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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 melanoma.

    PubMed

    Eggermont, Alexander M M; Spatz, Alan; Robert, Caroline

    2014-03-01

    In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.

  3. Cutaneous Melanoma in Asians

    PubMed Central

    Kim, Sang Yub

    2016-01-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians. PMID:27689028

  4. Cutaneous Melanoma in Asians.

    PubMed

    Kim, Sang Yub; Yun, Sook Jung

    2016-09-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians. PMID:27689028

  5. Cutaneous Melanoma in Asians

    PubMed Central

    Kim, Sang Yub

    2016-01-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians.

  6. 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

  7. 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

  8. 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

  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. Solar radiation and cutaneous melanoma.

    PubMed

    Viola, M V; Houghton, A N

    1982-09-01

    Exposure to solar radiation has been widely implicated in the dramatic rise in the incidence of cutaneous melanoma throughout the world. The association may be more complex than originally suspected, involving such factors as sunspot-activity cycles and changes in the ozone layer affecting ultraviolet flux at the earth's surface. The evidence for these relationships is examined.

  11. 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

  12. 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

  13. Solitary metachronous splenic metastasis from cutaneous melanoma

    PubMed Central

    Gavriilidis, Paschalis; Goupou, Eleni

    2012-01-01

    Melanoma has been found to metastasise to the spleen, usually in cases of disseminated disease. Solitary splenic metastasis from cutaneous melanoma is very rare. Herein we report the case of a 43-year-old man who developed solitary splenic metastasis from cutaneous melanoma. The patient was operated for T4b N1a Mo superficial spreading melanoma of the anterior thoracic wall. He subsequently underwent left axillary lymph node dissection due to a positive sentinel lymph node. The 33 retrieved lymph nodes were negative for metastasis. The patient received adjuvant therapy with high-dose interferon α-2b. After 27 months and during the follow-up visit an increasing lactate dehydrogenase serum level was observed. Furthermore, CT of the whole body revealed a solitary hypodense tumour of the spleen 9 cm×6 cm. Curative splenectomy was performed and the histopathological report confirmed metastatic melanoma to the spleen. PMID:23104633

  14. Cutaneous melanoma in genetically modified animals.

    PubMed

    Larue, Lionel; Beermann, Friedrich

    2007-12-01

    Cutaneous melanomas are tumors originating from skin melanocytes which are present in hair follicles, and interfollicular epidermal and dermal layers. Experimental work in model systems involves in silico, in vitro and in vivo analyses. Such models allow to mimick melanocytic aberrations characteristic of melanoma, and to potentially exploit novel therapies. Transgenic technologies can be used to modify specifically the genome of the model organism and thereby generate transgenic strains, and combinations of such strains, which may develop metastasizing melanoma. In such strains, metastasizing melanoma either arises spontaneously after a period of latency or requires additional physical or chemical induction. In this review, we summarize the work of currently available transgenic melanoma models and discuss the most recent progress in creating improved and/or inducible models reflecting the human disease.

  15. [Cutaneous malignant melanoma and the new drugs].

    PubMed

    Nieweg, Omgo E; Gallegos-Hernández, José Francisco

    2015-01-01

    The treatment of cutaneous melanoma has historically been essentially surgical. Much progress has been made in this area, and the resection margins have been established based on tumour depth. Candidates are also identified for lymphadenectomy, avoiding the morbidity of the procedure in patients who do not require it. But little progress has been made in systemic treatment, since the 70's when the use of dacarbazine was introduced for the treatment of patients with tumour progression or distant metastasis, with disappointing results. Despite this, Dacarbazine has been the most used drug to the present. Three years ago, two new drugs were introduced, one of them based on the target therapy and other one in the immunotherapy, offering, with the obtained results, an alternative in the treatment of cutaneous melanoma The objectives of this article are to show the pathways of these drugs, to describe the current role of surgery in cutaneous melanoma, with the arrival of these drugs, as well as to know the therapeutic alternatives that are emerging for the cutaneous melanoma based on scientific evidence. PMID:26001767

  16. Updates in Therapy for Advanced Melanoma.

    PubMed

    Singh, Bhavana P; Salama, April K S

    2016-01-15

    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.

  17. 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.

  18. Epidemiology of invasive cutaneous melanoma

    PubMed Central

    MacKie, R. M.; Hauschild, A.; Eggermont, A. M. M.

    2009-01-01

    Data are presented on the current incidence of melanoma with recent and predicted future trends illustrating a likely continuing increase in incidence. Risk factors for developing melanoma are discussed, including current known melanoma susceptibility genes. Phenotypic markers of high-risk subjects include high counts of benign melanocytic naevi. Other risk factors considered include exposure to natural and artificial ultraviolet radiation, the effect of female sex hormones, socioeconomic status, occupation, exposure to pesticides and ingestion of therapeutic drugs including immunosuppressives and non-steroidal anti-inflammatory drugs. Aids to earlier diagnosis are considered, including public education, screening and use of equipment such as the dermatoscope. Finally, the current pattern of survival and mortality is described. PMID:19617292

  19. Molecular Bases of Cutaneous and Uveal Melanomas

    PubMed Central

    Gaudi, Sudeep; Messina, Jane L.

    2011-01-01

    Intensive research in recent years has begun to unlock the mysteries surrounding the molecular pathogenesis of melanoma, the deadliest of skin cancers. The high-penetrance, low-frequency susceptibility gene CDKN2A produces tumor suppressor proteins that function in concert with p53 and retinoblastoma protein to thwart melanomagenesis. Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma. Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes. The proliferative effects of the MAPK pathway may be complemented by the antiapoptotic signals of the PI3K/AKT pathway. After skin, melanoma most commonly affects the eye. Data for the constitutive activation of the MAPK pathway in uveal melanoma exists as well, however, not through mutations of RAS and RAF. Rather, evidence implicates the proto-oncogene GNAQ. In the following discussion, we review the major molecular pathways implicated in both familial and sporadic cutaneous melanomagenesis, the former accounting for approximately 10% of cases. Additionally, we discuss the molecular pathways for which preliminary evidence suggests a role in uveal melanomagenesis. PMID:21876842

  20. Tissue prognostic biomarkers in primary cutaneous melanoma.

    PubMed

    Mandalà, Mario; Massi, Daniela

    2014-03-01

    Cutaneous melanoma (CM) causes the greatest number of skin cancer-related deaths worldwide. Predicting CM prognosis is important to determine the need for further investigation, counseling of patients, to guide appropriate management (particularly the need for postoperative adjuvant therapy), and for assignment of risk status in groups of patients entering clinical trials. Since recurrence rate is largely independent from stages defined by morphological and morphometric criteria, there is a strong need for identification of additional robust prognostic factors to support decision-making processes. Most data on prognostic biomarkers in melanoma have been evaluated in tumor tissue samples by conventional morphology and immunohistochemistry (IHC) as well as DNA and RNA analyses. In the present review, we critically summarize main high-quality studies investigating IHC-based protein biomarkers of melanoma outcome according to Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK)-derived criteria. Pathways have been classified and conveyed in the "biologic road" previously described by Hanahan and Weinberg. Data derived from genomic and transcriptomic technologies have been critically reviewed to better understand if any of investigated proteins or gene signatures should be incorporated into clinical practice or still remain a field of melanoma research. Despite a wide body of research, no molecular prognostic biomarker has yet been translated into clinical practice. Conventional tissue biomarkers, such as Breslow thickness, ulceration, mitotic rate and lymph node positivity, remain the backbone prognostic indicators in melanoma.

  1. Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases

    PubMed Central

    Kraehn, G M; Utikal, J; Udart, M; Greulich, K M; Bezold, G; Kaskel, P; Leiter, U; Peter, R U

    2001-01-01

    Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 α-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266–4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139316

  2. Swimming and the risk of cutaneous melanoma.

    PubMed

    Nelemans, P J; Rampen, F H; Groenendal, H; Kiemeney, L A; Ruiter, D J; Verbeek, A L

    1994-10-01

    Recreational exposure to the sun may not explain fully current trends in melanoma incidence. The hypothesis was examined whether carcinogens in water play a role in the development of cutaneous melanoma. In a case-control study, 128 melanoma patients and 168 patients with other types of malignancy completed a detailed questionnaire on aquatic leisure time activities. All relative risk estimates were adjusted for age, gender, educational level, pigmentation characteristics, and exposure to sun habits. Regular swimming during the summer months in swimming pools and in open waters such as rivers and seas before the age of 15 years, was associated with odds ratios of 2.20 (95% confidence interval (CI), 1.05-4.62) and 2.41 (95% CI, 1.04-5.58), respectively, compared with no swimming at all or swimming in relatively unpolluted waters, such as lakes and fens. Melanoma patients learned to swim at a younger age; compared with those who never learned to swim or who learned to swim after the age of 12 years, the odds ratio was 1.87 (95% CI, 0.91-3.78) for those who learned to swim at ages 9-12 years, and 2.22 (95% CI, 1.16-4.26) for those who learned to swim before 9 years of age. Compared with persons who had no swimming certificates, an odds ratio of 1.25 (95% CI, 0.71-2.23) was found for persons with one or two certificates, and an odds ratio of 2.96 (95% CI, 1.25-6.96) for persons with three or more certificates. The positive association between a history of swimming and melanoma risk suggests that carcinogenic agents in water, possibly chlorination by products, play a role in melanoma aetiology. PMID:7858410

  3. [Mandibular metastasis of a cutaneous melanoma or metachronous amelanotic melanoma of the oral cavity? A case report and literature review].

    PubMed

    Vierne, C; Hardy, H; Guichard, B; Barat, M; Péron, J-M; Trost, O

    2014-08-01

    Primary and metastatic mandibular melanoma are extremely rare. We report the original case of a 55-year-old woman treated 16 years before for a cutaneous melanoma, and now presenting with a huge mandibular amelanotic melanoma. Was it an histologically different mandibular metastasis of the previous cutaneous melanoma, or a metachronous oral amelanotic melanoma?

  4. Biomarker utility of circulating tumor cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Lorigan, Paul; Zhou, Cong; Lancashire, Matthew; Booth, Jessica; Cummings, Jeff; Califano, Raffaele; Clack, Glen; Hughes, Andrew; Dive, Caroline

    2013-06-01

    The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients. PMID:23223143

  5. 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

  6. 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.

  7. 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

  8. Epidemiological aspects of cutaneous malignant melanoma (review).

    PubMed

    Serraino, D; Fratino, L; Gianni, W; Campisi, C; Pietropaolo, M; Trimarco, G; Marigliano, V

    1998-01-01

    There is an increasing interest in the etiology of cutaneous malignant melanoma (CMM). Once considered a rare tumour, CMM is now the fourth commonest cancer in Australia and New Zeland, the tenth in the Usa, Canada and Scandinavia and the eighteenth in Great Britain. The growing scientific concern on the urgent need to highlight the cause/s of CMM is well documented by the large number of well-designed and well-conducted epidemiological studies reported in the last two decades. Such studies facilitated testing of many etiological hypotheses derived from earlier descriptive investigations and contributed to significant progress in understanding the etiology of such disease. The quantification of the extent to which the increases in CMM incidence and mortality rates are related to new lifestyles and to new patterns of exposure to potential carcinogenetic agents is essential in order to establish an appropriate preventive strategy. In population of mainly European origin a substantial proportion of the increased incidence of CMM is attributable to steady change from predominantly occupational to predominantly recreational exposure to solar radiation. Therefore the present review puts particular emphasis on exposure to sunlight as well as to artificial ultraviolet light, as modifiable causes of CMM. Incidence and mortality data and other potential risk factors for the development of CMM will also be briefly reviewed.

  9. 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.

  10. 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

  11. ABO blood group and risk of cutaneous malignant melanoma.

    PubMed

    de Giorgi, Vincenzo; Grazzini, Marta; Gori, Alessia; Alfaioli, Barbara; Rossari, Susanna; Crocetti, Emanuele; Vocioni, Franco; Lotti, Torello

    2011-03-01

    Although, for several decades, the role of ABO blood group antigens has been suspected in the development of cancer, to our knowledge, the association between ABO blood group and the risk of malignant melanoma has not been evaluated yet. We, therefore, examined the relationship between ABO blood group and risk of developing cutaneous malignant melanoma. We retrospectively reviewed 445 patients with a histological diagnosis of malignant melanoma. Blood groups were obtained from medical records. The control group was represented by 38 321 patients. We evaluated the data by investigation with statistical analysis to show a statistically significant increased risk of developing a malignant melanoma in the O Rh-negative group (odds ratio = 1.4). We suggest focus on the melanoma cases belonging to the blood groups O Rh-negative in future studies, because all the clues of this study seem to show a correlation between blood groups and the risk of malignant melanoma among these groups.

  12. Cutaneous malignant melanoma in association with mycosis fungoides.

    PubMed

    Evans, Alun V; Scarisbrick, Julia J; Child, F J; Acland, Katharine M; Whittaker, Sean J; Russell-Jones, Robin

    2004-05-01

    We retrospectively analyzed the first 461 cases entered into our cutaneous lymphoma database and found 285 cases of mycosis fungoides. We also identified 6 cases of malignant melanoma, all of which were found in patients with mycosis fungoides. The crude rate of melanoma in the general population in England, United Kingdom, in 1998 was 8.8/100,000 in men and 11.4/100,000 in women. The incidence of melanoma found in our cohort of patients with mycosis fungoides was far higher, and in 4 of the 6 patients cannot be explained on the basis of prior therapy. The reason for this association is unclear, but this report emphasizes the risk of second malignancies for patients with cutaneous T-cell lymphoma and melanoma.

