolytic vaccines (talimogene laherparepevec). Available treatments for select sites include adoptive T cell therapies and dendritic cell vaccines. In addition to reviewing the above agents and their mechanisms of action, this review will also focus on combination therapy as these strategies have shown promising results in clinical trials for metastatic melanoma treatment. PMID:25520039

  3. Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low-normal serum lactate dehydrogenase: 'The AGENDA trial'.

    PubMed

    Bedikian, Agop Y; Garbe, Claus; Conry, Robert; Lebbe, Celeste; Grob, Jean J

    2014-06-01

    In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline. PMID:24667300

  4. Molecular markers to complement sentinel node status in predicting survival in patients with high-risk locally invasive melanoma.

    PubMed

    Rowe, Casey J; Tang, Fiona; Hughes, Maria Celia B; Rodero, Mathieu P; Malt, Maryrose; Lambie, Duncan; Barbour, Andrew; Hayward, Nicholas K; Smithers, B Mark; Green, Adele C; Khosrotehrani, Kiarash

    2016-08-01

    Sentinel lymph node status is a major prognostic marker in locally invasive cutaneous melanoma. However, this procedure is not always feasible, requires advanced logistics and carries rare but significant morbidity. Previous studies have linked markers of tumour biology to patient survival. In this study, we aimed to combine the predictive value of established biomarkers in addition to clinical parameters as indicators of survival in addition to or instead of sentinel node biopsy in a cohort of high-risk melanoma patients. Patients with locally invasive melanomas undergoing sentinel lymph node biopsy were ascertained and prospectively followed. Information on mortality was validated through the National Death Index. Immunohistochemistry was used to analyse proteins previously reported to be associated with melanoma survival, namely Ki67, p16 and CD163. Evaluation and multivariate analyses according to REMARK criteria were used to generate models to predict disease-free and melanoma-specific survival. A total of 189 patients with available archival material of their primary tumour were analysed. Our study sample was representative of the entire cohort (N = 559). Average Breslow thickness was 2.5 mm. Thirty-two (17%) patients in the study sample died from melanoma during the follow-up period. A prognostic score was developed and was strongly predictive of survival, independent of sentinel node status. The score allowed classification of risk of melanoma death in sentinel node-negative patients. Combining clinicopathological factors and established biomarkers allows prediction of outcome in locally invasive melanoma and might be implemented in addition to or in cases when sentinel node biopsy cannot be performed. PMID:26990817

  5. Implications of age and conditional survival estimates for patients with melanoma

    PubMed Central

    Banerjee, Mousumi; Lao, Christopher D.; Wancata, Lauren M.; Muenz, Daniel G.; Haymart, Megan R.; Wong, Sandra L.

    2016-01-01

    Objective Overall cancer incidence is decreasing while melanoma cases increase. Conditional survival estimates offer a more accurate prognosis for patients as they survive past diagnosis. It is unknown the effect age and stage has on a melanoma patient’s conditional survival estimate. Methods Surveillance, Epidemiology, End Results (SEER) data was utilized, identifying new diagnosis cutaneous melanoma patients (N=95,041), from 1998–2005, with up to 12 year follow up. Estimates of disease-specific survival by stage and age were determined by Cox regression and transformed to estimate conditional five-year survival. Results Localized melanoma patients have an excellent five-year survival at diagnosis and subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70–79 years) to younger patients (<30 years): hazard ratio (HR) for mortality 3.79 (95% confidence interval (CI) 3.01–4.84) and HR 2.36 (95% CI 1.93–2.91), respectively. No age effect difference is observed in disease-specific survival for advanced disease: HR 1.14 (95% CI 0.87–1.53). Over time conditional survival estimates improve for older patients with localized and regional disease. This improvement is not seen in distant disease nor is the age gradient. Conclusions Disease-specific mortality and conditional survival for patients with localized and regional melanoma is initially impacted by older age with effects dissipating over time. Age does not affect survival in patients with advanced disease. Understanding the conditional five-year disease-specific survival of melanoma based on age and stage can help patients and physicians, informing decision making about treatment and surveillance. PMID:26479218

  6. Implications of age and conditional survival estimates for patients with melanoma.

    PubMed

    Banerjee, Mousumi; Lao, Christopher D; Wancata, Lauren M; Muenz, Daniel G; Haymart, Megan R; Wong, Sandra L

    2016-02-01

    Overall cancer incidence is decreasing, whereas melanoma cases are increasing. Conditional survival estimates offer a more accurate prognosis for patients the farther they are from time of diagnosis. The effect of age and stage on a melanoma patient's conditional survival estimate is unknown. Surveillance, Epidemiology, and End Results data were utilized to identify newly diagnosed cutaneous melanoma patients (N=95 041), from 1998 to 2005, with up to 12 years of follow-up. Estimates of disease-specific survival by stage and age were determined by Cox regression analysis and transformed to estimated conditional 5-year survival. Localized melanoma patients have an excellent 5-year survival at diagnosis and over subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70-79 years) with younger patients (<30 years): hazard ratio (HR) for mortality 3.79 [95% confidence interval (CI) 3.01-4.84] and HR 2.36 (95% CI 1.93-2.91), respectively. No age effect difference is observed in disease-specific survival for advanced disease: HR 1.14 (95% CI 0.87-1.53). Over time, conditional survival estimates improve for older patients with localized and regional disease. This improvement is not seen in distant disease, neither is the age gradient. Disease-specific mortality and conditional survival for patients with localized and regional melanomas are initially impacted by older age, with effects dissipating over time. Age does not affect survival in patients with advanced disease. Understanding the conditional 5-year disease-specific survival of melanoma based on age and stage can help patients and physicians, informing decision-making about treatment and surveillance. PMID:26479218

  7. Evaluating Biomarkers in Melanoma

    PubMed Central

    Karagiannis, Panagiotis; Fittall, Matthew; Karagiannis, Sophia N.

    2015-01-01

    The incidence of cutaneous melanoma has more than doubled over the last decades making it one of the fastest rising cancers worldwide. Improved awareness and early detection of malignant moles now permit earlier diagnosis aiming to decrease the likelihood of recurrence. However, it is difficult to identify those patients initially diagnosed with localized melanoma who subsequently develop metastatic disease. For this group, prognosis remains poor and clinical outcomes are variable and challenging to predict. Considerable efforts have focused on the search for novel prognostic tools, with numerous markers evaluated in the circulation and in tumor lesions. The most reliable predictors of patient outcome are the clinical and histological features of the primary tumor such as Breslow thickness, ulceration status, and mitotic rate. Elevated serum levels of the enzyme lactate dehydrogenase, likely to indicate active metastatic disease, are also routinely used to monitor patients. The emergence of novel immune and checkpoint antibody treatments for melanoma and increasing appreciation of key roles of the immune system in promoting or halting cancer progression have focused attention to immunological biomarkers. Validation of the most promising of these may have clinical applications in assisting prognosis, assessing endpoints in therapy, and monitoring responses during treatment. PMID:25667918

  8. Ipilimumab-Induced Granulomatous Disease Occurring Simultaneously With Disease Progression in a Patient With Metastatic Melanoma.

    PubMed

    Toumeh, Anis; Sakhi, Ramen; Shah, Sarthi; Arudra, Sri Krishna Chaitanya; De Las Casas, Luis E; Skeel, Roland T

    2016-01-01

    Malignant melanoma is the most aggressive cutaneous malignancy with dismal prognosis in the advanced setting. The food and drug administration approval of ipilimumab, the monoclonal antibody against cytotoxic T-lymphocyte antigen 4, has significantly changed treatment strategies for this disease. However, the spectrum of immune-related adverse events secondary to ipilimumab therapy is a growing area of research, and clinical observations of rare immune events as a result of such therapies continue to be reported since the approval. The co-occurrence of disease progression along with an immune-related adverse event is extremely rare. We here present the first case, to our knowledge, of diffuse nonnecrotizing granulomatous lymphadenopathy occurring simultaneously with disease progression in a patient with metastatic melanoma after receiving the second dose of ipilimumab. PMID:25933140

  9. Primary malignant melanoma of the urinary bladder and ureter.

    PubMed

    Khan, Munad; O'Kane, Dermot; Du Plessis, Justin; Hoag, Nathan; Lawrentschuk, Nathan

    2016-02-01

    Primary malignant melanoma of the urinary bladder is a rare lesion. We report the case of a 78-year-old male with no previous history of cutaneous melanoma who presented with hematuria. Further investigation with imaging and cystoscopy raised suspicion of a primary bladder and ureteric melanoma, which had subsequently metastasized. This was confirmed with histological assessment and a thorough search for alternative primary lesions. Unfortunately, our patient passed away prior to receiving any oncological treatment for his metastatic melanoma, underscoring both the high mortality of this lesion and the need for a consensus on definitive treatment. PMID:26892061

  10. Cutaneous tumors in pregnancy.

    PubMed

    Walker, Joanna L; Wang, Annie R; Kroumpouzos, George; Weinstock, Martin A

    2016-01-01

    Pregnancy alters the frequency and natural course of certain skin tumors. Pregnancy-associated changes in melanocytic nevi are transient, and there is no substantiated evidence of increased risk of malignant transformation of melanocytic nevi in gestation. Characteristic vascular and pigment-related dermatoscopic features are helpful in evaluating pigmented lesions, but a biopsy should be performed for significant change or other worrisome features in a lesion. Outcomes for pregnancy-associated melanoma do not appear to be poorer compared with nonpregnancy melanoma; however, data are limited for advanced (stage III/IV) melanoma. Some studies suggest increased propensity for lymphovascular spread, but more data are needed for definitive conclusions and guidelines on prognostication, workup, and treatment of pregnancy-associated melanoma. Vascular tumors, particularly pyogenic granuloma (granuloma gravidarum), occur with increased frequency and are associated with pro-angiogenic hormonal influences. Dermatofibrosarcoma protuberans has a more aggressive course during pregnancy with both prompt surgical treatment and close monitoring for recurrence being indicated. PMID:27265074

  11. Cutaneous protothecosis.

    PubMed

    Hillesheim, Paul B; Bahrami, Soon

    2011-07-01

    Prototheca species are an achlorophyllic algae that cause infections primarily in immunocompromised individuals. At least one-half of infectious cases are cutaneous. Because protothecosis is seldom suspected clinically, patients may be subjected to various treatment modalities for extended periods without satisfactory results. Cutaneous protothecosis shares similar clinical and pathologic findings with deep tissue fungal mycoses. The typical presentation occurs most commonly on the face and extremities as erythematous plaques, nodules, or superficial ulcers. Prototheca spp are spherical, unicellular, nonbudding organisms that are sometimes noted on routine hematoxylin-eosin staining but are best visualized with periodic acid-Schiff and Gomori methenamine-silver histochemical stains. Although protothecosis can be diagnosed on biopsy, culture of the organism on a medium such as Sabouraud dextrose agar is required for definitive diagnosis. Treatment may require a combination of surgical excision and antifungal agents. Therefore, cutaneous protothecosis should be considered in a lesion that appears suspicious for the more-common fungal infections. PMID:21732787

  12. Uveal melanoma: Estimating prognosis

    PubMed Central

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-01-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms “uvea,” “iris,” “ciliary body,” “choroid,” “melanoma,” “uveal melanoma” and “prognosis,” “metastasis,” “genetic testing,” “gene expression profiling.” Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID:25827538

  13. Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.