  13. Surgical treatment of advanced melanoma.

    PubMed

    Hussussian, Christopher J

    2010-01-01

    Primary surgical treatment should be considered for patients with metastatic melanoma. Because of the poor response of melanoma to chemotherapy or radiation therapy, surgery can be the best approach to quickly eliminate detectable disease and return the patient to normal activities. In properly selected patients, surgery can lead to significant palliation and prolongation of survival. This article reviews the principles of patient selection and the potential benefits of surgical management of melanoma metastatic to various sites. Novel adjuvant therapies are being developed to augment the benefits of surgical treatment of advanced melanoma in the future.

  14. 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

  15. 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

  16. Lymphangiogenesis and Anti-lymphangiogenesis in Cutaneous Melanoma.

    PubMed

    Raica, Marius; Jitariu, Adriana-Andreea; Cimpean, Anca Maria

    2016-09-01

    Cutaneous malignant melanoma is an aggressive tumor characterized by early lymph node metastasis and bad prognosis. Although the spread of tumor cells in the regional lymph nodes is very important in the staging, prognosis and therapeutic strategy of malignant melanoma, the mechanism(s) of initial lymphatic vessels invasion is are) not completely understood. In the present review, we analyze the main factors involved in melanoma-associated lymphangiogenesis, based on existing available evidence. Currently, there are no anti-lymphangiogenic drugs approved for clinical trials. On the other hand, inhibition of lymph node metastasis has been demonstrated in experimental models by inhibiting tumor-associated lymphangiogenesis. PMID:27630278

  17. 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

  18. [Update on surgical treatment of primary and metastatic cutaneous melanoma].

    PubMed

    Zuluaga-Sepúlveda, María Alejandra; Arellano-Mendoza, Ivonne; Ocampo-Candiani, Jorge

    2016-01-01

    Melanoma is a common cutaneous tumour. It is of great importance due to its increasing incidence and aggressive behaviour, with metastasis to lymph nodes and internal organs. When suspecting melanoma, excisional biopsy should be performed to obtain complete histological information in order to determine the adverse factors such as ulceration, mitosis rate, and Breslow depth, which influence preoperative staging and provide data for sentinel lymph biopsy decision making. The indicated management for melanoma is wide local excision, observing recommended and well-established excision margins, depending on Breslow depth and anatomical location of the tumour. Therapeutic lymphadenectomy is recommended for patients with clinically or radiologically positive lymph nodes. This article reviews surgical treatment of melanoma, adverse histological factors, sentinel lymph node biopsy, and radical lymphadenectomy. Details are presented on special situations in which management of melanoma is different due to the anatomical location (plantar, subungual, lentigo maligna), or pregnancy.

  19. Time-resolved fluorescence lifetime for cutaneous melanoma detection

    PubMed Central

    Pires, Layla; Nogueira, Marcelo Saito; Pratavieira, Sebastião; Moriyama, Lilian Tan; Kurachi, Cristina

    2014-01-01

    Melanoma is the most aggressive skin cancer type. It is characterized by pigmented lesions with high tissue invasion and metastatic potential. The early detection of melanoma is extremely important to improve patient prognosis and survival rate, since it can progress to the deadly metastatic stage. Presently, the melanoma diagnosis is based on the clinical analysis of the macroscopic lesion characteristics such as shape, color, borders following the ABCD rules. The aim of this study is to evaluate the time-resolved fluorescence lifetime of NADH and FAD molecules to detect cutaneous melanoma in an experimental in vivo model. Forty-two lesions were analyzed and the data was classified using linear discriminant analysis, a sensitivity of 99.4%, specificity of 97.4% and accuracy of 98.4% were achieved. These results show the potential of this fluorescence spectroscopy for melanoma detection. PMID:25401022

  20. 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.

  1. 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

  2. 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

  3. 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

  4. Data Set for Pathology Reporting of Cutaneous Invasive Melanoma

    PubMed Central

    Judge, Meagan J.; Evans, Alan; Frishberg, David P.; Prieto, Victor G.; Thompson, John F.; Trotter, Martin J.; Walsh, Maureen Y.; Walsh, Noreen M.G.; Ellis, David W.

    2013-01-01

    An accurate and complete pathology report is critical for the optimal management of cutaneous melanoma patients. Protocols for the pathologic reporting of melanoma have been independently developed by the Royal College of Pathologists of Australasia (RCPA), Royal College of Pathologists (United Kingdom) (RCPath), and College of American Pathologists (CAP). In this study, data sets, checklists, and structured reporting protocols for pathologic examination and reporting of cutaneous melanoma were analyzed by an international panel of melanoma pathologists and clinicians with the aim of developing a common, internationally agreed upon, evidence-based data set. The International Collaboration on Cancer Reporting cutaneous melanoma expert review panel analyzed the existing RCPA, RCPath, and CAP data sets to develop a protocol containing “required” (mandatory/core) and “recommended” (nonmandatory/noncore) elements. Required elements were defined as those that had agreed evidentiary support at National Health and Medical Research Council level III-2 level of evidence or above and that were unanimously agreed upon by the review panel to be essential for the clinical management, staging, or assessment of the prognosis of melanoma or fundamental for pathologic diagnosis. Recommended elements were those considered to be clinically important and recommended for good practice but with lesser degrees of supportive evidence. Sixteen core/required data elements for cutaneous melanoma pathology reports were defined (with an additional 4 core/required elements for specimens received with lymph nodes). Eighteen additional data elements with a lesser level of evidentiary support were included in the recommended data set. Consensus response values (permitted responses) were formulated for each data item. Development and agreement of this evidence-based protocol at an international level was accomplished in a timely and efficient manner, and the processes described herein may

  5. Genotypic analysis of primary and metastatic cutaneous melanoma.

    PubMed

    Rao, U N M; Jones, M W; Finkelstein, S D

    2003-01-01

    Microdissection genotyping was performed on 16 cases of melanoma, including two cutaneous and one lymph node metastases. Three benign nevi were used as controls. Where possible, tumor was microdissected at several sites. Genotyping involved assessment of loss of heterozygosity [LOH]), which was accomplished using a panel of nine polymorphic tetranucleotide microsatellites. Polymerase chain reaction was performed on the normal tissue sample to establish microsatellite heterozygous status. Informative markers were then tested on microdissected lesional tissue and scored for the presence and extent of allelic imbalance (AI). Microsatellite informativeness varied from 33% to 66%. Benign nevi were without AI. All invasive melanomas manifested acquired allelic loss, which involved 75% or 100% of the markers shown to be informative for each subject. Eleven of 13 (84%) primary melanomas demonstrated intratumoral heterogeneity of AI consistent with development of tumor subclones with differing genotypic profiles within thin as well as thick melanomas. Although a consistent pattern did not emerge among the markers, LOH of 9p21 (D9S254) occurred in 60% (9/15) of the cases followed by 40% of cases displaying LOH of 1p34, p53, 10q (MXI1), and 10q23 (D10S520) and 25% with 5q21 (D5S 592) abnormalities. A third of the cases including the metastatic foci demonstrated two different patterns of AI affecting alternative alleles of the same genomic marker within different parts of the melanoma. Two melanomas in situ did not display LOH of any markers in the informative cases although the in situ component in the invasive tumors had allelic losses that were in part similar to the invasive areas. The results of this study support the expanded use of microdissection genotyping and explore other markers to define the unique mutational profile for malignant melanoma that may complement other histologic characteristics of melanoma. PMID:12550756

  6. 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

  7. Long-term Survival of Patients With Invasive Ultra-thin Cutaneous Melanoma

    PubMed Central

    Vecchiato, Antonella; Zonta, Elisa; Campana, Luca; Dal Bello, Giacomo; Rastrelli, Marco; Rossi, Carlo Riccardo; Alaibac, Mauro

    2016-01-01

    Abstract The incidence of cutaneous melanoma is increasing worldwide, especially for thin melanoma (Breslow ≤1 mm). Thin cutaneous melanoma has a favorable prognosis but there are few data about the prognosis of patients with ultra-thin cutaneous melanoma (Breslow ≤ 0.5 mm). Our aim was to investigate the disease-free survival among patients with invasive cutaneous melanoma with Breslow ≤ 0.5 mm after 10 years from the initial diagnosis. A retrospective review of 240 cutaneous melanoma patients with Breslow ≤ 0.5 mm was performed. Recurrence, death from cutaneous melanoma, and disease-free survival were all identified. In the whole group of patients, we observed only 2 deaths from cutaneous melanoma. Median follow-up was 13, 11 years. Among all 240 patients, 221 were alive and disease free, 2 died of cutaneous melanoma, 11 died of other non-neoplastic diseases, 5 died of other neoplastic diseases different from melanoma, and 1 patient had a local recurrence; therefore the 10-year melanoma survival rate was 99.6%. Our data indicate that death from cutaneous melanoma in the group of patients with Breslow ≤0.5 mm was a very rare event and that diagnosis at this stage dramatically decreases the risk of developing metastatic tumors to a <0.5% also after a 10-year period of follow-up. Limitation of the study includes the fact that other risk factors for melanoma, notably ulceration, and mitotic rate, were not evaluated. PMID:26765437

  8. 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

  9. 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.

  10. Regional non-nodal metastases of cutaneous melanoma.

    PubMed

    Cascinelli, N; Bufalino, R; Marolda, R; Belli, F; Nava, M; Galluzzo, D; Santinami, M; Levene, A

    1986-06-01

    The authors studied the prognosis of patients with so called local recurrences, satellites and in-transit metastases from cutaneous melanoma on the basis of 291 patients. These are the 19.3% of the 1503 patients with stage I and II melanoma originally submitted to surgical treatment at the National Cancer Institute of Milano (Italy). The majority of patients were males (M/F = 0.7): 102 had local recurrence, 99 in-transit metastases, 24 satellites and 66 both local and in-transit metastases. Regional non-nodal metastases were not related with the site of origin, and inadequate treatment of primary. These metastases were more frequently observed in patients who were submitted to regional node dissection no matter whether in discontinuity or in continuity with primary tumor. The frequency of regional non-nodal metastases was found to increase with increasing thickness of primary melanoma or, in stage II patients, with the number of involved nodes. Local and in-transit metastases were related with prognostic criteria in the same way. The overall survival was very close between in-transit and local metastases. Similar survival rates were observed comparing regional non-nodes and disseminated cutaneous and subcutaneous metastases. The authors conclude that the distinction between local recurrences, satellites and in-transit metastases is artificial and that these metastatic events are not prognostically dissimilar from metastases in distant skin areas.

  11. Actinic DNA damage and the pathogenesis of cutaneous malignant melanoma.

    PubMed

    Ross, P M; Carter, D M

    1989-05-01

    The near epidemic of melanoma and non-melanoma skin cancer in the United States and certain other industrialized nations is attributable to cutaneous exposure to sunlight more than to any other factor. Chronic exposure to UV irradiation and a high total cumulative dose may be less deleterious than are periodic bursts of large amounts of sun exposure leading to severe sunburn. Such an exposure pattern is characteristic of individuals such as office workers whose outdoor activities are irregular rather than daily, as with farmers or fisherman. Although UV irradiation is injurious to many cellular elements, the mechanisms underlying UV-mediated skin cancer are thought to be most likely related to DNA damage to cutaneous cells. Various types of UV-induced DNA damage have been identified, and they differ in biologic significance. Damage which is apt to be most cytotoxic is probably less effective as an inducer of skin cancer than is more subtle damage, which is tolerated but can initiate malignant transformation. Repair of DNA damage involves specific cellular activities which vary in their effectiveness in restoring cutaneous cell function to normal. Other biologic effects of UV irradiation may contribute to the development of skin cancer through effects on such defenses as pigmentation and the immune response. Sun-induced damage to DNA, however, is apparently necessary. Biologic consequences of dangerous environmental exposure to UV irradiation can be modulated by changes in life-style, the depth of the ozone layer, use of sunscreens, and possibly by hormones or their synthetic analogs.

  12. Rare SF3B1 R625 mutations in cutaneous melanoma.

    PubMed

    Kong, Yong; Krauthammer, Michael; Halaban, Ruth

    2014-08-01

    RNA splicing is the cellular process that has only recently been found to be an important target for various cancers. Among the spliceosome genes that are involved in cancers, SF3B1 is most frequently mutated. Recurrent mutation in codon 625 has been found in uveal melanoma, but this mutation has not been identified in cutaneous melanoma. We used whole-exome sequencing to explore the mutational landscape of 295 melanoma samples, 231 of which are cutaneous melanoma. Among these cutaneous melanoma samples, we found two samples with R625 mutation in SF3B1 gene. The results were validated by Sanger sequencing. We conclude that SF3B1 R625 mutation does occur in cutaneous melanoma, although with a low frequency (∼1%).