    PubMed

    Goldinger, Simone M; Zimmer, Lisa; Schulz, Carsten; Ugurel, Selma; Hoeller, Christoph; Kaehler, Katharina C; Schadendorf, Dirk; Hassel, Jessica C; Becker, Juergen; Hauschild, Axel; Dummer, Reinhard

    2014-01-01

    BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies. PMID:24183461

  14. [Gastric melanoma--clinical case].

    PubMed

    Doran, H; Pătraşcu, Tr; Catrina, E; Mihalache, O; Degeratu, D; Predescu, G

    2009-01-01

    Malignant melanomas of the gastrointestinal tract and particulary of the stomach are very rare intra-operative findings. The majority of such melanomas are metastatic from a cutaneous primary. We present the clinical case of a 69-years-old woman with malignant melanoma of the left pectoral region resected in 1988, presented with epigastric pain, weight loss and anaemia. Endoscopy and CT-scan suggested the diagnosis of malignant tumor of the large curvature of the stomach. Explorative laparotomy revealed a large ulcerated tumor of the fornix, with spleno-pancreatic invasion. We also found several pigmented satellite nodules. The surgical solution consisted in a total gastrectomy and distal spleno-pancreatectomy. Histology revealed the tumor and the satellite nodules to be composed of nests of epithelioid cells with melanin pigment. After 3 months, the evolution was favorable. There are some articles in medical literature which present cases of primary gastric melanomas. According to these scientific criterias from the literature, we discussed the nature of this melanoma - a primary or a metastatic one. PMID:19943569

  15. Cutaneous Sarcoidosis.

    PubMed

    Wanat, Karolyn A; Rosenbach, Misha

    2015-12-01

    The skin is the second most common organ affected in sarcoidosis, which can affect patients of all ages and races, with African American women having the highest rates of sarcoidosis in the United States. The cutaneous manifestations are protean and can reflect involvement of sarcoidal granulomas within the lesion or represent reactive non-specific inflammation, as seen with erythema nodosum. Systemic work-up is necessary in any patient with cutaneous involvement of sarcoidal granulomas, and treatment depends on other organ involvement and severity of clinical disease. Skin-directed therapies are first line for mild disease, and immunomodulators or immunosuppressants may be necessary. PMID:26593142

  16. Methods of Melanoma Detection.

    PubMed

    Leachman, Sancy A; Cassidy, Pamela B; Chen, Suephy C; Curiel, Clara; Geller, Alan; Gareau, Daniel; Pellacani, Giovanni; Grichnik, James M; Malvehy, Josep; North, Jeffrey; Jacques, Steven L; Petrie, Tracy; Puig, Susana; Swetter, Susan M; Tofte, Susan; Weinstock, Martin A

    2016-01-01

    Detection and removal of melanoma, before it has metastasized, dramatically improves prognosis and survival. The purpose of this chapter is to (1) summarize current methods of melanoma detection and (2) review state-of-the-art detection methods and technologies that have the potential to reduce melanoma mortality. Current strategies for the detection of melanoma range from population-based educational campaigns and screening to the use of algorithm-driven imaging technologies and performance of assays that identify markers of transformation. This chapter will begin by describing state-of-the-art methods for educating and increasing awareness of at-risk individuals and for performing comprehensive screening examinations. Standard and advanced photographic methods designed to improve reliability and reproducibility of the clinical examination will also be reviewed. Devices that magnify and/or enhance malignant features of individual melanocytic lesions (and algorithms that are available to interpret the results obtained from these devices) will be compared and contrasted. In vivo confocal microscopy and other cellular-level in vivo technologies will be compared to traditional tissue biopsy, and the role of a noninvasive "optical biopsy" in the clinical setting will be discussed. Finally, cellular and molecular methods that have been applied to the diagnosis of melanoma, such as comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), will be discussed. PMID:26601859

  17. New developments in the treatment of metastatic melanoma – role of dabrafenib–trametinib combination therapy

    PubMed Central

    Luke, Jason J; Ott, Patrick A

    2014-01-01

    Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant melanoma. The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway. Combining selective BRAF and MEK inhibition, such as the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced melanoma while significantly alleviating the paradoxical activation of mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia and gastrointestinal or ocular toxicity. While combined BRAF–MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1 antibodies. Here we review the development of the dabrafenib plus trametinib combination, the characteristics of each drug and the combination, and the role of this combination in the management of patients with BRAF-mutant melanoma. PMID:25018652

  18. Rad6 is a Potential Early Marker of Melanoma Development

    PubMed Central

    Rosner, Karli; Adsule, Shreelekha; Haynes, Brittany; Kirou, Evangelia; Kato, Ikuko; Mehregan, Darius R.; Shekhar, Malathy P.V.

    2014-01-01

    Melanoma is the leading cause of death from skin cancer in industrialized countries. Several melanoma-related biomarkers and signaling pathways have been identified; however, their relevance to melanoma development/progression or to clinical outcome remains to be established. Aberrant activation of Wnt/β-catenin pathway is implicated in various cancers including melanoma. We have previously demonstrated Rad6, an ubiquitin-conjugating enzyme, as an important mediator of β-catenin stability in breast cancer cells. Similar to breast cancer, β-catenin-activating mutations are rare in melanomas, and since β-catenin signaling is implicated in melanoma, we examined the relationship between β-catenin levels/activity and expression of β-catenin transcriptional targets Rad6 and microphthalmia-associated transcription factor-M (Mitf-M) in melanoma cell models, and expression of Rad6, β-catenin, and Melan-A in nevi and cutaneous melanoma tissue specimens. Our data show that Rad6 is only weakly expressed in normal human melanocytes but is overexpressed in melanoma lines. Unlike Mitf-M, Rad6 overexpression in melanoma lines is positively associated with high molecular weight β-catenin protein levels and β-catenin transcriptional activity. Double-immunofluorescence staining of Rad6 and Melan-A in melanoma tissue microarray showed that histological diagnosis of melanoma is significantly associated with Rad6/Melan-A dual positivity in the melanoma group compared to the nevi group (P = .0029). In contrast to strong β-catenin expression in normal and tumor areas of superficial spreading malignant melanoma (SSMM), Rad6 expression is undetectable in normal areas and Rad6 expression increases coincide with increased Melan-A in the transformed regions of SSMM. These data suggest a role for Rad6 in melanoma pathogenesis and that Rad6 expression status may serve as an early marker for melanoma development. PMID:24831578

  19. Rad6 is a Potential Early Marker of Melanoma Development.

    PubMed

    Rosner, Karli; Adsule, Shreelekha; Haynes, Brittany; Kirou, Evangelia; Kato, Ikuko; Mehregan, Darius R; Shekhar, Malathy P V

    2014-05-12

    Melanoma is the leading cause of death from skin cancer in industrialized countries. Several melanoma-related biomarkers and signaling pathways have been identified; however, their relevance to melanoma development/progression or to clinical outcome remains to be established. Aberrant activation of Wnt/β-catenin pathway is implicated in various cancers including melanoma. We have previously demonstrated Rad6, an ubiquitin-conjugating enzyme, as an important mediator of β-catenin stability in breast cancer cells. Similar to breast cancer, β-catenin-activating mutations are rare in melanomas, and since β-catenin signaling is implicated in melanoma, we examined the relationship between β-catenin levels/activity and expression of β-catenin transcriptional targets Rad6 and microphthalmia-associated transcription factor-M (Mitf-M) in melanoma cell models, and expression of Rad6, β-catenin, and Melan-A in nevi and cutaneous melanoma tissue specimens. Our data show that Rad6 is only weakly expressed in normal human melanocytes but is overexpressed in melanoma lines. Unlike Mitf-M, Rad6 overexpression in melanoma lines is positively associated with high molecular weight β-catenin protein levels and β-catenin transcriptional activity. Double-immunofluorescence staining of Rad6 and Melan-A in melanoma tissue microarray showed that histological diagnosis of melanoma is significantly associated with Rad6/Melan-A dual positivity in the melanoma group compared to the nevi group (P=.0029). In contrast to strong β-catenin expression in normal and tumor areas of superficial spreading malignant melanoma (SSMM), Rad6 expression is undetectable in normal areas and Rad6 expression increases coincide with increased Melan-A in the transformed regions of SSMM. These data suggest a role for Rad6 in melanoma pathogenesis and that Rad6 expression status may serve as an early marker for melanoma development. PMID:24831578

  20. Cutaneous Horn

    MedlinePlus

    ... fair-skinned individuals with a history of significant sun exposure. Signs and Symptoms A cutaneous horn most often ... radiation therapy. Trusted Links MedlinePlus: Skin Conditions MedlinePlus: Sun Exposure References Bolognia, Jean L., ed. Dermatology , pp.1715. ...

  1. Melanoma immunotherapy dominates the field.

    PubMed

    Diamantopoulos, Panagiotis; Gogas, Helen

    2016-07-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  2. Melanoma immunotherapy dominates the field

    PubMed Central

    Diamantopoulos, Panagiotis

    2016-01-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  3. [Molecular alterations in melanoma and targeted therapies].

    PubMed

    Mourah, Samia; Lebbé, Céleste

    2014-12-01

    Melanoma is a skin cancer whose incidence is increasing steadily. The recent discovery of frequent and recurrent genetic alterations in cutaneous melanoma allowed a molecular classification of tumors into distinct subgroups, and paved the way for targeted therapy. Several signaling pathways are involved in the progression of this disease with oncogenic mutations affecting signaling pathways: MAPK, PI3K, cAMP and cyclin D1/CDK4. In each of these pathways, several potential therapeutic targets have been identified and specific inhibitors have already been developed and have shown clinical efficacy. The use of these inhibitors is often conditioned by tumors genotyping. In France, melanomas genotyping is supported by the platforms of the National Cancer Institute (INCA), which implemented a national program ensuring access to innovation for personalized medicine. The identification of new targets in melanoma supplies a very active dynamic development of innovative molecules contributing to changing the therapeutic landscape of this pathology. PMID:25776766

  4. Study Suggests Smaller Melanoma Excision Margins May Be Option for Some Patients

    Cancer.gov

    A randomized controlled trial of patients with stage IIA–C cutaneous melanoma thicker than 2-mm found that a 2-cm surgical resection margin is sufficient and is as safe for patients as a 4-cm margin.

  5. Sarcoidosis in Melanoma Patients: Case Report and Literature Review

    PubMed Central

    Beutler, Bryce D.; Cohen, Philip R.

    2015-01-01

    Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated sarcoidosis. In addition, we not only review the literature describing characteristics of other melanoma patients with sarcoidosis, but also the features of melanoma patients with antineoplastic therapy-associated sarcoidosis. Sarcoidosis has been described in 80 melanoma patients; sufficient information for analysis was provided in 39 of these individuals. In 43.6% of individuals (17 out of 39), sarcoidosis was directly associated with melanoma; in 56.4% of oncologic patients (22 out of 39), sarcoidosis was induced by antineoplastic therapy that had been administered for the treatment of their metastatic melanoma. The discovery of melanoma preceded the development of sarcoidosis in 12 of the 17 (70.5%) individuals who did not receive systemic treatment. Pulmonary and/or cutaneous manifestations of sarcoidosis were common among both groups of patients. Most patients did not require treatment for sarcoidosis. Melanoma patients—either following antineoplastic therapy or without systemic treatment—may be at an increased risk to develop sarcoidosis. In antineoplastic therapy naive melanoma patients, a common etiologic factor—such as exposure to ultraviolet light—may play a role in their developing melanoma and sarcoidosis. PMID:26083934

  6. Cutaneous metastasis of uterine adenocarcinoma: a case report and review of the literature.

    PubMed

    Selim, Abdulhafez A; Shaheen, Shagufta; Lockshin, Norman; Khachemoune, Amor

    2009-07-01

    Cutaneous metastases from cancer are relatively uncommon in clinical practice but when present may herald the diagnosis of internal malignancy. The most common sources of primary cancer are the breasts, lungs, large bowel, oral cavity, kidneys, stomach, ovaries, and malignant melanoma. Despite the high incidence of uterine adenocarcinoma, cutaneous metastases are uncommon. The most common presentation of cutaneous metastases is rapidly developing nodules or tumors. The diagnosis of cutaneous metastatic carcinoma hinges on histopathologic evaluation of the involved skin. We discuss and review the diagnosis and management of cutaneous metastasis of uterine adenocarcinoma. PMID:19743722

  7. Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer

    ClinicalTrials.gov

    2016-05-05

    Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Skin Melanoma; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  8. [Is UV-A a cause of malignant melanoma?].

    PubMed

    Moan, J

    1994-03-20

    The first action spectrum for cutaneous malignant melanoma was published recently (2). This spectrum was obtained using the fish Xiphophorus. If the same action spectrum applies to humans, the following statements are true: Sunbathing products (agents to protect against the sun) that absorb UV-B radiation provide almost no protection against cutaneous malignant melanoma. UV-A-solaria are more dangerous than expected so far. If people are determined to use artificial sources of radiation for tanning, they should choose UV-B-solaria rather than UV-A-solaria. Fluorescent tubes and halogen lamps may have weak melanomagnetic effects. Ozone depletion has almost no effect on the incidence rates of CMM, since ozone absorbs very little UV-A radiation. Sunbathing products which contain UV-A-absorbing compounds or neutral filters (like titanium oxide) provide real protection against cutaneous malignant melanoma, at least if they are photochemically inert. PMID:8191472

  9. Cutaneous Myiasis.

    PubMed

    Solomon, Michal; Lachish, Tamar; Schwartz, Eli

    2016-09-01

    Myiasis is defined as the infestation of live vertebrates, either humans or animals, with dipterous larvae. Many organs can be infested by these larvae with cutaneous myiasis being the most common form. Cutaneous myiasis can be divided into three categories: localized furuncular myiasis, migratory myiaisis and wound myiasis, which occurs when fly larvae infest the open wounds of the host. Human myiasis has worldwide distribution, with more species and a heavier burden in tropical and subtropical countries. In recent years with increased travel to the tropics, myiasis has become common in returning travelers from these regions, Furuncular myiasis, mainly Dermatobia homonis becomes the most common form seen among them. Treatment is based on full extraction of the larva and no antibiotic treatment is needed. Understanding the mode of transmission of each type of myiasis may help to prevent the infestation. PMID:27443558

  10. Cutaneous Listeriosis

    PubMed Central

    Godshall, Casey E.; Suh, Gina

    2013-01-01

    Cutaneous infections due to Listeria monocytogenes are rare. Typically, infections manifest as nonpainful, nonpruritic, self-limited, localized, papulopustular or vesiculopustular eruptions in healthy persons. Most cases follow direct inoculation of the skin in veterinarians or farmers who have exposure to animal products of conception. Less commonly, skin lesions may arise from hematogenous dissemination in compromised hosts with invasive disease. Here, we report the first case in a gardener that occurred following exposure to soil and vegetation. PMID:23966491

  11. Solitary pulmonary metastases in high-risk melanoma patients: a prospective comparison of conventional and computed tomography

    SciTech Connect

    Heaston, D.K.; Putman, C.E.; Rodan, B.A.; Nicholson, E.; Ravin, C.E.; Korobkin, M.; Chen, J.T.; Seigler, H.F.

    1983-07-01

    A prospective comparison of chest radiography, conventional tomography, and computed tomography (CT) in the detection or confirmation of solitary pulmonary nodules was made in 42 patients with high propensity for pulmonary metastases due to advanced local (Clark level IV or V) or regional malignant melanoma. Unequivocal nodules were revealed by chest radiography in 11 patients, conventional tomograhy in 16, and computed tomography in 20 patients. Both plain films and tomography in three of these 20 were normal, but follow-up verified pulmonary metastases. Computed tomography detected more pulmonary nodules than conventional tomography in 11 patients in addition to identifying lesions in extrapulmonary sites. Therefore, chest CT is recommended before institution of immunotherapy or surgical removal of a solitary pulmonary melanoma metastasis. Once chemotherapy had been instituted for bulky regional or cutaneous involvement, however, the findings of either conventional or computed tomography were comparable in this study.

  12. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

    PubMed Central

    Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

    2014-01-01

    Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. PMID:24128326

  13. Cutaneous endometriosis: non-invasive analysis by epiluminescence microscopy.

    PubMed

    De Giorgi, V; Massi, D; Mannone, F; Stante, M; Carli, P

    2003-05-01

    The clinical appearance of cutaneous endometriosis can share some features with malignant melanoma, thus representing a possible cause for concern in both patient and clinician. In recent years, the use of epiluminescence microscopy (ELM, dermoscopy) has proved useful in improving the accuracy of diagnosis of pigmented skin lesions. The purpose of this study was to analyse the dermoscopic features of cutaneous endometriosis with histopathological correlation. We studied a case which showed homogeneous reddish pigmentation, regularly distributed. Within this typical pigmentation there were small red globular structures, but more defined and of a deeper hue, which we called 'red atolls'. ELM thus revealed a distinctive pattern in cutaneous endometriosis. PMID:12780722

  14. Simulants of Malignant Melanoma

    PubMed Central

    Piérard-Franchimont, Claudine; Delvenne, Philippe

    2015-01-01

    During the recent period, dermoscopy has yielded improvement in the early disclosure of various atypical melanocytic neoplasms (AMN) of the skin. Beyond this clinical procedure, AMN histopathology remains mandatory for establishing their precise diagnosis. Of note, panels of experts in AMN merely report moderate agreement in various puzzling cases. Divergences in opinion and misdiagnosis are likely increased when histopathological criteria are not fine-tuned and when facing a diversity of AMN types. Furthermore, some AMN have been differently named in the literature including atypical Spitz tumor, metastasizing Spitz tumor, borderline and intermediate melanocytic tumor, malignant Spitz nevus, pigmented epithelioid melanocytoma or animal-type melanoma. Some acronyms have been further suggested such as MELTUMP (after melanocytic tumor of uncertain malignant potential) and STUMP (after Spitzoid melanocytic tumor of uncertain malignant potential). In this review, such AMN at the exclusion of cutaneous malignant melanoma (MM) variants, are grouped under the tentative broad heading skin melanocytoma. Such set of AMN frequently follows an indolent course, although they exhibit atypical and sometimes worrisome patterns or cytological atypia. Rare cases of skin melanocytomas progress to loco regional clusters of lesions (agminate melanocytomas), and even to regional lymph nodes. At times, the distinction between a skin melanocytoma and MM remains puzzling. However, multipronged immunohistochemistry and emerging molecular biology help profiling any malignancy risk if present. PMID:26779311

  15. Phase I study of tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours

    PubMed Central

    Millward, M; Underhill, C; Lobb, S; McBurnie, J; Meech, S J; Gomez-Navarro, J; Marshall, M A; Huang, B; Mather, C B

    2013-01-01

    Background: Tremelimumab, a fully human cytotoxic T-lymphocyte antigen 4 monoclonal antibody, and PF-3512676, a Toll-like receptor-9 agonist, are targeted immune modulators that elicit durable single-agent antitumour activity in advanced cancer. Methods: To determine the maximum tolerated dose (MTD) of these agents combined during this phase I study, patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg kg−1) every 12 weeks plus subcutaneous PF-3512676 (0.05, 0.10, or 0.15 mg kg−1) weekly. Primary end points were safety and tolerability; secondary end points included pharmacokinetics and antitumour activity. Results: Twenty-one patients with stage IV melanoma (n=17) or advanced solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%), influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most common treatment-related adverse events (TAEs). Grade ⩾3 TAEs were reported (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred in one of the six patients in the 10 mg kg−1 tremelimumab plus 0.05 mg kg−1 PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six patients in the 15 mg kg−1 tremelimumab plus 0.05 mg kg−1 PF-3512676 cohort (grade 3 diarrhoea). Consequently, 15 mg kg−1 tremelimumab plus 0.05 mg kg−1 PF-3512676 exceeded the MTD. Two melanoma patients achieved durable (⩾170 days) partial response. No human antihuman antibody responses to tremelimumab were observed. Conclusion: Weekly PF-3512676 (⩽0.15 mg kg−1) plus tremelimumab (⩽10 mg kg−1 every 12 weeks) was tolerable. PMID:23652314

  16. Immunologic abnormalities in melanoma-prone families.

    PubMed

    Dean, J H; Greene, M H; Reimer, R R; LeSane, F V; McKeen, E A; Mulvihill, J J; Blattner, W A; Herberman, R B; Fraumeni, J F

    1979-11-01

    Sixty members of 4 families prone to cutaneous malignant melanoma (CMM) and a genetically determined precursor nevus syndrome underwent extensive immunologic evaluation. The most consistent finding was a diminished in vitro response to pooled alloantigens in the one-way mixed leukocyte culture (MLC) and a tendency to low T-lymphocyte and B-lymphocyte levels. When compared to controls, low B-lymphocyte levels and reduced MLC responses were found not only in family members with CMM and/or precursor nevi but also in unaffected blood relatives and spouses. The genesis of the immune dysfunction and its possible relationship to melanoma pathogenesis remain to be clarified. PMID:159376

  17. Melanoma of the gallbladder: appropriate surgical management and review of the literature

    PubMed Central

    Christou, Demetris; Katodritis, Nicos; Decatris, Marios P; Katodritou, Angela; Michaelides, Ioannis; Nicolaou, Nicolaos; Kounoushis, Michalis; Hadjicostas, Panayiotis

    2014-01-01

    Key Clinical Message Melanomas of the gallbladder (GB) are extremely rare with a very poor prognosis. They feature in the literature as a few case reports and the method of their management is not clear. We report a case of patient with metastatic cutaneous melanoma to the GB, and our treatment suggestion. PMID:25548636