  13. 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

  14. Sentinel node identification by scintigraphic methods in cutaneous melanoma.

    PubMed

    Dias Moreira, R; Altino de Almeida, S; Maliska Guimarães, C M; Resende, J F; Gutfilen, B; Barbosa da Fonseca, L M

    2005-06-01

    In melanoma patients lymph node metastasis is an important prognostic factor that indicates the need for therapeutic lymph node dissection. Preoperative lymphoscintigraphy mapping associated with radioguided sentinel lymph node biopsy has become a well established procedure for cutaneous melanoma patients without clinically detectable lymph node metastases (stage I, II). This technique is a versatile way of characterizing the lymphatic basin at risk for metastases and identifying involved lymph nodes. The purpose of the present study was to examine the reproducibility of lymphoscintigraphy and sentinel lymph node biopsy in detecting micro metastases in cutaneous melanoma. The study was a single-institution prospective analysis of 74 melanoma patients, with primary tumors having Breslow thickness > 0.7 mm, who underwent lymphoscintigraphies between May 2002 and September 2003. Technetium-99m sulfur colloid was injected intradermally at the primary tumor site and dynamic images were obtained for 40 minutes. Two observers evaluated the images. One to two weeks after the first lymphoscintigraphy, radioguided lymph node biopsy was performed. For the biopsy, technetium-99m sulfer colloid was injected intradermally in the same manner as performed before. Lymph nodes were identified and removed with the aid of a gamma ray detecting probe (GDP), and were submitted to histopathological analysis. The histopathological analysis of the sentinel lymph nodes collected during surgery was performed in a sequential manner. First, frozen sections were analyzed during surgery. The lymph nodes considered negative by frozen section were analyzed by H&E staining. Subsequently, the slides considered negative with H&E were sent for immunohistochemical analysis. Lymphoscintigraphy identified at least one sentinel lymph node in all patients. Sentinel node biopsy detected metastases in 20 patients (27.2%). In all cases the lymph node basins identified during lymphoscintigraphy were found to

  15. 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)

  16. Management of a patient with advanced BRAF-mutant melanoma.

    PubMed

    Ashworth, Michelle T; Daud, Adil

    2014-03-01

    A 49-year-old man initially diagnosed in 1995 with cutaneous melanoma presented to the authors' institution in 2009 with metastatic, BRAF V600E-mutant melanoma. His treatment course to date has included surgery, adjuvant radiotherapy, and interferon, metastasectomies, granulocyte-macrophage colony-stimulating factors, a clinical trial with the BRAF inhibitor vemurafenib (PLX-4032), clinical trial with combination BRAF plus MEK inhibition with vemurafenib plus GDC-0973, and combination targeted and immune therapy with vemurafenib plus the anti-CTLA4 antibody ipilimumab. This case report illustrates the long-term management of a patient with metastatic melanoma using targeted and immune therapy, evolution in treatment guidelines, next directions in research, and the critical role of clinical trials in advancement of patient care.

  17. 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

  18. [Ileus caused by metastasis of cutaneous malignant melanoma: case report].

    PubMed

    Fajdić, Josip; Durović, Drazen; Gotovac, Nikola; Gugić, Damir; Stastny, Tomislav; Slisurić, Ferdinand

    2011-01-01

    In this case report we describe rare metastatic appearance of cutaneous malignant melanoma ( MM) in small intestine followed by clinical appearance of acute surgical abdomen. A 42-year old women operated in our hospital in April 2009. due to unusual naevus on her right arm. Pathologicaly it was MM grossly 1.5 cm, microscopically Breslow 11 mm, Clark's level IV (T4), number of mitosis 1.4 per mm2, without ulcerations. She was sent to continue treatment at the National Referal Center for Melanoma in KB "S. milosrdnice" Zagreb, Croatia. A month later wider excision (3 cm free margin) and sentinel lymph node biopsy (SLNB) was made there followed by axillary lymphadenectomy due to positive axillary finding. She received six cycles of chemotherapy. She arrived in our hospital in May 2010, under clinical picture of small intestine ileus and acute surgical abdomen. After preparation she was operated the same day. The cause of ileus was metastasis of MM in the small interstine. We made intestinal resection with termino-terminal anastomosis. The patient was released to home care ten days after operation without any complication. This case report demonstrates rarely described case of MM metastasis in the small intestine found causing ileus. PMID:22359897

  19. [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

  20. [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.

  1. 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

  2. Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

    PubMed Central

    Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

    2016-01-01

    Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression. PMID:27095580

  3. Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

    PubMed

    Montagnani, Valentina; Benelli, Matteo; Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

    2016-05-24

    Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

  4. 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.

  5. Progression of Cutaneous Vitiligo in a Patient with Large Posterior Choroidal Melanoma: A Case Report

    PubMed Central

    Ding, Angela; Elizalde, Javier; Barraquer, Rafael Ignacio

    2015-01-01

    Background/Aims The aim of our study was to report a case of progression of cutaneous vitiligo after large posterior choroidal melanoma diagnosis. Methods The clinical history, fundus findings and histopathological features suggest the diagnosis of cutaneous vitiligous progression after a diagnosis of large posterior choroidal melanoma. Results A 30-year-old female, with a personal history of cutaneous vitiligo for 12 years, was diagnosed with choroidal melanoma 18 months previously. The cutaneous vitiligo had progressed over her back, body and arms during the preceding 3 years. She refused treatment because she was in her 28th week of pregnancy. When she came to our clinic her visual symptoms had worsened, and the fundus examination showed a melanocytic choroidal mass. After confirming that there was no extraocular extension, she was treated with enucleation. A histopathological study confirmed the choroidal melanoma diagnosis. Conclusion The association between the progression of vitiligo and the diagnosis of uveal melanoma could be considered a good prognostic factor, as has been described in cases of cutaneous melanoma. A longer follow-up of these patients will allow us to confirm this association. PMID:27354983

  6. A Multi-Marker Prognostic Assay for Primary Cutaneous Melanoma

    PubMed Central

    Kashani-Sabet, Mohammed; Venna, Suraj; Nosrati, Mehdi; Rangel, Javier; Sucker, Antje; Egberts, Friederike; Baehner, Frederick L.; Simko, Jeff; Leong, Stanley P.L.; Haqq, Chris; Hauschild, Axel; Schadendorf, Dirk; Miller, James R.; Sagebiel, Richard W.

    2009-01-01

    Purpose To determine the prognostic significance of a multi-marker assay incorporating expression levels of three molecular markers in primary cutaneous melanoma. Experimental Design We assessed expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of 395 patients. For each marker, we identified optimal cut-points for expression intensity to predict disease-specific survival (DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative over-expression of all three markers was embodied in a multi-marker index, and its prognostic impact on DSS and SLN status was assessed using Cox regression, Kaplan-Meier analysis, and logistic regression. The prognostic impact of this multi-marker assay on DSS was assessed in an independent cohort of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections. Results Increasing multi-marker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient cohort. Multivariate logistic regression analysis revealed multi-marker expression scores as an independent predictor of SLN status (P=0.001). Multivariate Cox regression analysis showed the independent impact of the multi-marker index on DSS (P<0.001). The multi-marker index was the most significant factor predicting DSS, when compared to other clinical and histological factors, including SLN status (P=0.002). Multi-marker expression scores were also the most significantly predictive of DSS in the independent cohort (P=0.01). Conclusions These results describe a multi-marker assay with independent prognostic impact on the prediction of survival associated with melanoma in two distinct cohorts. PMID:19887476

  7. 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

  8. Immunotherapy for advanced melanoma: fulfilling the promise.

    PubMed

    Gogas, Helen; Polyzos, Aristidis; Kirkwood, John

    2013-12-01

    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 thirty 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 regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. 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 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:23725878

  9. Immunotherapy for advanced melanoma: future directions.

    PubMed

    Valpione, Sara; Campana, Luca G

    2016-02-01

    As calculated by the meta-analysis of Korn et al., the prognosis of metastatic melanoma in the pretarget and immunological therapy era was poor, with a median survival of 6.2 and a 1-year life expectancy of 25.5%. Nowadays, significant advances in melanoma treatment have been gained, and immunotherapy is one of the promising approaches to get to durable responses and survival improvement. The aim of the present review is to highlight the recent innovations in melanoma immunotherapy and to propose a critical perspective of the future directions of this enthralling oncology subspecialty.

  10. 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

  11. Cutaneous melanoma in Latin America: a population-based descriptive study.

    PubMed

    Sortino-Rachou, Ana Maria; Curado, Maria Paula; Cancela, Marianna de Camargo

    2011-03-01

    Cutaneous melanoma incidences vary between geographic regions and are a health concern for Caucasians and for all ethnic populations. In Latin America, data from population-based cancer registries of cutaneous melanoma incidence rates have rarely been reported. We searched the Cancer Incidence in Five Continents volume IX (CI5-IX) database for cutaneous melanoma and select cases by topography (C43) from 11 population-based cancer registries in Latin America. Between 1998 and 2002, a total of 4,465 cutaneous melanoma cases were reported in Latin America. The average age-standardized incidence rates (per 100,000 persons-year) was 4.6 (male) and 4.3 (female). This study presents an overview of cutaneous melanoma incidence in Latin America, highlighting the need to enhance coverage of population-based cancer registries in Latin America, to allow for a better understanding of this neoplasm in the region. Thus it can help in implementing primary prevention programs for the whole Latino population. At this point in time, early detection messages should target young women and older men in Latin America.

  12. Clinicopathologic findings and BRAF mutation in cutaneous melanoma in young adults.

    PubMed

    Estrozi, Bruna; Machado, Juliana; Rodriguez, Rubens; Bacchi, Carlos E

    2014-01-01

    Cutaneous melanoma in young patients is rare with increasing incidence. It is not clear whether the etiology and clinical outcome are similar to cutaneous melanoma in the elderly. Mutations in BRAF gene in patients with cutaneous melanoma, in general, range in frequency from 20% to 80%; however, the status and clinical significance of BRAF mutations in the young population have not been evaluated. We investigated 132 cases of primary cutaneous melanoma in patients aged between 18 and 30 years with emphasis on clinical characteristics, pathologic features, and molecular evaluation of mutation in the BRAF gene (BRAF(V600E)). It was predominantly seen in female individuals (61.4%), trunk was the most common site of involvement (40.4%), and superficially spreading melanoma was the predominant histologic type (79.5%). Mutation in BRAF(V600E) was analyzed successfully in 93 cases using an RT-PCR. The BRAF(V600E) mutation was identified in 38.7% (36/93) and was associated with vertical growth phase (P=0.01) and mild inflammatory infiltrate (P=0.02). No case of melanoma with regression phenomenon presented with BRAF(V600E) mutation (P<0.05). There was no significant association between BRAF(V600E) mutation and sex, histologic type, the Clark level, the Breslow index, solar elastosis, angiolymphatic and perineural invasion, satellitosis, and coexisting nevus. As in melanomas in older patients, these results probably indicate that BRAF mutation may not be the only key factor in melanoma tumorigenesis, and that there should be multiple alternative genetic pathways related to melanoma.

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. [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.

  1. [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

  2. 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

  3. Adoptive immunotherapy of advanced melanoma.

    PubMed

    Shapira-Frommer, Ronnie; Schachter, Jacob

    2012-09-01

    Adoptive cell therapy (ACT) has emerged as an effective therapy for patients with metastatic melanoma. Since the first introduction of the protocol in 1988 [1], major improvements have been achieved with response rates of 40%-72% among patients who were resistant to previous treatment lines. Both cell product and conditioning regimen are major determinants of treatment efficacy; therefore, developing ACT protocols explore diverse ways to establish autologous intra-tumoral lymphocyte cultures or peripheral effector cells as well as different lymphodepleting regimens. While a proof of feasibility and a proof of concept had been established with previous published results, ACT will need to move beyond single-center experiences, to confirmatory, multi-center studies. If ACT is to move into widespread practice, it will be necessary to develop reproducible high quality cell production methods and accepted lymphodepleting regimen. Two new drugs, ipilimumab (Yervoy, Bristol-Myers Squibb) and vemurafenib (Zelboraf, Roche), were approved in 2011 for the treatment of metastatic melanoma based on positive phase III trials. Both drugs show a clear overall survival benefit, so the timing of when to use ACT will need to be carefully thought out. In contrast to these 2 new, commercially available outpatient treatments, ACT is a personally-specified product and labor-intensive therapy that demands both acquisition of high standard laboratory procedures and close clinical inpatient monitoring during treatment. It is unique among other anti-melanoma treatments, providing the potential for a durable response following a single, self-limited treatment. This perspective drives the efforts to make this protocol accessible for more patients and to explore modifications that may optimize treatment results.