  18. TERT Promoter Mutations Are Frequent in Cutaneous Basal Cell Carcinoma and Squamous Cell Carcinoma

    PubMed Central

    Griewank, Klaus G.; Murali, Rajmohan; Schilling, Bastian; Schimming, Tobias; Möller, Inga; Moll, Iris; Schwamborn, Marion; Sucker, Antje; Zimmer, Lisa; Schadendorf, Dirk; Hillen, Uwe

    2013-01-01

    Activating mutations in the TERT promoter were recently identified in up to 71% of cutaneous melanoma. Subsequent studies found TERT promoter mutations in a wide array of other major human cancers. TERT promoter mutations lead to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide, avoiding senescence or apoptosis. TERT promoter mutations in cutaneous melanoma often show UV-signatures. Non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, are very frequent malignancies in individuals of European descent. We investigated the presence of TERT promoter mutations in 32 basal cell carcinomas and 34 cutaneous squamous cell carcinomas using conventional Sanger sequencing. TERT promoter mutations were identified in 18 (56%) basal cell carcinomas and in 17 (50%) cutaneous squamous cell carcinomas. The recurrent mutations identified in our cohort were identical to those previously described in cutaneous melanoma, and showed a UV-signature (C>T or CC>TT) in line with a causative role for UV exposure in these common cutaneous malignancies. Our study shows that TERT promoter mutations with UV-signatures are frequent in non-melanoma skin cancer, being present in around 50% of basal and squamous cell carcinomas and suggests that increased expression of telomerase plays an important role in the pathogenesis of these tumors. PMID:24260374

  19. Choroidal melanoma

    PubMed Central

    Singh, Parul; Singh, Abhishek

    2012-01-01

    Choroidal melanoma is the most common primary intra-ocular malignant tumor and second most common site of ten malignant melanoma sites in the body. Current diagnosis of choroidal melanoma is based on both the clinical experience of the specialist and modern diagnostic techniques such as indirect ophthalmoscopy, A- and B-ultrasonography scans, fundus fluorescein angiography, and transillumination. Invasive studies such as fine needle aspiration cytology can have significant morbidity and should only be considered if therapeutic intervention is indicated and diagnosis cannot be established by any other means. Several modes of treatment are available for choroidal melanoma. Multiple factors are taken into account when deciding one approach over other approaches, such as visual acuity of the affected eye, visual acuity of the contralateral eye, tumor size, location, ocular structures involved and presence of metastases. A comprehensive review of literature available in books and indexed journals was done. This article discusses in detail epidemiology, diagnosis, current available treatment options, and prognosis and survival of choroidal melanoma. PMID:22557869

  20. Melanoma Diagnosis

    NASA Astrophysics Data System (ADS)

    Horsch, Alexander

    The chapter deals with the diagnosis of the malignant melanoma of the skin. This aggressive type of cancer with steadily growing incidence in white populations can hundred percent be cured if it is detected in an early stage. Imaging techniques, in particular dermoscopy, have contributed significantly to improvement of diagnostic accuracy in clinical settings, achieving sensitivities for melanoma experts of beyond 95% at specificities of 90% and more. Automatic computer analysis of dermoscopy images has, in preliminary studies, achieved classification rates comparable to those of experts. However, the diagnosis of melanoma requires a lot of training and experience, and at the time being, average numbers of lesions excised per histology-proven melanoma are around 30, a number which clearly is too high. Further improvements in computer dermoscopy systems and their competent use in clinical settings certainly have the potential to support efforts of improving this situation. In the chapter, medical basics, current state of melanoma diagnosis, image analysis methods, commercial dermoscopy systems, evaluation of systems, and methods and future directions are presented.

  1. Malignant Melanoma

    PubMed Central

    Perera, Eshini; Gnaneswaran, Neiraja; Jennens, Ross; Sinclair, Rodney

    2013-01-01

    Melanomas are a major cause of premature death from cancer. The gradual decrease in rates of morbidity and mortality has occurred as a result of public health campaigns and improved rates of early diagnosis. Survival of melanoma has increased to over 90%. Management of melanoma involves a number of components: excision, tumor staging, re-excision with negative margins, adjuvant therapies (chemo, radiation or surgery), treatment of stage IV disease, follow-up examination for metastasis, lifestyle modification and counseling. Sentinel lymph node status is an important prognostic factor for survival in patients with a melanoma >1 mm. However, sentinel lymph node biopsies have received partial support due to the limited data regarding the survival advantage of complete lymph node dissection when a micrometastasis is detected in the lymph nodes. Functional mutations in the mitogen-activated pathways are commonly detected in melanomas and these influence the growth control. Therapies that target these pathways are rapidly emerging, and are being shown to increase survival rates in patients. Access to these newer agents can be gained by participation in clinical trials after referral to a multidisciplinary team for staging and re-excision of the scar. PMID:27429256

  2. Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: A study of 522 consecutive cases

    PubMed Central

    2011-01-01

    Background Malignant melanoma is a rare disease in Asia, and knowledge on its characteristics and clinical outcome in Asian patients is limited. The purpose of this observational study was to determine the clinical presentation and outcome of patients with melanoma in China. Methods A database was prospectively established for the purpose of this analysis. The elements of the database included basic demographic data of patients and prognosticators previously reported in literature, as well as follow-up data including clinical outcome after treatment. Medical record of all patients with pathologically diagnosed malignant melanoma consulted in our center since 2006 were retrieved and reviewed. No patient was excluded in this study. Statistical analyses including survival and multivariate analyses of factors associated with survival were respectively performed by Kaplan-Meier method and Cox proportional hazard model. Results A total of 522 consecutive and nonselected cases were evaluated. There were 218 cases (41.8%) of acral lentiginous melanoma (ALM), 118 (22.6%) of mucosal melanoma (MCM), 103 (19.7%) of nodular melanoma (NM), 33 (6.3%) of superficial spreading melanoma (SSM), and others were Lentigo maligna melanoma or unclassifiable disease. The proportion of patients with clinical stage I, II, III, and IV diseases were 6.1%, 55.9%, 25.1%, and 12.8%, respectively. Among the 357 cases of cutaneous melanoma, 234 patients (65.5%) had ulceration. The 5-year overall survival rate of all 522 patients was 41.6%, and the median survival time was 3.92 years (95% CI, 3.282 to 4.558). Five-year survival rates of patients with stage I, II, III, and IV diseases were 94.1%, 44.0%, 38.4% and 4.6% respectively (P < 0.001). Multivariate analysis revealed that clinical stage and the ulceration were two significant prognosticators for OS. In addition, extent of surgery and use of adjuvant therapy were significant prognosticators for DFS in patients with non-metastatic disease after

  3. Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma

    PubMed Central

    Haverkos, Bradley M.; Gru, Alejandro A.; Geyer, Susan M.; Bingman, Anissa K.; Hemminger, Jessica A.; Mishra, Anjali; Wong, Henry K.; Pancholi, Preeti; Freud, Aharon G.; Caligiuri, Michael A.; Baiocchi, Robert A.; Porcu, Pierluigi

    2016-01-01

    Discovering prognostic factors that simultaneously describe tumor characteristics and improve risk stratification is a priority in cutaneous T-cell lymphoma (CTCL). More than a third of advanced stage CTCL patients in this cohort had detectable cell free plasma Epstein–Barr virus (EBV)-DNA (pEBVd) using quantitative real-time polymerase chain reaction. An increased level of pEBVd was highly concordant with EBV (ie, Epstein–Barr virus RNAs) in tumor tissue and was associated with inferior survival. Introduction Outcomes in advanced stage (AS) cutaneous T-cell lymphomas (CTCL) are poor but with great variability. Epstein–Barr virus (EBV) is associated with a subset of non-Hodgkin lymphomas. Frequency of plasma EBV-DNA (pEBVd) detection, concordance with EBV RNA (EBER) in tumor tissue, codetection of plasma cytomegalovirus DNA (pCMVd), and prognostic effect in AS CTCL are unknown. Patients and Methods Patients (n = 46; 2006–2013) with AS CTCL (≥IIB) were retrospectively studied. pEBVd and pCMVd were longitudinally measured using quantitative real-time polymerase chain reaction. EBER in situ hybridization (ISH) was performed on tumor samples. Survival from time of diagnosis (ToD) and time of progression to AS was assessed. Results Plasma EBV-DNA and pCMVd were detected in 37% (17 of 46) and 17% (8 of 46) of AS CTCL patients, respectively. pCMVd detection was significantly more frequent in pEBVd-positive (pEBVd+) than pEBVd− patients (35% vs. 7%; P = .038). Tumor tissue for EBER-ISH was available in 14 of 17 pEBVd+ and 22 of 29 pEBVd− patients; 12 of 14 (85.7%) pEBVd+ patients were EBER+ versus 0 of 22 pEBVd− patients. Frequency of large cell transformation (LCT) tended to be greater in pEBVd+ patients, but was not significant (10 of 14 pEBVd+ vs. 10 of 23 pEBVd−; P = .17). No notable differences in rates of increased levels of serum lactate dehydrogenase (LDH) were observed (17 of 17 pEBVd+ vs. 27 of 29 pEBVd−). pEBVd detection was associated with

  4. Histone variants and melanoma: facts and hypotheses.

    PubMed

    Konstantinov, Nikifor K; Ulff-Møller, Constance J; Dimitrov, Stefan

    2016-07-01

    Melanoma is the most aggressive form of skin cancer with rising incidence and morbidity. Despite advances in treatment, the 10-yr survival for patients with metastatic disease is less than 10%. During the past few years, ongoing research on different epigenomic aberrations in melanoma has catalyzed better understanding of its pathogenesis and identification of new therapeutics. In our review, we will focus on the role of histone variants, key epigenetic players in melanoma initiation and progression. Specifically, incorporation of histone variants enables additional layers of chromatin structure, and here, we will describe how alterations in this epigenetic behavior impact melanoma. PMID:26909678

  5. Eleven Primary Melanomas, Colon Cancer, and Atypical Nevi in the Same Patient: A Case Report and Literature Review

    PubMed Central

    Juul Nielsen, Lea; Rosenkrantz Hölmich, Lisbet

    2016-01-01

    Background. As the incidence of cutaneous malignant melanoma increases in the Caucasian population, an increasing population of melanoma survivors is at risk of developing multiple primary melanomas (MPM) as well as secondary primary cancers. Objective. To present a case of a patient with atypical nevi, 11 primary melanomas over 33 years, and colon cancer and to review the literature on multiple primary melanomas, atypical nevi, and correlation of nonmelanoma cancers. Conclusion. The literature indicates that patients with MPM are not uncommon, although 11 primary melanomas are rarely described, that patients with MPM may have a better survival than patients with single primary melanoma, that atypical nevi are a risk marker of not only melanoma in general but also MPM, and that melanoma patients have a significantly increased risk of developing nonmelanoma skin and other cancers, which may be even higher for patients with MPM. PMID:27022491