  4. 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

  5. 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

  6. 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

  7. EFFECT OF TIME TO SENTINEL-NODE BIOPSY ON THE PROGNOSIS OF CUTANEOUS MELANOMA

    PubMed Central

    Tejera-Vaquerizo, Antonio; Nagore, Eduardo; Puig, Susana; Robert, Caroline; Saiag, Philippe; Martín-Cuevas, Paula; Gallego, Elena; Herrera-Acosta, Enrique; Aguilera, José; Malvehy, Josep; Carrera, Cristina; Cavalcanti, Andrea; Rull, Ramón; Vilalta-Solsona, Antonio; Lannoy, Emilie; Boutros, Celine; Benannoune, Naima; Tomasic, Gorana; Aegerte, Philippe; Vidal-Sicart, Sergi; Palou, Josep; Alos, LLúcia; Requena, Celia; Traves, Víctor; Pla, Ángel; Bolumar, Isidro; Soriano, Virtudes; Guillén, Carlos; Herrera-Ceballos, Enrique

    2016-01-01

    Instroduction In patients with primary cutaneous melanoma, there is generally a delay between excisional biopsy of the primary tumor and sentinel-node biopsy. The objective of this study is to analyze the prognostic implications of this delay. Patients and method This was an observational, retrospective, cohort study in four tertiary referral hospitals. A total of 1963 patients were included. The factor of interest was the interval between the date of the excisional biopsy of the primary melanoma and the date of the sentinel-node biopsy (delay time) in the prognosis. The primary outcome was melanoma-specific survival and disease-free survival. Results A delay time of 40 days or less (HR, 1.7; CI, 1.2 to 2.5) increased Breslow thickness (Breslow ≥2 mm, HR >3.7; CI 1.4 to 10.7), ulceration (HR 1.6; CI, 1.1 to 2.3), sentinel-node metastasis (HR, 2.9; CI, 1.9 to 4.2), and primary melanoma localized in the head or neck were independently associated with worse melanoma-specific survival (all P<0.03). The stratified analysis showed that the effect of delay time was at the expense of the patients with a negative sentinel-node biopsy and without regression. Conclusion Early sentinel-node biopsy is associated with worse survival in patients with cutaneous melanoma. PMID:26072362

  8. 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.

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

    PubMed

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

    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.

  10. 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

  11. 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.

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

    PubMed

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

    2014-06-10

    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.

  13. Ancestry reported by white adults with cutaneous melanoma and control subjects in central Alabama

    PubMed Central

    Acton, Ronald T; Barton, Ellen H; Hollowell, William W; Dreibelbis, Amy L; Go, Rodney CP; Barton, James C

    2004-01-01

    Background We sought to evaluate the hypothesis that the high incidence of cutaneous melanoma in white persons in central Alabama is associated with a predominance of Irish and Scots descent. Methods Frequencies of country of ancestry reports were tabulated. The reports were also converted to scores that reflect proportional countries of ancestry in individuals. Using the scores, we computed aggregate country of ancestry indices as estimates of group ancestry composition. HLA-DRB1*04 allele frequencies and relationships to countries of ancestry were compared in probands and controls. Results were compared to those of European populations with HLA-DRB1*04 frequencies. Results Ninety evaluable adult white cutaneous melanoma probands and 324 adult white controls reported countries of ancestry of their grandparents. The respective frequencies of Ireland, and Scotland and "British Isles" reported countries of ancestry were significantly greater in probands than in controls. The respective frequencies of Wales, France, Italy and Poland were significantly greater in controls. 16.7% of melanoma probands and 23.8% of controls reported "Native American" ancestry; the corresponding "Native American" country of ancestry index was not significantly different in probands and controls. The frequency of HLA-DRB1*04 was significantly greater in probands, but was not significantly associated with individual or aggregate countries of ancestry. The frequency of DRB1*04 observed in Alabama was compared to DRB1*04 frequencies reported from England, Wales, Ireland, Orkney Island, France, Germany, and Australia. Conclusion White adults with cutaneous melanoma in central Alabama have a predominance of Irish, Scots, and "British Isles" ancestry and HLA-DRB1*04 that likely contributes to their high incidence of cutaneous melanoma. PMID:15310399

  14. [The reevaluation of neoangiogenesis indices in cutaneous melanoma].

    PubMed

    Marasà, S; Sciancalepore, G; Marasà, L

    2007-02-01

    The melanoma today represents one of more diffuse malignant neoplasm and known, object of numerous studies and you debate yourself, topic more and more puts into effect them, observed and estimated under more it varies aspects to you. Our study has been lead taking in consideration the process of neoangiogenesis, fundamental stage in the progression graduates them of the malignant melanoma, than it comes true through the release of VEGF and many other angiogenic molecules from part of the same neoplastic cells. The evolution of such process represents a critical moment for the development of whichever neoplasm, but in particular way in the melanoma it is in charge of the transition from the phase of horizontal increase to that one of vertical increase. We have therefore place the attention on the appraisal of objective indices of the vascularization as factor I prognosticate of the melanoma; particularly way we have correlated the indices of vascularisation in 54 cases of melanomas, all to III the level of Clark, and have obtained of turns out to you that confirm the possibility to insert between the prognostic factors determinants also those.

  15. 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

  16. The Prognostic Value of Age, Sex, and Subsite in Cutaneous Head and Neck Melanoma: A Clinical Review of Recent Literature

    PubMed Central

    Kadakia, Sameep; Chan, David; Mourad, Moustafa; Ducic, Yadranko

    2016-01-01

    Context Cutaneous head and neck melanoma is a challenging disease owing to its aggressive nature and often times advanced stage at presentation. Age, sex, and subsite are three prognostic indicators which can be determined prior to treatment or testing, and can allow the practitioner to counsel the patient before initiating therapy. Evidence Acquisition A PubMed search was conducted utilizing various terms relating to the subject matter. Articles over the past 25 years were analyzed and appropriately selected for review. Results It appears that patients older than 65 have a decreased overall 5 year survival compared to their younger counterparts. Male patients have poorer prognosis compared to female patients as noted by the decreased overall survival, decreased disease specific survival, and shorter time to distant metastasis. Scalp subsite was most uniformly accepted as having the worst prognosis in the head and neck, and may even serve as an independent prognostic indicator. Conclusions Advanced age, male sex, and scalp subsite all portend poor prognosis in patients with cutaneous head and neck melanoma. PMID:27703647

  17. [Late metastases of abdominal cutaneous malignant melanoma in the small and large bowels].

    PubMed

    Füredi, Gábor; Varga, István; Illés, Iván; Békefi, Péter; Molnár, Anna; Altorjay, Aron

    2005-09-25

    The authors reported the case of a 56 years old man, who was operated with abdominal cutaneous malignant melanoma 5 years ago. He had chemo-immunotherapy. His complaints were epigastric pain, melena, hematochezia, anorexia, lack of appetite, fatigue. The upper panendoscopy showed tumor mass in the duodenojejunal flexure and the colonoscopy showed tumor in the large bowel. The patient underwent jejunal resection and right hemicolectomy. The authors survey the metastases of malignant melanoma as well as their clinical signs, therapeutic measures and prognosis.

  18. Dermatoscopic features of cutaneous non-facial non-acral lentiginous growth pattern melanomas

    PubMed Central

    Keir, Jeff

    2014-01-01

    Background: The dermatoscopic features of facial lentigo maligna (LM), facial lentigo maligna melanoma (LMM) and acral lentiginous melanoma (ALM) have been well described. This is the first description of the dermatoscopic appearance of a clinical series of cutaneous non-facial non-acral lentiginous growth pattern melanomas. Objective: To describe the dermatoscopic features of a series of cutaneous non-facial non-acral lentiginous growth pattern melanomas in an Australian skin cancer practice. Method: Single observer retrospective analysis of dermatoscopic images of a one-year series of cutaneous non-facial, non-acral melanomas reported as having a lentiginous growth pattern detected in an open access primary care skin cancer clinic in Australia. Lesions were scored for presence of classical criteria for facial LM; modified pattern analysis (“Chaos and Clues”) criteria; and the presence of two novel criteria: a lentigo-like pigment pattern lacking a lentigo-like border, and large polygons. Results: 20 melanomas occurring in 14 female and 6 male patients were included. Average patient age was 64 years (range: 44–83). Lesion distribution was: trunk 35%; upper limb 40%; and lower limb 25%. The incidences of criteria identified were: asymmetry of color or pattern (100%); lentigo-like pigment pattern lacking a lentigo-like border (90%); asymmetrically pigmented follicular openings (APFO’s) (70%); grey blue structures (70%); large polygons (45%); eccentric structureless area (15%); bright white lines (5%). 20% of the lesions had only the novel criteria and/or APFO’s. Limitations: Single observer, single center retrospective study. Conclusions: Cutaneous non-facial non-acral melanomas with a lentiginous growth pattern may have none or very few traditional criteria for the diagnosis of melanoma. Criteria that are logically expected in lesions with a lentiginous growth pattern (lentigo-like pigment pattern lacking a lentigo-like border, APFO’s) and the novel

  19. 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

  20. Vitamin D receptor polymorphisms in patients with cutaneous melanoma.

    PubMed

    Orlow, Irene; Roy, Pampa; Reiner, Anne S; Yoo, Sarah; Patel, Himali; Paine, Susan; Armstrong, Bruce K; Kricker, Anne; Marrett, Loraine D; Millikan, Robert C; Thomas, Nancy E; Gruber, Stephen B; Anton-Culver, Hoda; Rosso, Stefano; Gallagher, Richard P; Dwyer, Terence; Kanetsky, Peter A; Busam, Klaus; From, Lynn; Begg, Colin B; Berwick, Marianne

    2012-01-15

    The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.

  1. Vitamin D receptor polymorphisms in patients with cutaneous melanoma

    PubMed Central

    Orlow, Irene; Roy, Pampa; Reiner, Anne S.; Yoo, Sarah; Patel, Himali; Paine, Susan; Armstrong, Bruce K.; Kricker, Anne; Marrett, Loraine D.; Millikan, Robert C.; Thomas, Nancy E.; Gruber, Stephen B.; Anton-Culver, Hoda; Rosso, Stefano; Gallagher, Richard P.; Dwyer, Terence; Kanetsky, Peter A.; Busam, Klaus; From, Lynn; Begg, Colin B.; Berwick, Marianne

    2011-01-01

    The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene SNPs in a large international multi-center population-based case-control study of melanoma. Buccal DNAs were obtained from 1207 people with incident multiple primary melanoma and 2469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, htSNPs with ≥10% MAF in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3’ gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25% to 33% for 6 polymorphisms: rs10875712 (OR 1.28; 95%CI, 1.01–1.62), rs4760674 (OR 1.33; 95% CI, 1.06–1.67), rs7139166 (OR 1.26; 95%CI, 1.02–1.56), rs4516035 (OR 1.25; 95%CI, 1.01–1.55), rs11168287 (OR 1.27; 95%CI, 1.03–1.57), rs1544410 (OR 1.30; 95%CI, 1.04–1.63); for 2 polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65–1.02), rs7965281 (OR, 0.78; 95%CI, 0.62–0.99). We recognize the potential false positive findings due to multiple comparisons; however the 8 significant SNPs in this study outnumbered the 2 significant tests expected to occur by chance. The vitamin D receptor may play a role in melanomagenesis. PMID:21365644

  2. 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.

  3. 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

  4. Neoadjuvant therapy for locally advanced melanoma: new strategies with targeted therapies.

    PubMed

    La Greca, Michele; Grasso, Giuseppe; Antonelli, Giovanna; Russo, Alessia Erika; Bartolotta, Salvatore; D'Angelo, Alessandro; Vitale, Felice Vito; Ferraù, Francesco

    2014-01-01

    Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma.

  5. Neoadjuvant therapy for locally advanced melanoma: new strategies with targeted therapies

    PubMed Central

    La Greca, Michele; Grasso, Giuseppe; Antonelli, Giovanna; Russo, Alessia Erika; Bartolotta, Salvatore; D’Angelo, Alessandro; Vitale, Felice Vito; Ferraù, Francesco

    2014-01-01

    Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma. PMID:24971022

  6. 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

  7. 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

  8. Prevalence and heterogeneity of circulating tumour cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Shenjere, Patrick; Hodgson, Clare; Hodgetts, Jackie; Clack, Glen; Hughes, Andrew; Lorigan, Paul; Dive, Caroline

    2014-02-01

    We previously demonstrated that circulating tumour cells (CTCs) are detectable by the MelCAM and high molecular weight melanoma-associated antigen (HMW-MAA)-dependent CellSearch platform. However, CTCs which do not express these capture and detection markers are not detectable by CellSearch. Consequently, we explored the use of isolation by size of epithelial tumour cells (ISET), a marker independent, filtration-based device to determine the prevalence and heterogeneity of CTCs in metastatic cutaneous melanoma patients. Ninety patients were prospectively recruited and blood samples taken before treatment. Patients' blood was filtered using the ISET platform. CTCs were enumerated using dual immunohistochemistry with positive selection by S100 expression and exclusion of leucocytes and endothelial cells expressing CD45 or CD144, respectively. A panel of markers (Melan-A, MITF, MelCAM, high molecular melanoma-associated antigen, CD271 and MAGEC) was also examined. Fifty-one patients (57%) had CTCs (range 1-44 CTCs/4 ml blood) and 12 patients also had circulating tumour microemboli. Seven patients had S100- CTCs, 11 patients' CTCs were S100+ and 33 patients had S100+ and S100- CTCs. Substantial intrapatient and interpatient heterogeneity was observed for all other melanoma-associated markers. CTCs in metastatic cutaneous melanoma are detectable using the flexible marker-independent ISET platform. CTCs display significant marker expression heterogeneity implying that marker-dependent platforms would not detect all CTCs and multimarker assays are now required to reveal the biological significance of this CTC heterogeneity.

  9. Prevalence and heterogeneity of circulating tumour cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Shenjere, Patrick; Hodgson, Clare; Hodgetts, Jackie; Clack, Glen; Hughes, Andrew; Lorigan, Paul; Dive, Caroline

    2014-02-01

    We previously demonstrated that circulating tumour cells (CTCs) are detectable by the MelCAM and high molecular weight melanoma-associated antigen (HMW-MAA)-dependent CellSearch platform. However, CTCs which do not express these capture and detection markers are not detectable by CellSearch. Consequently, we explored the use of isolation by size of epithelial tumour cells (ISET), a marker independent, filtration-based device to determine the prevalence and heterogeneity of CTCs in metastatic cutaneous melanoma patients. Ninety patients were prospectively recruited and blood samples taken before treatment. Patients' blood was filtered using the ISET platform. CTCs were enumerated using dual immunohistochemistry with positive selection by S100 expression and exclusion of leucocytes and endothelial cells expressing CD45 or CD144, respectively. A panel of markers (Melan-A, MITF, MelCAM, high molecular melanoma-associated antigen, CD271 and MAGEC) was also examined. Fifty-one patients (57%) had CTCs (range 1-44 CTCs/4 ml blood) and 12 patients also had circulating tumour microemboli. Seven patients had S100- CTCs, 11 patients' CTCs were S100+ and 33 patients had S100+ and S100- CTCs. Substantial intrapatient and interpatient heterogeneity was observed for all other melanoma-associated markers. CTCs in metastatic cutaneous melanoma are detectable using the flexible marker-independent ISET platform. CTCs display significant marker expression heterogeneity implying that marker-dependent platforms would not detect all CTCs and multimarker assays are now required to reveal the biological significance of this CTC heterogeneity. PMID:24201293

  10. Pembrolizumab: A Review in Advanced Melanoma.

    PubMed

    Deeks, Emma D

    2016-03-01

    Pembrolizumab (Keytruda(®)) is a humanized monoclonal antibody against programmed death receptor-1 (PD-1), a key immunoinhibitory checkpoint protein implicated in down-regulating anti-tumour immune responses. This intravenous drug is indicated for the treatment of advanced (unresectable or metastatic) melanoma, on the basis of its clinical benefit in this setting in the phase I KEYNOTE 001 trial (expansion cohorts) and the phase II and III trials, KEYNOTE 002 and 006. These studies were conducted in ipilimumab-naïve and/or ipilimumab-experienced patients and assessed varying pembrolizumab regimens administered every 2 or 3 weeks, all of which helped to determine the recommended dosage of 2 mg/kg every 3 weeks. In the trials with active comparator arms, pembrolizumab regimens significantly improved progression-free survival (PFS), overall survival (OS) and overall response rates (ORR) relative to ipilimumab in ipilimumab-naïve patients (KEYNOTE 006), and significantly improved PFS and ORR, but not OS (although OS data are immature), relative to chemotherapy in ipilimumab-refractory patients, who had also received BRAF/MEK inhibitor therapy if BRAF-mutation positive (KEYNOTE 002). Pembrolizumab has an acceptable tolerability profile, with immune-related adverse events that are generally manageable/reversible. Thus, pembrolizumab is a valuable treatment option for patients with advanced melanoma, including those who have progressed on ipilimumab and BRAF/MEK inhibitors.

  11. Long-lasting response to electrochemotherapy in melanoma patients with cutaneous metastasis

    PubMed Central

    2013-01-01

    Background Treatment of early and multiple cutaneous unresectable recurrences is a major therapeutic problem with around 80% of patients relapsing within 5 years. For lesions refractory to elective treatments, electrochemotherapy (ECT) involving electroporation combined with antineoplastic drug treatment appears to be a new potential option. This study was undertaken to analyze the short- and long-term responses of lesions treated with ECT with intravenous injection of bleomycin in melanoma patients with in-transit disease or distant cutaneous metastases. Methods Between June 2007 and September 2012, 60 patients with relapsed and refractory cutaneous melanoma metastases or in-transit disease underwent 100 courses of ECT with intravenous injection of bleomycin. Response to treatment was evaluated three months after ECT. A long-lasting response was defined as no cutaneous or in-transit relapse after a minimum of six months. Results Three months after ECT, a complete response was observed in 29 patients (48.4%), a partial response in 23 patients (38.3%) and no change or progressive disease in 8 patients (13.3%). The objective response rate of all treated lesions was 86.6%. Thirteen patients (44.8% of complete responders) experienced a long-lasting response after one ECT session and were disease-free after a mean duration of follow-up of 27.5 months. Conclusions The favorable outcome obtained in the present study demonstrates that ECT is a reliable, and effective procedure that provides long-term benefit in terms of curative and palliative treatment for unresectable cutaneous lesions without adversely impacting the quality of life of patients. PMID:24289268

  12. 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

  13. 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

  14. Familial cutaneous malignant melanoma: autosomal dominant trait possibly linked to the Rh locus.

    PubMed Central

    Greene, M H; Goldin, L R; Clark, W H; Lovrien, E; Kraemer, K H; Tucker, M A; Elder, D E; Fraser, M C; Rowe, S

    1983-01-01

    Segregation and linkage analyses were undertaken in families with multiple cases of cutaneous malignant melanoma (CMM) and a recently-described melanoma precursor, the dysplastic nevus syndrome (DNS). Clinical and laboratory data, including 23 genetic markers, were collected on 401 members of 14 high-risk kindreds. Pedigree analysis was compatible with an autosomal dominant mode of inheritance for the familial CMM trait. Although a similar model probably applies to the DNS trait as well, segregation analysis could not confirm the presence of a major locus. However, linkage analysis suggested that an autosomal dominant model was appropriate for the DNS, and that a DNS/CMM susceptibility gene may be located on the short arm of chromosome 1, within 30 map units of the Rh locus [maximum logarithm of odds (lod) score = 2.00]. Images PMID:6577466

  15. Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research

    PubMed Central

    Bhatia, Parisha; Friedlander, Paul; Zakaria, Elmageed A.

    2015-01-01

    This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few available targeted therapies that is FDA approved and provides promising results in metastatic disease. However, its resistance at an early stage is of great concern. Recent implementation of combinational therapies including “targeted therapy”, immunotherapy, and biological agents has appealed many researchers to define the adjunctive role of available therapies and their limitations in advanced stage and metastatic melanoma. This commends the need for future multi-institutional studies to confirm the clinical validity of different therapeutic strategies on a large scale population. PMID:25738144

  16. 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.

  17. 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

  18. Reflectance confocal microscopy of cutaneous melanoma. Correlation with dermoscopy and histopathology*

    PubMed Central

    Rstom, Silvia Arroyo; Libório, Lorena Silva; Paschoal, Francisco Macedo

    2015-01-01

    In vivo Confocal Microscopy is a method for non-invasive, real-time visualization of microscopic structures and cellular details of the epidermis and dermis, which has a degree of resolution similar to that obtained with histology. We present a case of cutaneous melanoma in which diagnosis was aided by confocal microscopy examination. We also correlate the observed features with the dermoscopic and histopathological findings. Confocal microscopy proved to be an useful adjunct to dermoscopy, playing an important role as a method 'between clinical evaluation and histopathology'. PMID:26131877

  19. 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

  20. Tissue Biomarkers for Prognosis in Cutaneous Melanoma: A Systematic Review and Meta-analysis

    PubMed Central

    Rothberg, Bonnie E. Gould; Bracken, Michael B.

    2009-01-01

    In the clinical management of early-stage cutaneous melanoma, it is critical to determine which patients are cured by surgery alone and which should be treated with adjuvant therapy. To assist in this decision, many groups have made an effort to use molecular information. However, although there are hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the course of cutaneous melanoma, at this time, no molecular method to improve risk stratification is part of recommended clinical practice. To help understand this disconnect, we conducted a systematic review and meta-analysis of the published literature that reported immunohistochemistry-based protein biomarkers of melanoma outcome. Three parallel search strategies were applied to the PubMed database through January 15, 2008, to identify cohort studies that reported associations between immunohistochemical expression and survival outcomes in melanoma that conformed to the REMARK criteria. Of the 102 cohort studies, we identified only 37 manuscripts, collectively describing 87 assays on 62 distinct proteins, which met all inclusion criteria. Promising markers that emerged included melanoma cell adhesion molecule (MCAM)/MUC18 (all-cause mortality [ACM] hazard ratio [HR] = 16.34; 95% confidence interval [CI] = 3.80 to 70.28), matrix metalloproteinase-2 (melanoma-specific mortality [MSM] HR = 2.6; 95% CI = 1.32 to 5.07), Ki-67 (combined ACM HR = 2.66; 95% CI = 1.41 to 5.01), proliferating cell nuclear antigen (ACM HR = 2.27; 95% CI = 1.56 to 3.31), and p16/INK4A (ACM HR = 0.29; 95% CI = 0.10 to 0.83, MSM HR = 0.4; 95% CI = 0.24 to 0.67). We further noted incomplete adherence to the REMARK guidelines: 14 of 27 cohort studies that failed to adequately report their methods and nine studies that failed to either perform multivariable analyses or report their risk estimates were published since 2005. PMID:19318635

  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. 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

  3. 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.

  4. Neurotropic cutaneous malignant melanoma with contiguous spread to spinal cord, an extremely rare presentation.

    PubMed

    Asad, Sheikh; Sher, Idrees; Peters-Willke, Jens; Jessup, Peter

    2016-03-01

    Neurotropic melanoma (NM) is a rare variant of cutaneous melanomas. Compared with conventional melanoma, NM is more locally aggressive with an increased tendency for local recurrence but less likely for nodal or distant metastases. The often amelanotic, benign appearance may lead to treatment issues such as late presentation, diagnostic delay, misdiagnosis, insufficient surgical margins, and recurrence with resulting poor outcome. To our knowledge, this is the first case report of NM with contiguous spread to the spinal cord. We present a case report of a 73-year-old male with gradual decline in mobility over the period of few months. He deteriorated very rapidly whilst inpatient with progressive myelopathy, loss of sphincter function and dysphonia with dysphagia due to involvement of lower cranial nerves. The neurotropic nature of the disease and prevalence in the head and neck region results in perineural and neural invasion with resulting neuropathies. Patient underwent posterior cervical decompression and resection of the higher cervical intramedullary spinal cord NM lesion. He recovered well with improvement of his limb weakness as well as bulbar function. Wide local excision (WLE) with adjuvant radiotherapy where indicated remains the current practice for treatment, with chemotherapy predominately being reserved as a salvage treatment for patients with disseminated disease. PMID:27683701

  5. 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

  6. 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

  7. Neurotropic cutaneous malignant melanoma with contiguous spread to spinal cord, an extremely rare presentation

    PubMed Central

    Sher, Idrees; Peters-Willke, Jens; Jessup, Peter

    2016-01-01

    Neurotropic melanoma (NM) is a rare variant of cutaneous melanomas. Compared with conventional melanoma, NM is more locally aggressive with an increased tendency for local recurrence but less likely for nodal or distant metastases. The often amelanotic, benign appearance may lead to treatment issues such as late presentation, diagnostic delay, misdiagnosis, insufficient surgical margins, and recurrence with resulting poor outcome. To our knowledge, this is the first case report of NM with contiguous spread to the spinal cord. We present a case report of a 73-year-old male with gradual decline in mobility over the period of few months. He deteriorated very rapidly whilst inpatient with progressive myelopathy, loss of sphincter function and dysphonia with dysphagia due to involvement of lower cranial nerves. The neurotropic nature of the disease and prevalence in the head and neck region results in perineural and neural invasion with resulting neuropathies. Patient underwent posterior cervical decompression and resection of the higher cervical intramedullary spinal cord NM lesion. He recovered well with improvement of his limb weakness as well as bulbar function. Wide local excision (WLE) with adjuvant radiotherapy where indicated remains the current practice for treatment, with chemotherapy predominately being reserved as a salvage treatment for patients with disseminated disease.

  8. Neurotropic cutaneous malignant melanoma with contiguous spread to spinal cord, an extremely rare presentation

    PubMed Central

    Sher, Idrees; Peters-Willke, Jens; Jessup, Peter

    2016-01-01

    Neurotropic melanoma (NM) is a rare variant of cutaneous melanomas. Compared with conventional melanoma, NM is more locally aggressive with an increased tendency for local recurrence but less likely for nodal or distant metastases. The often amelanotic, benign appearance may lead to treatment issues such as late presentation, diagnostic delay, misdiagnosis, insufficient surgical margins, and recurrence with resulting poor outcome. To our knowledge, this is the first case report of NM with contiguous spread to the spinal cord. We present a case report of a 73-year-old male with gradual decline in mobility over the period of few months. He deteriorated very rapidly whilst inpatient with progressive myelopathy, loss of sphincter function and dysphonia with dysphagia due to involvement of lower cranial nerves. The neurotropic nature of the disease and prevalence in the head and neck region results in perineural and neural invasion with resulting neuropathies. Patient underwent posterior cervical decompression and resection of the higher cervical intramedullary spinal cord NM lesion. He recovered well with improvement of his limb weakness as well as bulbar function. Wide local excision (WLE) with adjuvant radiotherapy where indicated remains the current practice for treatment, with chemotherapy predominately being reserved as a salvage treatment for patients with disseminated disease. PMID:27683701

  9. 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

  10. Risk of subsequent cutaneous malignancy in patients with prior melanoma: a systematic review and meta-analysis.

    PubMed

    van der Leest, R J T; Flohil, S C; Arends, L R; de Vries, E; Nijsten, T

    2015-06-01

    Melanoma patients are known to be at risk of developing multiple cutaneous (pre-) malignancies, however, the exact dimensions of these risks are unknown. In this meta-analysis, risks of developing a melanoma, basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) after a melanoma were investigated. An extensive systematic literature search was conducted (last performed on 18 January 2012). Studies reporting risks, i.e. proportions, standardized incidence ratios (SIR) and cumulative risks (CRs) were included. Fifty, of 233 fully read articles, met selection criteria. Two independent reviewers extracted data on study characteristics and risks measurements. Random-effects meta-analyses were used to pool the risk estimates for the three tumour combinations. In melanoma patients, pooled proportions for a subsequent melanoma, BCC or SCC were respectively 3.8% (n = 47), 2.8% (n = 5) and 1.0% (n = 6). The pooled SIRs for a subsequent melanoma, BCC or SCC in melanoma patients were respectively 10.4 (n = 12), 4.6 (n = 2) and 2.8 (n = 2). Mean 20-year CRs of a subsequent melanoma, BCC or SCC in melanoma patients were respectively 5.4% (n = 3), 14.0% (n = 1) and 4.0% (n = 1). Subgroup analyses showed substantial differences in reported risks between continents and study design. In conclusion, a history of a prior melanoma is a strong predictor for development of a subsequent melanoma (approximately 10-fold increased risk) and to a lesser extent BCC or SCC. This information could serve as information for health care systems. Further, secondary prevention seems pivotal in this patient group. PMID:25491923

  11. 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

  12. 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

  13. Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8.