  6. Melanoma susceptibility genes and risk assessment.

    PubMed

    Marzuka-Alcalá, Alexander; Gabree, Michele Jacobs; Tsao, Hensin

    2014-01-01

    Familial melanoma accounts for approximately a tenth of all melanoma cases. The most commonly known melanoma susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which is transmitted in an autosomal dominant fashion and accounts for approximately 20-50 % of familial melanoma cases. Mutated p16INK4a shows impaired capacity to inhibit the cyclin D1-CDK4 complex, allowing for unchecked cell cycle progression. Mutations in the second protein coded by CDKN2A, p14ARF, are much less common and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage as the cell progresses through the cell cycle without a functional p53-mediated DNA damage response. Mutations in CDK4 that impair the inhibitory interaction with p16INK4a also increase melanoma risk but these mutations are extremely rare. Genes of the melanin biosynthetic pathway, including MC1R and MITF, have also been implicated in melanomagenesis. MC1R variants were traditionally thought to increase risk for melanoma secondary to intensified UV-mediated DNA damage in the setting of absent photoprotective eumelanin. Accumulation of pheomelanin, which appears to have a carcinogenic effect regardless of UV exposure, may be a more likely mechanism. Impaired SUMOylation of the E318K variant of MITF results in increased transcription of genes that confer melanocytes with a pro-malignant phenotype. Mutations in the tumor suppressor BAP1 enhance the metastatic potential of uveal melanoma and predispose to cutaneous/ocular melanoma, atypical melanocytic tumors, and other internal malignancies (COMMON syndrome). Genome-wide association studies have identified numerous low-risk alleles. Although several melanoma susceptibility genes have been identified, risk assessment tools have been developed only for the most common gene implicated with hereditary melanoma, CDKN2A. MelaPRO, a validated model that relies on Mendelian inheritance and Bayesian probability theories, estimates carrier

  7. Role of TRPM in melanocytes and melanoma

    PubMed Central

    Guo, Huazhang; Carlson, J. Andrew; Slominski, Andrzej

    2012-01-01

    Transient receptor potential (TRP) cation channel superfamily plays important roles in variety cellular processes including polymodal cellular sensing, cell adhesion, cell polarity, proliferation, differentiation, and apoptosis. One of its subfamilies are TRPM channels. mRNA expression of its founding member, TRPM1 (melastatin), correlates with terminal melanocytic differentiation and loss of its expression has been identified as an important diagnostic and prognostic marker for primary cutaneous melanoma. Because TRPM1 gene codes two transcripts: TRPM1 channel protein in its exons, and miR-211 in one of its introns, we propose a dual role for TRPM1 gene where the loss of TRPM1 channel protein is an excellent marker of melanoma aggressiveness, while the expression of miR-211 is linked to the tumor suppressor function of TRPM1. In addition, three other members of this subfamily, TRPM 2, 7 and 8 are implicated in regulation of melanocytic behavior. TRPM2 is capable of inducing melanoma apoptosis and necrosis. TRPM7 can be a protector and detoxifier in both melanocytes and melanoma cells. TRPM8 can mediate agonist-induced melanoma cell death. Therefore, we propose that TRPM1, TRPM2, TRPM7, and TRPM8 play crucial roles in melanocyte physiology and melanoma oncology, and are excellent diagnostic markers and theraputic targets. PMID:22897572

  8. Gallbladder melanoma mimicking acute acalculous cholecystitis.

    PubMed

    De Simone, P; Mainente, P; Bedin, N

    2000-06-01

    Gallbladder (GB) melanoma is a rare entity with a dismal prognosis. Its primary or secondary status is difficult to establish in the absence of an overt cutaneous localization. We report herein the case of a misdiagnosed GB melanoma mimicking acute acalculous cholecystitis that was treated by means of laparoscopic cholecystectomy (LC). A 54-year-old man was referred to our institution for acute cholecystitis. Apart from the ablation of some nevocytic nevi 7 years before admission, the patient's medical history was unremarkable. The ultrasound (US) examination showed a slightly enlarged acalculous gallbladder with thickened walls and a well-circumscribed polypoid mass in the fundus. The patient was treated medically and referred to LC. At surgery, some satellite nodules were visualized in the GB hepatic bed. The GB was removed, and two hepatic nodules were excised. Histology showed a pT3 melanoma. The patient underwent an open hepatic wedge resection 3 weeks after laparoscopy. No recurrence was observed at 6-month follow-up. To date, only one case of melanoma of the gallbladder treated with LC has been reported. GB melanoma is a diagnostic challenge when there is no evidence of a primary lesion. However, the occurrence of acalculous cholecystitis and a GB polyp in patients with a positive history of mole ablation should alert surgeons to the possibility of a melanoma. PMID:11265063

  9. Malignant Melanoma of the Foot

    MedlinePlus

    ... Javascript in your browser. Malignant Melanoma of the Foot What is Malignant Melanoma? Melanoma is a cancer ... age groups, even the young. Melanoma in the Foot Melanoma that occurs in the foot or ankle ...

  10. Molecular targets in melanoma: time for `ethnic personalization'

    PubMed Central

    Morita, Shane Y; Markovic, Svetomir N

    2016-01-01

    Worldwide, the incidence of melanoma continues to rise. Although not the most common cutaneous malignancy, it is the most lethal. Until recently, while other oncologic patients benefited from the nuances of targeted therapy, those afflicted with melanoma lacked that option. In 2011, the US FDA approved an oral agent that targets the BRAF oncogene. As this information is promising, it is essential that other populations (in addition to Caucasians) are examined, in order to further comprehend the biology of melanoma. Recent studies profiling various ethnicities, including Asians, have provided novel data with respect to the molecular characterization (c-KIT, BRAF, NRAS) of melanoma. It is hopeful that the management of melanoma will be universally applicable to all ethnic groups. PMID:22594895

  11. Targeted Therapy for Melanoma.

    PubMed

    Wong, Deborah J L; Ribas, Antoni

    2016-01-01

    Vemurafenib and dabrafenib, two potent tyrosine kinase inhibitors (TKIs) of the BRAF(V600E) kinase, are highly effective in the treatment of a BRAF (V600) -mutant metastatic melanoma. These are selective type I inhibitors (functional against the active conformation of the kinase) of the RAF kinases, which are key players in the mitogen-activated protein kinase (MAPK) pathway. BRAF (V600) mutations are present in approximately 7 % of all cancers, including high frequencies of mutations reported in 50 % of advanced melanomas and 100 % of hairy cell leukemias. As with most targeted therapies, resistance to BRAF inhibitors is an issue, and mechanisms of resistance are varied. Combining BRAF inhibitors with MEK inhibitors such as trametinib delays the development of resistance. Rationally combining targeted therapies to address the mechanism of resistance or combining BRAF inhibitors with other effective therapies such as immunotherapy may result in further improvement in outcomes for patients. PMID:26601866

  12. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound

    SciTech Connect

    Mishima, Y.; Ichihashi, M.; Tsuji, M.; Hatta, S.; Ueda, M.; Honda, C.; Suzuki, T.

    1989-05-01

    As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using 10B-dopa (melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA), followed by 10B(n, alpha)7Li reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14 mu, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of 10B1-BPA. Chemical and prompt gamma ray spectrometry assays of 10B accumulated within melanoma cells after 10B1-BPA administration in vitro and in vivo show high affinity, e.g., 10B melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of 10B1-BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.

  13. Primary small bowel melanomas: fact or myth?

    PubMed Central

    Hadjittofi, Christopher; Athanasopoulos, Panagiotis G.; Shah, Rahul; Ala, Aftab A.

    2016-01-01

    Small bowel melanoma (SBM) is a rare entity, which often evades diagnosis and therefore presents late. Its origin, whether arising primarily or metastatically from an unidentified or regressed primary cutaneous melanoma, remains debatable. In this report, we present a rare case of primary SBM and review the current literature. A 60-year-old man presented with melena and microcytic anemia. A series of investigations including abdominal ultrasonography (US), esophago-gastro-duodenoscopy (EGD) and colonoscopy were normal. Abdominal computed tomography revealed no specific pathology. Subsequent capsule endoscopy identified a jejunal mass, which was confirmed on laparotomy, was resected, and histologically diagnosed as melanoma. Extensive postoperative clinical examination revealed no cutaneous lesions. This report discusses gastrointestinal (GI) malignant melanoma, and examines the evidence both for and against the existence of true primary vs. metastatic disease. Furthermore, this case highlights the capabilities of capsule endoscopy in identifying an extremely rare GI tumor, which evaded other diagnostic modalities. Finally, the origins and pathophysiology of this rare cancer are evaluated, with the aim of promoting early diagnosis and treatment, and therefore improving current poor outcomes. PMID:27127766

  14. Cutaneous manifestations of lupus erythematosus.

    PubMed

    Laman, S D; Provost, T T

    1994-02-01

    Lupus erythematosus is an autoimmune disease that demonstrates cutaneous, systemic, or both cutaneous and systemic manifestations. This article reviews the cutaneous manifestations of lupus erythematosus. PMID:8153399

  15. Trp2 peptide vaccine adjuvanted with (R)-DOTAP inhibits tumor growth in an advanced melanoma model

    PubMed Central

    Vasievich, Elizabeth A.; Ramishetti, Srinivas; Zhang, Yuan; Huang, Leaf

    2012-01-01

    Previously we have shown cationic lipid (R)-DOTAP as the immunologically active enantiomer of the DOTAP racemic mixture, initiating complete tumor regression in an exogenous antigen model (murine cervical cancer model). Here, we investigate the use of (R)-DOTAP as an efficacious adjuvant delivering an endogenous antigen in an aggressive murine solid tumor melanoma model. (R)-DOTAP/Trp2 peptide complexes showed decreasing size and charge with increasing peptide concentration, taking a rod-shape at highest concentrations. The particles were stable for at 2 weeks at 4°C. A dose of 75nmol Trp2 (formulated in (R)-DOTAP) was able to show statistically significant tumor growth delay compared to lower doses of 5 and 25nmol which were no different than untreated tumors. (R)-DOTAP/Trp2 (75nmol) treated mice also showed increased T cell IFN-γ secretion after restimulation with Trp2, as well as CTL activity in vivo. This vaccination group also showed the highest population of functionally active tumor-infiltrating lymphocytes, indicated by IFN-γ secretion after restimulation with Trp2. Thus, (R)-DOTAP has shown the ability to break tolerance as an adjuvant. Its activity to enhance immunogenicity of other tumor associated antigens should be studied further. PMID:22142394

  16. [Endocrine factors influencing melanoma progression].

    PubMed

    Dobos, Judit

    2009-03-01

    According to recent findings that beside cancers traditionally considered as hormone-dependent, several other tumor types show different behavior in the two sexes, indicating the possible role of endocrine factors in the course of these diseases. The possibility that endocrine factors may influence the clinical course of human malignant melanoma is suggested by the higher survival rate in premenopausal vs. postmenopausal women or men of any ages. However, investigations on the sex hormone receptor status of human cutaneous melanomas and experiments attempting to support the epidemiological results yielded conflicting results. In our human melanoma cell lines we failed to detect steroid receptors at protein level, while quantitative PCR demonstrated that their mRNA expression level was orders of magnitude lower compared to the positive control cell lines. Sex hormones did not influence the in vitro features of the human melanoma cells considerably. On the other hand, glucocorticoid receptor was present both at mRNA and protein level, although dexamethasone was effective in vitro only at high doses. Our previous experiments showed that intrasplenic injection of human melanoma cells resulted in a significantly higher number of liver colonies in male than in female SCID mice. We now show that this difference evolves during the first day. After injection into the tail vein we did not observe gender-dependent difference in the efficiency of pulmonary colonization. Examining the pattern of metastasis formation after intracardiac injection, we have found differences between the two sexes in the incidence or number of colonies only in the case of the liver but not in other organs. We concluded that the observed phenomenon is specific to the liver; therefore we investigated the effects of 2-methoxyestradiol, an endogenous metabolite of estradiol produced mainly in the liver, with an estrogen receptor-independent antitumor activity. 2ME2 effectively inhibited melanoma cell

  17. Diagnostic Immunohistochemistry in Cutaneous Neoplasia: An Update

    PubMed Central

    Compton, Leigh A.; Murphy, George F.; Lian, Christine G.

    2015-01-01

    Immunohistochemistry (IHC) is an important adjunct in the diagnosis of neoplastic skin diseases. In addition to the many established IHC markers currently in use, new markers continue to emerge, although their general acceptance and routine application requires robust validation. Here, we summarize the most well-established and commonly used biomarkers along with an array of newer ones reported in the past several decades that either demonstrate or hold high clinical promise in the field of cutaneous pathology. We also highlight recent applications of novel IHC markers in melanoma diagnosis including genetic mutation status markers [e.g. BRAF (v-raf murine sarcoma viral oncogene homolog B) and NRAS (neuroblastoma RAS viral oncogene homolog)] and an epigenetic alteration marker (e.g. 5-hydroxymethylcytosine). We specifically focus on the role of IHC in the differential diagnosis of cutaneous lesions that fall under the following categories: melanoma, epidermal tumors with an intraepidermal epitheliomatous pattern, spindle cell lesions of the dermis, small round blue cell tumors of the dermis, and cutaneous adnexal tumors. While IHC is a valuable tool in diagnostic dermatopathology, marker selection and interpretation must be highly informed by clinical context and the histologic differential diagnosis. With rapid progress in our understanding of the genetic and epigenetic mechanisms of tumorigenesis, new IHC markers will continue to emerge in the field of diagnostic dermatopathology. PMID:27047932

  18. Melanoma arising after imiquimod use.

    PubMed

    Paul, Sharad P

    2014-01-01

    Imiquimod belongs to the class of 1H-imidazo-[4,5-c]quinolones-drugs originally developed as nucleoside analogues with the aim of finding new potential antiviral agents (Harrison et al., 1988). Indeed, Imiquimod was first released as treatment for genital warts before its actions against skin cancer were studied. Imiquimod is a relatively small sized molecule (Mr = 240.3) and is hydrophobic, allowing it to penetrate the skin epidermal barrier and therefore making it suitable for topical formulations (Gerster et al., 2005). Imiquimod has shown itself effective against skin cancers and precancerous lesions, especially basal cell cancers and actinic keratosis (Salasche et al., 2002, Beutner et al., 1999). There have been reports of Imiquimod being used as topical treatment against cutaneous metastases of melanoma and some authors have reported its use as first-line therapy against melanoma in situ (Smyth et al., 2011, Gagnon, 2011). We report a case of an invasive malignant melanoma arising de novo at the specific site of application of Imiquimod (Aldara cream 5%) for a biopsy-proven superficial BCC. Therefore while Imiquimod has added to our topical armamentarium against skin cancer, care must be exercised in prescribing this treatment and it is especially important to follow up patients regularly. PMID:25431597

  19. Primary Malignant Melanoma of Pleura: A Case Report and Literature Review.

    PubMed

    Agarwal, Poojan; Nambiyar, Kaniyyapan; Manju Kaushal; Bhardwaj, Minakshi

    2016-07-01

    Malignant melanoma is one of the most aggressive and treatment resistant skin cancers. India enjoys a low incidence of melanoma, and age specific incidence rates for cutaneous malignant melanoma (CMM) are being less than 0.5 per 1,000,000. This could be due to under-reporting of melanoma on account of a low index of suspicion by clinicians and pathologists alike. Most common site for origin of primary melanoma is skin, accounting for about 91.2% of all reported primary malignant melanoma cases. Other primary sites are relatively uncommon. Primary pleural melanoma is a very rare tumor and to the best of our knowledge, only seven cases have been reported so far worldwide. We hereby discuss a new case, only second from India. Our patient also had coexistent congenital hairy nevus, an unusual association also noted in two previously reported cases. Excluding primary cutaneous melanoma with pleural metastasis was a diagnostic challenge in this case but multiple cutaneous biopsies together with clinical and findings helped us arrive at this unusual diagnosis. Unfortunately, the patient succumbed to his illness. Diagn. Cytopathol. 2016;44:648-652. © 2016 Wiley Periodicals, Inc. PMID:27164972

  20. Satellite in transit metastases in rapidly fatal conjunctival melanoma: implications for angiotropism and extravascular migratory metastasis (description of a murine model for conjunctival melanoma).

    PubMed

    Barnhill, Raymond L; Lemaitre, Stéphanie; Lévy-Gabrielle, Christine; Rodrigues, Manuel; Desjardins, Laurence; Dendale, Rémi; Vincent-Salomon, Anne; Roman-Roman, Sergio; Lugassy, Claire; Cassoux, Nathalie

    2016-02-01

    Little information is currently available concerning loco-regional metastases such as satellite and in transit metastases and their natural history in conjunctival melanoma as compared to cutaneous melanoma. Angiotropism, a marker of extravascular migration of melanoma cells along vascular channels, often appears responsible for microscopic satellite, satellite and in transit metastases development in cutaneous melanoma. In addition, diffuse tissue microscopic satellites are correlated with widespread melanoma dissemination and death. Herein we report rapid conjunctival melanoma progression and a fatal outcome in four of five patients following recurrence as satellite in transit metastases. Five patients aged 31, 60, 63, 56, and 67 years developed primary conjunctival melanoma, histologically characterised by tumour thicknesses of 4, 4, 1.1, 3, and 2 mm. Two or more conjunctival melanomas manifested ulceration, significant mitotic rates, necrosis, angiotropism, and intralesional transformation. The conjunctival melanoma recurred in a matter of months as one or more discrete satellite in transit lesions in the vicinity of the primary melanoma. Histological examination revealed well-defined micronodules containing atypical melanocytes in the subepithelial connective tissue stroma. All lesions were extravascular and most appeared angiotropic. Four of five patients subsequently developed parotid or other loco-regional nodal disease and rapidly ensuing widespread metastases and death. The time course from diagnosis to the demise of the patients averaged about 13 (range 7-20) months. Our findings suggest that satellite in transit metastases constitute an important new risk marker for possible rapid metastatic disease progression and death in patients with conjunctival melanoma. This finding appears to take on even greater significance if such lesions develop rapidly, i.e., in a matter of weeks or months following diagnosis of primary conjunctival melanoma, and if the

  1. Population-based incidence of vulvar and vaginal melanoma in various races and ethnic groups with comparisons to other site-specific melanomas.

    PubMed

    Hu, Dan-Ning; Yu, Guo-Pei; McCormick, Steven A

    2010-04-01

    Little is known on the difference in the incidence of vulvar and vaginal melanomas in various racial/ethnic groups. Population-based incidence of these melanomas in Asian and Hispanic individuals is almost unknown. Using 1992-2005 data provided by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, we calculated age-adjusted incidence rates of vulvar and vaginal melanomas in various racial/ethnic groups. From 1992 to 2005, there were 324 vulvar melanomas and 125 vaginal melanomas diagnosed in this group. The annual age-adjusted incidence rates (per million female population) of vulvar and vaginal melanomas in the different racial/ethnic groups was 0.87 (Blacks), 0.75 (American-Indian), 1.03 (Asians and Pacific Islanders), 1.22 (Hispanics), and 1.90 (non-Hispanic Whites). The overall white/black incidence ratio in vulvar and vaginal melanomas was 3.14 : 1 and 1.02 : 1, respectively; which is much less than that of cutaneous melanoma (13 : 1-17 : 1) and uveal melanoma (18 : 1) and is similar to that of conjunctival melanoma (2.6 : 1) and other mucosal melanomas (2.1 : 1-2.3 : 1). The low racial difference in vulvar and vaginal melanomas (as well as conjunctival and other mucosal melanomas) may be determined by their microenvironment factors (all originate from mucosa or semi-mucosa tissues). The incidence of vulvar and vaginal melanomas has does not increased in recent decades or toward the south (more sun exposure), indicating that ultraviolet radiation is not a causative factor in these melanomas. The slight decrease of incidence of vulvar melanoma in dark pigmented individuals may be related to the biochemical protective effects of melanin (as an antioxidant) rather than their photo-screen effects. PMID:20147857

  2. Adjuvant Therapy for Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad A.

    2012-01-01

    Estimates from the U.S. Surveillance, Epidemiology, and End Results (SEER) registry suggest that melanoma incidence will reach 70,230 in 2011, of which 8,790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society. High-dose interferon-α2b is the only agent approved for adjuvant therapy of melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However toxicity affects compliance and current research is focusing upon biomarkers that may allow selection of patients with greater likelihood of response, and exploring new agents either singly or in combination that may improve upon the benefit of IFN. In this article, we review the data for the adjuvant therapy of malignant melanoma - focusing on the results obtained with various regimens testing the several formulations of interferon-α2, and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, and raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway. PMID:22453021

  3. Cutaneous cryosurgery.

    PubMed

    Zimmerman, Ethan E; Crawford, Paul

    2012-12-15

    Cutaneous cryosurgery refers to localized application of freezing temperatures to achieve destruction of skin lesions. It can be used to treat a broad range of benign and premalignant skin conditions, and certain malignant skin conditions, with high cure rates. Cellular destruction is accomplished by delivery of the cryogen via dipstick, probe, or spray techniques. It is widely used in primary care because of its safety, effectiveness, low cost, ease of use, good cosmetic results, and lack of need for anesthesia. Cryosurgery is as effective as alternative therapies for most cases of molluscum contagiosum, dermatofibromas, keloids, and plantar or genital warts. It is a more effective cure for common warts than salicylic acid or observation. Cryosurgery is generally the treatment of choice for actinic keratosis. Contraindications to cryosurgery include cryofibrinogenemia, cryoglobulinemia, Raynaud disease, agammaglobulinemia, and multiple myeloma. Complications from cryosurgery include hypopigmentation and alopecia, and can be avoided by limiting freeze times to less than 30 seconds. Referral to a dermatologist should be considered in cases of diagnostic uncertainty or for treatment of skin cancer, which requires larger amounts of tissue destruction, resulting in higher complication rates. PMID:23316984

  4. Increased mortality for pregnancy-associated melanoma: systematic review and meta-analysis.

    PubMed

    Byrom, L; Olsen, C; Knight, L; Khosrotehrani, K; Green, A C

    2015-08-01

    Among women, pregnancy-associated melanomas may have a poorer prognosis than other melanomas, but evidence is inconsistent. We conducted a systematic review and meta-analysis to assess the effect on melanoma outcome of a coinciding pregnancy. The objective of the study was to conduct a systematic review and meta-analysis of risk of death from, or recurrence of, pregnancy-associated melanomas compared with other melanomas in women of reproductive age. Cochrane (1996-2013), MEDLINE (1950-2013), EMBASE (1966-2013), CINAHL (1982-2013), and PUBMED (1951-2013) databases were searched for studies assessing the risk of death and recurrence in pregnancy-associated melanomas. Eligible studies investigated melanoma outcomes in women with pregnancy-associated melanomas (diagnosed during pregnancy or in 12 months following pregnancy), included a comparison group and reported measures of risk of melanoma death or disease-free survival. Eligible study designs were cohort studies of women of childbearing age with confirmed diagnoses of cutaneous melanoma. Individual study effect estimates were pooled using the weighted average method. Studies that did not report a quantitative estimate were summarized narratively. Of 304 citations identified, 14 studies met the inclusion criteria, with assessed outcomes being melanoma death (7), recurrence (3), or both (4). Pooled estimates of mortality risk from four studies showed increased risk of melanoma death after adjustment for patient age and stage of melanoma (pHR 1.56, 95% CI 1.23-1.99) for pregnancy-associated melanoma compared with other melanomas. Based on limited quantitative evidence, pregnancy-associated melanomas appear to have poorer outcomes than other melanomas. PMID:25690106

  5. An overview of cutaneous T cell lymphomas

    PubMed Central

    Bagherani, Nooshin; Smoller, Bruce R.