    PubMed

    Singh, R K; Gutman, M; Reich, R; Bar-Eli, M

    1995-08-15

    UV radiation has been shown to play a role in the initiation of human cutaneous melanoma, but its role in the development of malignant melanoma to the metastatic state is not very well defined. Although previous studies have concentrated on the effect of UV-B on the host immune response, the effect of UV-B on the tumor cells was not elucidated. Here we show that UV-B can induce interleukin 8 (IL-8) mRNA and protein secretion in human cutaneous melanoma with negligible expression of IL-8. UV-B-induced IL-8 was constitutively expressed 60 days after irradiation in tumors implanted in mice. Induction of IL-8 was UV-B dose dependent and blocked by cyclohexamide, indicating that de novo protein synthesis is required for its expression. The UV-irradiated cells demonstrated enhanced tumorigenicity and metastatic potential in nude mice. The increase in tumorigenicity and metastatic ability could be explained by the increase in Mr 72,000 type IV collagenase activity and angiogenesis attributed to the induction of IL-8 after irradiation. The acquisition of the metastatic phenotype induced by UV-B could not be attributed to abnormalities in the p53 or MTS-1 (p16INK4) genes. To the best of our knowledge, this is the first report to show that UV-B can increase the aggressiveness of human cutaneous melanoma for growth and metastasis. PMID:7543020

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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

  1. Cutaneous melanoma: hints from occupational risks by anatomic site in Swedish men

    PubMed Central

    Perez-Gomez, B; Pollan, M; Gustavsson, P; Plato, N; Aragones, N; Lopez-Abente, G

    2004-01-01

    Aims: To improve knowledge of the epidemiology of melanoma by comparing occupational risks of cutaneous melanoma (CM) by anatomic site in Swedish workers. Methods: Male workers employed in 1970 and living in the country in 1960 were followed up from 1971 to 1989 using the Swedish Registers of Death and Cancer. A more specifically exposed subcohort included men reporting the same occupation in 1960 and 1970. For each location, occupational risk ratios (RRs) were extracted from Poisson regression models adjusted by age, period, town size, and geographical area. To diminish the influence of socioeconomic factors, intrasector analyses, comparing only jobs belonging to the same occupational sector, were performed. Risk patterns for different locations were compared. Results: High RRs for different sites were found among workers exposed to UV sources (dentists, physiotherapists, and lithographers), and sun exposed workers (harbour masters, and lighthouse/related work). Risk excesses were seen in fur tailors, tanners/fur dressers, patternmakers/cutters, electrical fitters/wiremen, telephone/telegraph installers/repairmen, and some glass/pottery/tile workers. Results for lower and upper limbs were significantly correlated but somewhat independent of those found in thorax, the most frequent location. Correlation between head/neck and thorax was moderate. Specific risk excesses were found for rolling mill workers in head/neck, for chimney sweeps in upper limbs, and for aircraft pilots/navigators/flight engineers in lower limbs. Conclusions: High RRs in the trunk among occupations with UV exposure from artificial sources suggest an effect not restricted to exposed sites. An unusual distribution of cases and RRs in chimney sweeps, rolling-mill, or glass/pottery/tile workers suggests local effects of exposures. The not previously reported risk excess in this job and in fur related processes, and the RR in electrical fitters and telephone/telegraph installers deserve further

  2. 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

  3. Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure.

    PubMed

    Candido, Saverio; Rapisarda, Venerando; Marconi, Andrea; Malaponte, Grazia; Bevelacqua, Valentina; Gangemi, Pietro; Scalisi, Aurora; McCubrey, James A; Maestro, Roberta; Spandidos, Demetrios A; Fenga, Concettina; Libra, Massimo

    2014-03-01

    Sun-exposure is one of the risk factors associated with the development of a cutaneous neoplasm. In melanoma, the Ras-Raf-MEK-ERK (MAPK) signaling pathway is constitutively activated through multiple mechanisms, including B-Raf mutation. It has been hypothesized that B-Raf mutations in melanocytic lesions arise from DNA damage induced by ultraviolet (UV) radiation. However, it is still discussed if B-Raf mutations are associated with melanoma patients exposed to the sun. Therefore, in the present study, the known B-RafV600E mutation was analysed in melanoma samples from 30 indoor and 38 outdoor workers. B-RafV600E mutation was detected in 52 and 73% of outdoor workers and indoor workers, respectively. Of note, this mutation was identified in 12 of 14 (85%) melanoma of the trunk diagnosed in indoor workers and in 9 of 19 (47%) samples from outdoor workers (p=0.03). By analyzing melanomas of other body sites, no statistical difference in the frequency of B-RafV600E mutation was identified between the groups of workers. It appears that the mutation detected among indoor workers may be associated with a recreational or intermittent exposure to the sun, as usually the trunk is a sun-protected body site. Overall, these data indicate that the B-RafV600E mutation detected in melanoma is not associated with a chronic exposure to the sun. Mutations detected in other genes may also contribute to melanoma development in the subset of patients exposed to UV radiation.

  4. 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

  5. Lock-in thermal imaging for the early-stage detection of cutaneous melanoma: a feasibility study.

    PubMed

    Bonmarin, Mathias; Le Gal, Frédérique-Anne

    2014-04-01

    This paper theoretically evaluates lock-in thermal imaging for the early-stage detection of cutaneous melanoma. Lock-in thermal imaging is based on the periodic thermal excitation of the specimen under test. Resulting surface temperature oscillations are recorded with an infrared camera and allow the detection of variations of the sample's thermophysical properties under the surface. In this paper, the steady-state and transient skin surface temperatures are numerically derived for a different stage of development of the melanoma lesion using a two-dimensional axisymmetric multilayer heat-transfer model. The transient skin surface temperature signals are demodulated according to the digital lock-in principle to compute both a phase and an amplitude image of the lesions. The phase image can be advantageously used to accurately detect cutaneous melanoma at an early stage of development while the maximal phase shift can give precious information about the lesion invasion depth. The ability of lock-in thermal imaging to suppress disturbing subcutaneous thermal signals is demonstrated. The method is compared with the previously proposed pulse-based approaches, and the influence of the modulation frequency is further discussed.

  6. Second cancer following cutaneous melanoma and cancers of the brain, thyroid, connective tissue, bone, and eye in Connecticut, 1935-82.

    PubMed

    Tucker, M A; Boice, J D; Hoffman, D A

    1985-12-01

    The risk of second primary cancers developing was evaluated in individuals with 6 rare tumors in Connecticut between 1935 and 1982. Small but significant excesses of all second cancers occurred in patients with cutaneous melanoma (42%), and cancers of the brain (59%), thyroid (49%), connective tissue (23%), bone (66%), and eye (40%). In individuals with cutaneous melanoma, the highest risks were for subsequent cutaneous melanomas [relative risk (RR) = 8.5] that persisted throughout all intervals of observation. The risk for second melanomas was higher in persons under age 40, consistent with a heritable component. Connective tissue tumors and breast cancers also occurred in excess. Among patients with brain cancer, an increase of melanoma was observed that may represent an underlying neural crest abnormality, although no excess of brain cancer was seen after melanoma. Reciprocal increases of bone cancer after connective tissue cancer and connective tissue cancer after bone cancer point to shared risk factors, such as high dose radiotherapy or genetic susceptibility states. An anticipated high risk of osteogenic sarcoma following Ewing's sarcoma was not seen. An excess of breast cancer (RR = 1.9) after thyroid cancer indicates common etiologic factors. Expected excesses of bilateral retinoblastoma and bone cancer after retinoblastoma were seen. Tumors commonly treated with alkylating agents or nitrosoureas (melanoma, brain, connective tissue) showed slightly elevated risks of acute nonlymphocytic leukemia. Prostate cancer was frequently found to be in excess, but this is likely an artifact due to ascertainment bias.

  7. CD40 is a prognostic marker in primary cutaneous malignant melanoma.

    PubMed Central

    van den Oord, J. J.; Maes, A.; Stas, M.; Nuyts, J.; Battocchio, S.; Kasran, A.; Garmyn, M.; De Wever, I.; De Wolf-Peeters, C.

    1996-01-01

    CD40 is a receptor at the surface of B lymphocytes with important functions in the immune response. CD40 has also been found on a variety of carcinoma and melanoma cell lines where it has been suggested to serve as a possible receptor for mitogenic signals. We studied the expression and distribution of CD40 in paraffin sections of 71 uniformly treated malignant melanomas (MMs) with a long clinical follow-up using well known monoclonal antibodies. For comparison, 71 benign nevi were also studied. Common acquired nevi occasionally expressed CD40 in nests or single cells at the dermo-epidermal junction; no immunoreactivity was observed in the dermal part of acquired nevi, and all Spitz' nevi were entirely negative. One-third of large congenital nevi expressed CD40 in small clusters of heavily pigmented, epithelioid cells, corresponding to so-called proliferative nodules. In 41 of 71 MMs, CD40 was expressed in single or clustered neoplastic melanocytes; 9 cases showed CD40 expression only in the radial growth phase, and in 32 cases, the vertical growth phase showed CD40 expression. The same staining pattern was obtained with other anti-CD40 monoclonal antibodies, directed to different epitopes of the CD40 molecule. In 29 of 32 MMs showing CD40 in the vertical growth phase, expression of the CD40 ligand (CD40L) was studied; in 13 of these 29, CD40L was found in the same tumor areas that expressed CD40. Analysis of 28 metastases from 24 MM patients showed in the majority of cases a similar, scattered or nodular staining pattern as observed in the primary tumor. Patients expressing CD40 in the vertical growth phase of their MM did not differ significantly from CD40-negative patients with respect to any of the known prognostic parameters but showed a significantly shorter tumor-free survival. Patients with CD40+ CD40L+ MM tended to have a shorter tumor-free survival than those lacking CD40L. We conclude that CD40 represents a novel prognostic parameter in primary cutaneous

  8. Immunolabeling for p16, WT1, and Fli-1 in the assignment of growth phase for cutaneous melanomas.

    PubMed

    Strickler, Allen G; Schaefer, Jochen T; Slingluff, Craig L; Wick, Mark R

    2014-09-01

    Distinction between radial growth phase (RGP) and vertical growth phase (VGP) in cutaneous melanomas is prognostically significant. Despite established morphological criteria, molecular markers to separate RGP and VGP have not been well established. The goal of this study was to investigate associations of p16, WT1, and Fli-1 with RGP-to-VGP progression, by immunohistochemistry. The p16 is a tumor suppressor, whereas WT1 and Fli-1 are transcriptional activators. The authors hypothesized that entry into VGP would be associated with decreased p16 and increased WT1 and Fli-1. Paraffin sections from 18 RGP and 15 VGP melanomas were immunostained with well-characterized antibodies to p16, WT1, and Fli-1. Melanoma growth phases were determined using precodified morphological attributes. In RGP melanomas, p16 was expressed in 15 of 18 (83%), WT1 in 17 of 17 (100%), and Fli-1 at least focally in 6 of 18 (33%). The deep dermal component of VGP melanomas stained positively for Fli-1 in 9 of 14 (64%), strongly for WT1 in 10 of 14 (71%), and strongly for p16 in only 2 of 15 (13%). Observed patterns of WT1 immunopositivity did not support the authors' hypothesis; it is not likely to be a good indicator of VGP. On the other hand, Fli-1 staining trended toward more positive deep tumor compartment staining and p16 to weaker staining in the deep compartment. At present, application of histological criteria remains the best method for assignment of growth phase in melanomas; however, p16 and possibly Fli-1 immunostains may serve as useful adjuncts in morphologically indeterminate cases.