    2016-01-01

    Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. They typically afflict adults with a median age of 55 to 60 years, and the annual incidence is about 0.5 per 100,000. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T cell lymphomas not otherwise specified are the most important subtypes of CTCL. CTCL is a complicated concept in terms of etiopathogenesis, diagnosis, therapy, and prognosis. Herein, we summarize advances which have been achieved in these fields. PMID:27540476

  6. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

    PubMed Central

    Mangana, Joanna; Cheng, Phil F.; Schindler, Katja; Weide, Benjamin; Held, Ulrike; Frauchiger, Anna L.; Romano, Emanuella; Kähler, Katharina C.; Rozati, Sima; Rechsteiner, Markus; Moch, Holger; Michielin, Olivier; Garbe, Claus; Hauschild, Axel; Hoeller, Christoph; Dummer, Reinhard; Goldinger, Simone M.

    2015-01-01

    Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78–13.2) compared to 8.26 months (95% CI 6.02–19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn’t reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs. PMID:26426340

  7. Screening Program Reduced Melanoma Mortality at the Lawrence Livermore National Laboratory, 1984-1996

    SciTech Connect

    Schneider, MD, J S; II, PhD, D; MD, PhD, M

    2006-10-12

    Worldwide incidence of cutaneous malignant melanoma has increased substantially, and no screening program has yet demonstrated reduction in mortality. We evaluated the education, self examination and targeted screening campaign at the Lawrence Livermore National Laboratory (LLNL) from its beginning in July 1984 through 1996. The thickness and crude incidence of melanoma from the years before the campaign were compared to those obtained during the 13 years of screening. Melanoma mortality during the 13-year period was based on a National Death Index search. Expected yearly deaths from melanoma among LLNL employees were calculated by using California mortality data matched by age, sex, and race/ethnicity and adjusted to exclude deaths from melanoma diagnosed before the program began or before employment at LLNL. After the program began, crude incidence of melanoma thicker than 0.75 mm decreased from 18 to 4 cases per 100,000 person-years (p = 0.02), while melanoma less than 0.75mm remained stable and in situ melanoma increased substantially. No eligible melanoma deaths occurred among LLNL employees during the screening period compared with a calculated 3.39 expected deaths (p = 0.034). Education, self examination and selective screening for melanoma at LLNL significantly decreased incidence of melanoma thicker than 0.75 mm and reduced the melanoma-related mortality rate to zero. This significant decrease in mortality rate persisted for at least 3 yr after employees retired or otherwise left the laboratory.

  8. Increase in NRAS mutant allele percentage during metastatic melanoma progression.

    PubMed

    Funck-Brentano, Elisa; Hélias-Rodzewicz, Zofia; Longvert, Christine; Mokhtari, Karima; Saiag, Philippe; Emile, Jean-François

    2016-06-01

    One-fifth of cutaneous melanomas have dominant gain-of-function mutations of the NRAS oncogene. We report the first two cases of increasing NRAS mutant allele frequency in melanoma metastases and show that the chromosomal mechanism of this homozygosity is an increased polysomy of chromosome 1. We observed an increase in NRAS mutant allele percentage (NRAS-MA%) in the metastatic melanoma progression from 2 patients with melanomas harbouring a NRAS mutation (p.Q61K in case 1 and p.Q61R in case 2). In case 1, we observed a NRAS-MA% increase from 18% within the first metastatic node to 81%, 92% and 85% respectively in the three subsequent metastases: lymph node, brain and subcutaneous metastases biopsied 1, 6 and 17 months, respectively, after the initial lymph node biopsy. In case 2, we observed an increase in NRAS-MA% from 40% within the primary melanoma to 63% within the metastatic lymph node. FISH analysis showed the same results in both cases: a frequent polysomy of chromosome 1 in metastasis samples with NRAS mutant allele percentage >60%, while most cells were disomic in the samples with well-balanced heterozygous mutations. The percentage of NRAS mutant allele may increase during metastatic progression and may be associated with chromosomal instability. Further studies are needed to evaluate the prognostic impact of the NRAS homozygous status and/or polyploidy in metastatic cutaneous melanomas. PMID:26990546

  9. Adjuvant Immunotherapy of Melanoma, and Development of New Approaches Using the Neo- Adjuvant Approach in Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad

    2013-01-01

    Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. While early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death–the latter approaching 70% or more at 5 years. In patients at high-risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse free and overall survival. Neo-adjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFNα. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neo-adjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neo-adjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFNα, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab [BMS], and BRAF inhibitor vemurafenib [Genentech]) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 [BMS, Merck, Curetech] and anti

  10. Karnofsky Performance Status and Lactate Dehydrogenase Predict the Benefit of Palliative Whole-Brain Irradiation in Patients With Advanced Intra- and Extracranial Metastases From Malignant Melanoma

    SciTech Connect

    Partl, Richard; Richtig, Erika; Avian, Alexander; Berghold, Andrea; Kapp, Karin S.

    2013-03-01

    Purpose: To determine prognostic factors that allow the selection of melanoma patients with advanced intra- and extracerebral metastatic disease for palliative whole-brain radiation therapy (WBRT) or best supportive care. Methods and Materials: This was a retrospective study of 87 patients who underwent palliative WBRT between 1988 and 2009 for progressive or multiple cerebral metastases at presentation. Uni- and multivariate analysis took into account the following patient- and tumor-associated factors: gender and age, Karnofsky performance status (KPS), neurologic symptoms, serum lactate dehydrogenase (LDH) level, number of intracranial metastases, previous resection or stereotactic radiosurgery of brain metastases, number of extracranial metastasis sites, and local recurrences as well as regional lymph node metastases at the time of WBRT. Results: In univariate analysis, KPS, LDH, number of intracranial metastases, and neurologic symptoms had a significant influence on overall survival. In multivariate survival analysis, KPS and LDH remained as significant prognostic factors, with hazard ratios of 3.3 (95% confidence interval [CI] 1.6-6.5) and 2.8 (95% CI 1.6-4.9), respectively. Patients with KPS ≥70 and LDH ≤240 U/L had a median survival of 191 days; patients with KPS ≥70 and LDH >240 U/L, 96 days; patients with KPS <70 and LDH ≤240 U/L, 47 days; and patients with KPS <70 and LDH >240 U/L, only 34 days. Conclusions: Karnofsky performance status and serum LDH values indicate whether patients with advanced intra- and extracranial tumor manifestations are candidates for palliative WBRT or best supportive care.

  11. Malicious masquerade: myxoid melanoma.

    PubMed

    Hitchcock, M G; White, W L

    1998-08-01

    The morphological spectrum of malignant melanoma is broad. Unusual stromal changes can distract pathologists from the correct diagnosis. Fibroblastic, chondroid, osteoid, and myxoid stroma have been documented in melanomas. Myxoid melanoma is problematic--introducing carcinomas and soft tissue sarcomas into the differential diagnosis. This review examines the clinicopathologic aspects of myxoid malignant melanoma, with emphasis on its differential diagnosis. PMID:9711669

  12. Microwave plaque thermoradiotherapy for choroidal melanoma.

    PubMed Central

    Finger, P. T.

    1992-01-01

    Microwave thermoradiotherapy was used as a primary treatment for 44 patients with choroidal melanoma. An episcleral dish-shaped microwave antenna was placed beneath the tumour at the time of plaque brachytherapy. While temperatures were measured at the sclera, the tumour's apex was targeted to receive a minimum of 42 degrees C for 45 minutes. In addition, the patients received full or reduced doses of plaque radiotherapy. No patients have been lost to follow-up. Two eyes have been enucleated: one for rubeotic glaucoma, and one for uveitic glaucoma. Though six patients have died, only one death was due to metastatic choroidal melanoma (39 months after treatment). Clinical observations suggest that the addition of microwave heating to plaque radiation therapy of choroidal melanoma has been well tolerated. There has been a 97.7% local control rate (with a mean follow-up of 22.2 months). We have reduced the minimum tumour radiation dose (apex dose) to levels used for thermoradiotherapy of cutaneous melanomas (50 Gy/5000 rad). Within the range of this follow-up period no adverse effects which might preclude the use of this microwave heat delivery system for treatment of choroidal melanoma have been noted. Images PMID:1622949

  13. Endothelin-1 in the tumor microenvironment correlates with melanoma invasion.

    PubMed

    Chiriboga, Luis; Meehan, Shane; Osman, Iman; Glick, Michael; de la Cruz, Gelo; Howell, Brittny S; Friedman-Jiménez, George; Schneider, Robert J; Jamal, Sumayah

    2016-06-01

    Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed. Twenty-six percent of melanocytic nevi and 44% of melanoma in situ lesions demonstrate ET-1 expression in the perilesional microenvironment, whereas expression in nevus or melanoma cells was rare to absent. In striking contrast, 100% of moderately to highly pigmented invasive melanomas contained numerous ET-1-positive cells in the tumor microenvironment, with 79% containing ET-1-positive melanoma cells, confirmed by co-staining with melanoma tumor marker HMB45. Hypopigmented invasive melanomas had reduced ET-1 expression, suggesting a correlation between ET-1 expression and pigmented melanomas. ET-1-positive perilesional cells were CD68-positive, indicating macrophage origin. Sixty-two percent of highly pigmented metastatic melanomas demonstrated ET-1 expression in melanoma cells, in contrast to 28.2% of hypopigmented specimens. Eighty-nine percent of benign nevi, known as blue nevi, which have a dermal localization, were associated with numerous ET-1-positive macrophages in the perilesional microenvironment, but no ET-1 expression was detected in the melanocytes. We conclude that ET-1 expression in the microenvironment increases with advancing stages of melanocyte transformation, implicating a critical role for ET-1 in melanoma progression, and the importance of the tumor microenvironment in the melanoma phenotype. PMID:26825037

  14. Ex Vivo Derived Primary Melanoma Cells: Implications for Immunotherapeutic Vaccines

    PubMed Central

    Suriano, Robert; Rajoria, Shilpi; L.George, Andrea; Geliebter, Jan; Wallack, Marc; Tiwari, Raj K.