  9. 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

  10. 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

  11. Red meat and fruit intake is prognostic among patients with localized cutaneous melanomas more than 1 mm thick

    PubMed Central

    Gould Rothberg, Bonnie E.; Bulloch, Kaleigh J.; Fine, Judith A.; Barnhill, Raymond L.; Berwick, Marianne

    2014-01-01

    Background As the 10-year mortality for localized cutaneous melanoma more than 1.00 mm thick approaches 40% following complete resection, non-therapeutic interventions that can supplement recommended active surveillance are needed. Although guidelines recommending nutrition, physical activity and tobacco cessation for cancer survivors have been published, data describing their associations with melanoma survivorship are lacking. Methods Analysis of modifiable lifestyle behaviors collected on the 249 cases with melanomas more than 1.00 mm thick enrolled in the Connecticut Case-Control Study of Skin Self-Examination study was conducted. Independent associations with melanoma-specific survival were evaluated through Cox proportional hazards modeling adjusting for age, gender, Breslow thickness, ulceration and the presence of microsatellites. Independently significant variables were then combined into a single model and backwards elimination was employed until all remaining variables were significant at p<0.05. Results Following adjustment for age, Breslow thickness and anatomic site of the index melanoma, daily fruit consumption was associated with improved melanoma-specific survival (HR=0.54; 95% CI: 0.34–0.86) whereas at least weekly red meat consumption was associated with worse outcomes (HR=1.84; 95% CI: 1.02–3.30). Natural red (HR=0.44; 95% CI: 0.22–0.88) or blond (HR=0.52; 95% CI: 0.29–0.94) hair were also favorably prognostic. Higher fish consumption was of borderline significance for improved survival only when considered independently (HR=0.65; 95% CI: 0.40–1.05); no association was seen following adjustment for red meat and fruit consumption (p>0.10). Conclusions Dietary choices at the time of diagnosis are associated with melanoma-specific survival in patients with melanomas more than 1.00 mm thick. Further validation of our findings in larger cohorts with repeated post-diagnostic measures is warranted to further evaluate whether dietary

  12. A Bayesian destructive weighted Poisson cure rate model and an application to a cutaneous melanoma data.

    PubMed

    Rodrigues, Josemar; Cancho, Vicente G; de Castro, Mário; Balakrishnan, N

    2012-12-01

    In this article, we propose a new Bayesian flexible cure rate survival model, which generalises the stochastic model of Klebanov et al. [Klebanov LB, Rachev ST and Yakovlev AY. A stochastic-model of radiation carcinogenesis--latent time distributions and their properties. Math Biosci 1993; 113: 51-75], and has much in common with the destructive model formulated by Rodrigues et al. [Rodrigues J, de Castro M, Balakrishnan N and Cancho VG. Destructive weighted Poisson cure rate models. Technical Report, Universidade Federal de São Carlos, São Carlos-SP. Brazil, 2009 (accepted in Lifetime Data Analysis)]. In our approach, the accumulated number of lesions or altered cells follows a compound weighted Poisson distribution. This model is more flexible than the promotion time cure model in terms of dispersion. Moreover, it possesses an interesting and realistic interpretation of the biological mechanism of the occurrence of the event of interest as it includes a destructive process of tumour cells after an initial treatment or the capacity of an individual exposed to irradiation to repair altered cells that results in cancer induction. In other words, what is recorded is only the damaged portion of the original number of altered cells not eliminated by the treatment or repaired by the repair system of an individual. Markov Chain Monte Carlo (MCMC) methods are then used to develop Bayesian inference for the proposed model. Also, some discussions on the model selection and an illustration with a cutaneous melanoma data set analysed by Rodrigues et al. [Rodrigues J, de Castro M, Balakrishnan N and Cancho VG. Destructive weighted Poisson cure rate models. Technical Report, Universidade Federal de São Carlos, São Carlos-SP. Brazil, 2009 (accepted in Lifetime Data Analysis)] are presented.

  13. Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma.

    PubMed

    Manusow, Joshua S; Khoja, Leila; Pesin, Nataly; Joshua, Anthony M; Mandelcorn, Efrem D

    2014-01-01

    We report on a 36-year-old woman treated with the anti PD-1 antibody Pembrolizumab for metastatic cutaneous melanoma in the first line setting. She achieved a complete response and then relapsed with metastases to the vitreous cavity with an associated angiographically determined retinal vasculitis. Vitreous metastasis without choroidal involvement is unusual and may be due to individual cell extravasation, vitreous hemorrhage containing malignant cells, or direct spread through the optic nerve. This finding highlights the need for immune sanctuary sites to be monitored in the presence of PD-1 inhibition and we hypothesize that the use of PD-1 inhibitor potentiated the patient's angiographically determined retinal vasculitis. PMID:25516805

  14. 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

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

    PubMed

    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

  16. Ipilimumab for advanced melanoma: experience from the Spanish Expanded Access Program

    PubMed Central

    Arance, Ana; Lopez Martin, Jose Antonio; Soriano, Virtudes; Muñoz, Eva; Alonso, Lorenzo; Espinosa, Enrique; Lopez Criado, Pilar; Valdivia, Javier; Martin Algarra, Salvador

    2014-01-01

    Ipilimumab, a fully human, recombinant, monoclonal antibody to cytotoxic T-lymphocyte antigen 4 improves overall survival (OS) in previously treated and untreated metastatic melanoma. This retrospective analysis reports data gathered by a questionnaire on the demographics, outcomes, and toxicity of ipilimumab administered through an Expanded Access Program (EAP). Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for four cycles to adults with metastatic melanoma. Efficacy outcomes included complete response, partial response (PR), progressive disease, stabilized disease, and OS. EAP data were collected from EAP physicians. A subgroup analysis examined efficacy in elderly patients (≥70 years) and factors predictive of survival were identified. Of 355 requests for ipilimumab, resulting in 288 treatments, completed questionnaires were received for 153 ipilimumab recipients (median age 58 years, 57.2% men). Efficacy was evaluated in 144 patients: complete response in 1.3%, PR in 9.6%, PR with previous progression 8.4%, stabilized disease in 14.5%, and progressive disease in 66.2%. The median OS was 6.5 months (199 days); 1-year survival was 32.9%. Predictive survival factors included lymphocytes over 1000/ml (P=0.0008) and lactate dehydrogenase more than 1.5×upper limit of normal (P=0.003). Cutaneous, hepatic, and gastrointestinal toxicities were mild. In 30 patients aged more than 70 years, ipilimumab efficacy and tolerability was similar to that of the overall population. In the clinical practice setting, ipilimumab is effective and well tolerated in patients with advanced melanoma, including elderly patients, when administered at the recommended dosage. Ipilimumab improves treatment options for patients who, until recently, have had little hope of an improved prognosis. PMID:25046550

  17. Pembrolizumab for Treatment of Patients with Advanced or Unresectable Melanoma.

    PubMed

    Sullivan, Ryan J; Flaherty, Keith T

    2015-07-01

    From Coley's toxin to combination immune checkpoint inhibition, strategies to activate the immune system and generate anticancer immunity have been ongoing for well over a century. Over the past decade, the so-called immune checkpoint inhibitors, generally monoclonal antibodies that target key regulators of T-cell activation, emerged as the most effective immune-targeted agents. Pembrolizumab is the first anti-programmed death 1 (PD-1) antibody approved by the FDA for the treatment of metastatic melanoma. With responses seen in 25% to 40% of patients, depending on dose and setting (i.e., before or after ipilimumab), pembrolizumab specifically and anti-PD-1 antibodies generally are revolutionizing the treatment of melanoma. However, in the setting of other recent advances in the field, a number of practical issues are emerging that need to be addressed to optimize the care of patients with melanoma. First, the optimal sequencing of therapy (first-line immunotherapy over molecular targeted therapy, ipilimumab versus pembrolizumab as initial immune checkpoint inhibitor) is unknown and must be evaluated through randomized trials. Second, there is a strong rationale to combine immune checkpoint inhibitors (i.e., anti-PD-1 with ipilimumab) and to combine immune therapies with targeted therapy agents, so determining whether combination therapy is better than direct sequencing is another critical issue that needs to be addressed in carefully carried out studies.

  18. 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…

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

    PubMed

    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 gasses.

  20. 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.

  1. Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas.

    PubMed Central

    Chi, D. D.; Merchant, R. E.; Rand, R.; Conrad, A. J.; Garrison, D.; Turner, R.; Morton, D. L.; Hoon, D. S.

    1997-01-01

    Both melanocytes and glial cells are derived embryologically from the neural ectoderm. Their malignant transformed counterparts, melanoma and glioma cells, respectively, may share common antigens. Numerous tumor-associated antigens have been identified in melanomas but only a few a gliomas. Using an established reverse transcriptase polymerase chain reaction plus Southern blot assay, we compared the mRNA expression of melanoma-associated antigens (MAAs) of melanomas to brain tumors primarily derived from glial cells. The MAAs studied included tyrosinase (Tyr), tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2), gp100, human melanoma antigen-encoding genes 1 and 3 (MAGE-1 and MAGE-3), and melanotransferrin (p97). Glioblastoma multiforme (n = 21), anaplastic astrocytoma (n = 3), ependymoma (n = 2), meningioma (n = 3), oligodendroglioma (n = 1), and melanoma (n = 12) tumor specimens were assayed for MAA mRNA expression. Glioblastoma multiforme, astrocytoma, and melanoma cell lines were also assayed. We observed that individual MAA mRNAs were expressed in these brain tumors and cell lines at varying frequencies. The melanogenesis-pathway-related MAAs Tyr, TRP-1, TRP-2, and gp100 mRNAs were also expressed at different levels in normal brain tissues but at a much lower frequency than in glioblastoma multiforme and melanoma. MAGE-1 and MAGE-3 mRNA were expressed in different types of tumor specimens and cell lines but never in normal brain tissue. Tumor antigen p97 was expressed in all types of tumors and also in normal brain tissues. These studies demonstrate that melanomas and primary brain tumors express common MAAs and could be exploited in patients with malignant glioma by active specific immunotherapy against these common MAAs. Images Figure 1 Figure 2 Figure 3 PMID:9176405

  2. Immunohistochemical detection of CDK4 and p16INK4 proteins in cutaneous malignant melanoma.

    PubMed

    Wang, Y L; Uhara, H; Yamazaki, Y; Nikaido, T; Saida, T

    1996-02-01

    p16INK4 gene, which encodes a specific inhibitor of cyclin-dependent kinase 4 (CDK4), has been recently reported as an important tumour suppressor gene. It is mapped to chromosome 9p21, which is frequently deleted or mutated in many tumour cell lines including malignant melanoma. Since the CDK4/cyclin D complex propels a cell to go through the G1 check point of the cell cycle, a critical phase of cell division, alteration of the p16INK4 gene could lead a cell to uncontrolled proliferation and malignant transformation. To clarify any role for p16INK4 and CDK4 proteins in the development of human malignant melanoma, we have examined, immunohistochemically, the expression of these two proteins in melanocytic neoplasms including 19 primary lesions of non-familial melanoma. Intense nuclear and/or cytoplasmic expression of the CDK4 protein was observed in 11 of 19 cases (58%) of melanoma. In contrast, virtually no nuclear or cytoplasmic staining for CDK4 protein was detected in 28 benign melanocytic naevi, including six Spitz naevi. Expression of p16INK4 protein was observed in three of 19 melanomas (16%) and in 17 of 28 benign naevi (61%). Inverse expression of CDK4 and p16INK4, at individual cell level, was detected in one case of melanoma. The present study suggests that CDK4 overexpression is characteristic for malignant melanoma, and probably reflects its autonomous accelerated cell proliferation. The expression rate of p16INK4 protein in malignant melanoma was lower than that in benign naevi, although the significance of p16INK4 deletion in melanoma development has not been definitely confirmed.

  3. 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

  4. Time trends in incidence of cutaneous melanoma by detailed anatomical location and patterns of ultraviolet radiation exposure: a retrospective population-based study.

    PubMed

    Gordon, Daniela; Gillgren, Peter; Eloranta, Sandra; Olsson, Henrik; Gordon, Max; Hansson, Johan; Smedby, Karin E

    2015-08-01

    Given the wide public health implications of the melanoma epidemic, ultraviolet radiation (UVR) exposure patterns contributing to cutaneous melanoma development should be clearly identified. To describe time trends of anatomic sites of melanoma using a UVR exposure model based on clothing and sun habits, we reviewed the medical records of all patients diagnosed with primary invasive melanoma or melanoma in situ (MIS) during the years 1977-78, 1983-84, 1989-90, 1995-96, and 2000-01 (n=3058) in one healthcare region of Sweden. Age-standardized incidence rates and relative risks (RRs) of melanoma by calendar period were estimated for intermittent and chronic UVR exposure sites. From 1977-78 to 2000-01, the incidence rates of all melanomas at intermittent UVR exposure sites increased both among men (7.8-16.5/10 person-years) and among women (7.6-14.6/10 person-years), with a sex-adjusted and age-adjusted RR of 2.1 [95% confidence interval (CI) 1.8-2.4, Ptrend<0.0001]. This increase was evident for both invasive melanoma and MIS. Melanoma at chronic sites increased among men from 1.7 to 2.3/10 person-years, and among women from 1.4 to 1.8/10 person-years, with a corresponding adjusted RR of 1.4 (95% CI 1.0-1.9, Ptrend=0.01), driven primarily by MIS. For melanomas at intermittent UVR exposure sites, the male sex was positively associated with central (core) areas (chest, back, neck, shoulders, thighs; RR 1.7, 95% CI 1.5-1.9), but negatively associated with peripheral areas (lateral arms, lower legs, dorsum of feet; RR 0.3, 95% CI 0.3-0.4), compared with the female sex. Sex-specific intermittent UVR exposure patterns drove the observed increase in melanoma incidence, whereas chronic UVR exposure contributed less.