    2013-01-01

    Transformation of the pigment producing melanocytes into melanoma is a complex multi-step process involving the enhanced expression of various antigens considered as immunotherapeutic targets. Significant progress in melanoma research has been made over the years and has resulted in the identification of various antigens over expressed in melanoma as well as advances in immunotherapeutic treatments, which focus on modulating the immune systems response to melanoma. Despite these advances, incidences of melanoma are still on the rise thus warranting additional research in identifying new therapeutic treatments. Our focus is on developing a multivalent immunotherapeutic vaccine that targets various melanoma associated antigens. The approach focuses on the use of five primary patient derived melanoma cells (MEL-2, MEL-V, 3MM, KFM, and GLM-2, which have been characterized in this study. These cells express differential amounts of various melanoma associated antigens such as MART-1, gp100 (Pmel17), MAGE-A1 and tyrosinase as well a cell surface antigens essential for melanoma cell metastasis, such as CD146 and CD71. In addition these cells display differential in vitro migratory and invasive properties as well as have the ability to form solid tumors when implanted into BALB/c nude mice. The retention of the innate phenotype of these primary patient derived cells together with the expression of a multitude repertoire of melanoma associated antigens offers a novel opportunity to target melanoma so as to avoid immune evasion. PMID:23833682

  15. Type I Interferons: Key Players in Normal Skin and Select Cutaneous Malignancies

    PubMed Central

    2014-01-01

    Interferons (IFNs) are a family of naturally existing glycoproteins known for their antiviral activity and their ability to influence the behavior of normal and transformed cell types. Type I Interferons include IFN-α and IFN-β. Currently, IFN-α has numerous approved antitumor applications, including malignant melanoma, in which IFN-α has been shown to increase relapse free survival. Moreover, IFN-α has been successfully used in the intralesional treatment of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In spite of these promising clinical results; however, there exists a paucity of knowledge on the precise anti-tumor action of IFN-α/β at the cellular and molecular levels in cutaneous malignancies such as SCC, BCC, and melanoma. This review summarizes current knowledge on the extent to which Type I IFN influences proliferation, apoptosis, angiogenesis, and immune function in normal skin, cutaneous SCC, BCC, and melanoma. PMID:24516470

  16. Black Pleural Effusion: A Unique Presentation of Metastatic Melanoma.

    PubMed

    Chhabra, Akansha; Mukherjee, Vikramjit; Chowdhary, Mudit; Danckers, Mauricio; Fridman, David

    2015-01-01

    Metastatic melanoma is a rare form of skin cancer, but one that comes with a high mortality rate. Pulmonary involvement is frequently seen in metastatic melanoma with only 2% of malignant melanoma patients with thorax metastasis presenting with pleural effusions. Herein, we report an extremely rare case of black pleural effusion from thoracic metastasis of cutaneous malignant melanoma. A 74-year-old man with known metastatic melanoma presented with a 1-month history of worsening lower back and hip pain and was found to have extensive osseous metastatic disease and multiple compression fractures. The patient underwent an uneventful kyphoplasty; however, the following day, he became acutely hypoxic and tachypneic with increased oxygen requirements. Radiographic evaluation revealed new bilateral pleural effusions. Bedside thoracentesis revealed a densely exudative, lymphocyte-predominant black effusion. Cytological examination showed numerous neoplastic cells with melanin deposition. A diagnosis of thoracic metastasis of malignant melanoma was established based on the gross and microscopic appearance of the pleural fluid. To the best of our knowledge, this is the first reported case of black pleural effusions secondary to metastatic melanoma in the United States. Despite the rarity of this presentation, it is important to determine the etiology of the black pleural effusion and to keep metastatic melanoma as a differential diagnosis. PMID:26078741

  17. Nutrition and melanoma prevention.

    PubMed

    Jensen, J Daniel; Wing, Gregory J; Dellavalle, Robert P

    2010-01-01

    Melanoma has continued to rise in incidence despite public efforts to promote sun protection behaviors. Because sunscreen use does not completely prevent skin cancer induced by ultraviolet radiation, additional chemopreventive methods for protecting against and reversing the effects of ultraviolet photodamage need evaluation. Recent years have brought increased interest in dietary factors, such as natural botanicals and vitamins, for the prevention of melanoma. This contribution provides a narrative review of the relevant, nutrition-related literature found by searching the keywords "melanoma chemoprevention," "nutrition and melanoma," "dietary botanicals and melanoma prevention," "green tea and melanoma," "vitamin D and melanoma," and "vitamin E and melanoma" in the PubMed database. Although randomized controlled trials of humans are lacking, basic science and epidemiologic studies show promising benefits of many natural products in chemoprevention for melanoma. Future studies, hopefully, will yield concrete answers and clarify the role of commonly available dietary nutrients in melanoma chemoprevention. PMID:21034988

  18. Other targeted drugs in melanoma

    PubMed Central

    Rodón, Jordi; Karachaliou, Niki; Sánchez, Jesús; Santarpia, Mariacarmela; Viteri, Santiago; Pilotto, Sara; Teixidó, Cristina; Riso, Aldo; Rosell, Rafael

    2015-01-01

    Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are “targeted” to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other “druggable” kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials. PMID:26605312

  19. Update in genetic susceptibility in melanoma.

    PubMed

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep; Puig, Susana

    2015-09-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID:26488006

  20. Update in genetic susceptibility in melanoma

    PubMed Central

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep

    2015-01-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID:26488006

  1. Multiple Cutaneous Reticulohistiocytoma

    PubMed Central

    Hemmady, Karishma D; Someshwar, Shylaja S; Jerajani, Hemangi R

    2016-01-01

    Multicentric reticulohistiocytosis is a rare non-Langerhans cell histiocytosis characterized in its full form by severe destructive arthritis, cutaneous nodules, and systemic manifestations. Cutaneous lesions may precede, accompany, or more commonly develop later than other features in this disease. We describe a case of multiple cutaneous reticulohistiocytoma without any systemic associations after thorough investigations. PMID:26955136

  2. Ubiquitin ligase UBE3C promotes melanoma progression by increasing epithelial-mesenchymal transition in melanoma cells

    PubMed Central

    Tang, Li; Yi, Xue-Mei; Chen, Jia; Chen, Fu-Juan; Lou, Wei; Gao, Yun-Lu; Zhou, Jing; Su, Li-Na; Xu, Xin; Lu, Jia-Qing; Ma, Jun; Yu, Ning; Ding, Yang-Feng

    2016-01-01

    Melanoma is the most aggressive type of skin cancer, exhibiting extensive local invasion and early distant metastasis. Aberrant expression of ubiquitin-protein ligase E3C (UBE3C) plays a key role in tumor development and progression. In the present study, we analyzed UBE3C expression in samples of cancerous and normal skin tissue. Levels of UBE3C expression were much higher in primary and metastatic melanoma tissues than in normal skin, cutaneous squamous cell carcinoma or basal cell carcinoma. Melanoma cells overexpressing UBE3C frequently exhibited a mesenchymal phenotype, including reduced expression of the epithelial marker E-cadherin and expression of the mesenchymal marker vimentin. Knockdown of UBE3C expression in melanoma cells significantly suppressed melanoma growth and progression. Furthermore, silencing UBE3C led to increased E-cadherin expression and decreased vimentin and Snail1 expression. Thus UBE3C promotes melanoma progression, possibly by inducing epithelial-mesenchymal transition in melanoma cells. Inhibiting UBE3C activity may suppress melanoma invasion and metastasis and may represent a targeted therapeutic approach. PMID:26894856

  3. Recombinant Interferon Alfa-2b in Treating Patients With Melanoma

    ClinicalTrials.gov

    2016-05-17

    Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  4. CXCR4 pathway associated with family history of melanoma

    PubMed Central

    Li, Wen-Qing; Han, Jiali; Widlund, Hans R.; Correll, Mick; Wang, Yaoyu E.; Quackenbush, John; Mihm, Martin C.; Canales, Alvaro Laga; Wu, Shaowei; Golub, Todd; Hoshida, Yujin; Hunter, David J.; Murphy, George; Kupper, Thomas S.; Qureshi, Abrar A.

    2014-01-01

    Purpose Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family history-associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma. Methods Based on the Nurses’ Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports and tumor blocks were collected by mail from across the United States. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene Set Enrichment Analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes. Results The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases. Conclusions We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives. PMID:24158781

  5. Increased Risk of Second Primary Cancers After a Diagnosis of Melanoma

    PubMed Central

    Bradford, Porcia T.; Michal Freedman, D.; Goldstein, Alisa M.; Tucker, Margaret A.

    2011-01-01

    Objective To quantify the risk of subsequent primary cancers among patients with primary cutaneous malignant melanoma. Design Population-based registry study. Setting We evaluated data from 9 cancer registries of the Surveillance, Epidemiology, and End Results program from 1973–2006. Participants We included 89 515 patients who survived at least 2 months after their initial melanoma diagnosis. Results Of the patients with melanoma, 10 857 (12.1%) developed 1 or more subsequent primary cancers. The overall risk of a subsequent primary cancer increased by 28% (observed to expected [O:E] ratio=1.28). One quarter of the cancers were subsequent primary melanomas (O:E=8.61). Women with head and neck melanoma and patients younger than 30 had markedly increased risks (O:E=13.22 and 13.40, respectively) of developing a subsequent melanoma. Second melanomas were more likely to be thin than were the first of multiple primary melanomas (thickness at diagnosis <1.00mm, 77.9% vs 70.3%, respectively; P<.001). Melanoma survivors had increased risk of developing several cancers; the most common cancers with elevated risks were breast, prostate, and non-Hodgkin lymphoma (O:E=1.10, 1.15, and 1.25, respectively). Conclusions Melanoma survivors have an approximately 9-fold increased risk of developing subsequent melanoma compared with the general population. The risk remains elevated more than 20 years after the initial melanoma diagnosis. This increased risk may be owing to behavioral factors, genetic susceptibility, or medical surveillance. Although the percentage of subsequent primary melanomas thicker than 1 mm is lower than for the first of multiple primary melanomas, it is still substantial. Melanoma survivors should remain under surveillance not only for recurrence but also for future primary melanomas and other cancers. PMID:20231496

  6. Melanoma risk perception and prevention behavior among African-Americans: the minority melanoma paradox

    PubMed Central

    Goldenberg, Alina; Vujic, Igor; Sanlorenzo, Martina; Ortiz-Urda, Susana

    2015-01-01

    Introduction Melanoma is the most deadly type o