  5. [Immune Checkpoint Inhibitors for Advanced Melanoma - Evidences and Future Perspectives].

    PubMed

    Nakamura, Yasuhiro; Teramoto, Yukiko; Asami, Yuri; Matsuya, Taisuke; Yamamoto, Akifumi

    2016-09-01

    Recently developed immune checkpoint inhibitors, such as anti-PD-1 antibodies, have shown a clear improvement in clinical efficacy compared with conventional cytotoxic chemotherapy in the treatment of patients with advanced melanoma. Treatment with anti-PD-1 antibodies has resulted in improved objective response rates, longer durations of response, and longer overall survival rates. Although the incidence rate of adverse events associated with anti-PD-1 antibodies is lower than that associated with cytotoxic agents, characteristic severe adverse events such as pneumonia, endocrinopathy, and colitis can occur. A recent clinical trial that evaluated the utility of an anti-PD-1 antibody in combination with an anti-CTLA-4 antibody reported that the treatment enhanced clinical efficacy in terms of response rate and progression-free survival. However, the incidence of adverse events and treatment discontinuation also increased. For optimal selection of immune checkpoint inhibitors for treating patients with advanced melanoma, biomarkers capable of predicting clinical efficacy, prognosis, and adverse events in each patient need to be identified. In addition, novel combination therapies, including immune checkpoint inhibitors and MAP kinase pathway-targeting agents, should result in more favorable clinical responses and prolonged overall survival rates. PMID:27628544

  6. 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

  7. 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

  8. MicroRNA-21 expression and its pathogenetic significance in cutaneous melanoma.

    PubMed

    Saldanha, Gerald; Potter, Linda; Lee, Yee Shin; Watson, Sophie; Shendge, Priya; Pringle, James H

    2016-02-01

    Identification of prognostic biomarkers is timely for melanoma as clinicians seek ways to stratify patients for molecular therapy. MicroRNAs are promising as tissue biomarkers because they can be assayed directly from formalin-fixed paraffin-embedded clinical samples. We previously reported that microRNA-21 (miR-21) was strongly expressed in melanoma relative to naevi and now sought to further assess the significance of this by assessing its relationship with its putative target, PTEN. Clinical melanoma samples were analysed by immunohistochemical analysis for PTEN, stem-loop qRT-PCR for miR-21 and PCR for BRAF/NRAS mutation status. Cell lines were investigated for the effect of anti-miR-21 on PTEN. A total of 81 clinical melanocytic tumour samples were investigated, with uniformly high PTEN expression in the nucleus and cytoplasm of naevi and with preferential loss of PTEN expression in the nucleus of melanoma cells. miR-21 expression was inversely associated with nuclear PTEN expression but not with cytoplasmic PTEN expression. An anti-miR-21 preferentially altered nuclear PTEN in melanoma cell lines. The presence of a BRAF or NRAS mutation had no significant effect on miR-21 expression. These data suggest miR-21 may exert an oncogenic effect in melanoma by favouring redistribution of PTEN to the nucleus.

  9. 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

  10. 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

  11. 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

  12. 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

  13. [Cutaneous malignant melanoma: a retrospective study of seven years (2006-2012)].

    PubMed

    Moreira, Jorge; Moreira, Elisabete; Azevedo, Filomena; Mota, Alberto

    2014-01-01

    Introdução: O melanoma maligno é a neoplasia cutânea mais agressiva, e a sua incidência tem vindo a aumentar nas últimas décadas. A possibilidade de cura depende de um diagnóstico atempado, sendo fundamental o conhecimento da sua epidemiologia para a implementação de programas de prevenção primária e deteção precoce do melanoma. Material e Métodos: Foi efetuada revisão dos processos clínicos dos doentes com melanoma maligno cutâneo primário, diagnosticados entre janeiro de 2006 e dezembro de 2012, no Centro Hospitalar de São João, Porto. Resultados: Analisaram-se os 148 casos de melanoma diagnosticados neste período, tendo-se observado um predomínio do sexo feminino (razão F:M - 1,6:1). A média etária na altura do diagnóstico foi de 61 anos. As localizações mais frequentemente envolvidas foram os membros inferiores e o tronco. No sexo masculino o dorso foi o local mais afetado, enquanto no sexo feminino as lesões ocorreram, preferencialmente, nas pernas. O melanoma de extensão superficial foi o subtipo predominante em quase todas as faixas etárias. Verificou-se um predomínio dos melanomas finos e o índice mitótico foi intermédio (1-6 mitoses/ mm2) na maioria dos doentes. A ulceração esteve presente em 22,3% dos casos e predominou nos melanomas espessos e no subtipo nodular. A maioria dos doentes encontrava-se no estádio IA. A progressão para doença metastática ocorreu em 20 doentes. Discussão: O perfil do doente com melanoma cutâneo, no Centro Hospitalar de São João, apresenta características relativamente semelhantes às descritas na literatura. Conclusão: O predomínio dos melanomas finos, considerados de melhor prognóstico, é provavelmente, o resultado de um diagnóstico cada vez mais precoce.

  14. [Clinical studies and accepted therapies of advanced melanoma].

    PubMed

    Liszkay, Gabriella

    2016-03-01

    The objective of the work is presentation of the available therapeutic results of the clinical trials with anti CTLA-4 and anti PD-1 treatment, which are operating on the immune checkpoints registered in advanced melanoma, and the results of T-VEC vaccination (NCT00094653, NCT00324155, KEYNOTE-001, -002, -006, CheckMate-066, -037, -067, NCT00769704). With ipilimumab therapy, long-term survival can be achieved in the case of 20% of patients, with low (10%) therapeutic response, and grade 3-4 treatment related, predominantly autoimmune adverse events occurring in 10-15% of patients. Anti-PD-1 therapy proved more effective compared to ipilimumab, resulting in 21-40% therapeutic response, with 60-74% one-year survival rate and significantly less severe and frequent side effects. Progression-free survival achieved with ipilimumab/nivolumab combination was 11.5 months with grade 3-4 side effects occurring in 55% of patients. T-VEC therapy resulted in 26.4% objective response rate without a significant survival advantage. In the possession of the new immunotherapeutic possibilities, knowledge of the results of clinical studies is essential for the optimal complex therapy of melanoma. PMID:26934345

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

    PubMed Central

    Shi, Jianxin; Yang, Xiaohong R.; Ballew, Bari; Rotunno, Melissa; Calista, Donato; Fargnoli, Maria Concetta; Ghiorzo, Paola; Paillerets, Brigitte Bressac-de; 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

    2014-01-01

    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 POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of 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 American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations. PMID:24686846

  16. Risk factors for cutaneous malignant melanoma among aircrews and a random sample of the population

    PubMed Central

    Rafnsson, V; Hrafnkelsson, J; Tulinius, H; Sigurgeirsson, B; Hjaltalin, O

    2003-01-01

    Aims: To evaluate whether a difference in the prevalence of risk factors for malignant melanoma in a random sample of the population and among pilots and cabin attendants could explain the increased incidence of malignant melanoma which had been found in previous studies of aircrews. Methods: A questionnaire was used to collect information on hair colour, eye colour, freckles, number of naevi, family history of skin cancer and naevi, skin type, history of sunburn, sunbed, all sunscreen use, and number of sunny vacations. Results: The 239 pilots were all males and there were 856 female cabin attendants, which were compared with 454 males and 1464 females of the same age drawn randomly from the general population. The difference in constitutional and behavioural risk factors for malignant melanoma between the aircrews and the population sample was not substantial. The aircrews had more often used sunscreen and had taken more sunny vacations than the other men and women. The predictive values for use of sunscreen were 0.88 for pilots and 0.85 for cabin attendants and the predictive values for sunny vacation were 1.36 and 1.34 respectively. Conclusion: There was no substantial difference between the aircrew and the random sample of the population with respect to prevalence of risk factors for malignant melanoma. Thus it is unlikely that the increased incidence of malignant melanoma found in previous studies of pilots and cabin attendants can be solely explained by excessive sun exposure. PMID:14573711

  17. 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

  18. 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

  19. 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

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

    PubMed

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

    2012-01-01

    Unlike breast and prostate cancers, the nature and sequence of critical genetic and epigenetic events involved in the initiation and progression of melanoma are 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.

  1. 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

  2. Epigenetic inactivation of tumor suppressor genes in serum of patients with cutaneous melanoma.

    PubMed

    Marini, Alessandra; Mirmohammadsadegh, Alireza; Nambiar, Sandeep; Gustrau, Annett; Ruzicka, Thomas; Hengge, Ulrich R

    2006-02-01

    Small amounts of cell-free DNA circulate in both healthy and diseased human blood, while increased concentrations of DNA are present in the serum of cancer patients. Tumor-specific mutations or epigenetic modifications have predominantly been detected in tissue specimens. The purpose of this study was to investigate methylation of five different genes involved in tumor suppression and DNA repair (suppressors of cytokine signaling 1 and 2 (SOCS1, SOCS2)), Ras-association domain family protein 1A (RASSF1a), D-type p16(INK4a) cyclin-dependent kinase inhibitor (CDKN), and O6-methylguanine DNA-methyltransferase (MGMT)) in the serum of 100 patients using methylation-specific PCR. In all, 41 melanoma patients (stage I = 18; stage II = 10; stage III/IV = 13), 13 healthy controls without nevi, and 10 individuals with more than 15 nevi of >5 mm in size were investigated. For comparison, sera from patients with other skin tumors (nine basal cell cancers, five Kaposi's sarcoma), different metastasized cancers (five breast cancers, five colon cancers), and several chronic inflammatory diseases (n = 12) were also analyzed. In addition, we examined if methylation was involved in silencing transcription of these genes in 12 melanoma specimens. SOCS1, SOCS2, RASSF1a, CDKN2a, and MGMT were methylated in 75, 43, 64, 75, and 64% of melanoma samples, respectively. Of the 41 melanoma patients, 83% had one hypermethylated gene, while 66, 51, and 41% had two, three, or four hypermethylated genes, respectively. Also, 20% of these patients showed hypermethylation for all genes, while only 17% showed no methylation. Importantly, the methylation profile of the selected genes from melanoma patients was distinct from the other analyzed tumors. Transcription of SOCS1, SOCS2, CDKN2a, and RASSF1a genes was significantly reduced in fresh melanoma samples, while MGMT showed a 12-fold upregulation at the messenger ribonucleic acid level (P < 0.001). Our findings suggest that epigenetic silencing of

  3. [Late metastases of cutaneous malignant melanoma on the abdominal wall to the small and large bowel].

    PubMed

    Füredi, Gábor; Altorjay, Aron; Varga, István; Illés, Iván; Kovács, Csaba; Békefi, Péter; Molnár, Anna

    2005-08-01

    We describe the case of a 56 years old man, who was operated on with abdominal wall skin malignant melanoma 5 years ago. He received postoperative DTIC + Intron A treatment. Five years later he presented with complaints of epigastric pain, melena, hematochezia, anorexia and fatigue. Upper gastrointestinal tract endoscopy showed a tumour mass in the duodeno-jejunal flexure and colonoscopy showed a tumour in the large bowel. Histology verified anaplastic carcinoma. The patient was operated on. We found metastases in the small and the large bowel The patient underwent resection of the jejunum and right hemicolectomy. We describe the different types of metastases of malignant melanomas symptoms, therapies and prognosis.

  4. Surviving cutaneous melanoma: a clinical review of follow-up practices, surveillance, and management of recurrence.

    PubMed

    Mrazek, Amy A; Chao, Celia

    2014-10-01

    The number of melanoma survivors in the United States continues to steadily increase 2.6% per year, while death rates have remained stable over time. Although controversy exists regarding optimal surveillance strategies, recommendations for clinical monitoring are based on tumor stage, tumor phenotype, likelihood of recurrence, prognosis, risk factors, psychosocial impact of disease, and patient well-being. Management guidelines for recurrent disease depend on the type of recurrence: local, satellite/in-transit, regional, or distant metastasis. This article is a current review of the literature concerning melanoma survivorship.

  5. 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

  6. 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

  7. Fully Regressive Melanoma

    PubMed Central

    Ehrsam, Eric; Kallini, Joseph R.; Lebas, Damien; Modiano, Philippe; Cotten, Hervé

    2016-01-01

    Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. AH of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis.

  8. Fully Regressive Melanoma

    PubMed Central

    Ehrsam, Eric; Kallini, Joseph R.; Lebas, Damien; Modiano, Philippe; Cotten, Hervé

    2016-01-01

    Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. AH of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis. PMID:27672418

  9. 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 ...

  10. 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

    2016-11-03

    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

  11. Nodular malignant melanoma and multiple cutaneous neoplasms under immunosuppression with azathioprine.

    PubMed

    Guenova, Emmanuella; Lichte, Verena; Hoetzenecker, Wolfram; Woelbing, Florian; Moehrle, Matthias; Roecken, Martin; Schaller, Martin

    2009-08-01

    Immunosuppressed patients are at increased risk of skin cancer. A 67-year-old renal transplant recipient developed a nodular malignant melanoma after 30 years of immunosuppression with azathioprine and prednisolone. The patient died of metastatic disease 3 months after the diagnosis was made. The function of the renal graft was not affected at all. Renal transplant recipients are at high risk of developing nonmelanocytic skin tumors when on immunosuppressive therapy with cyclosporine A. Less common is the development of skin cancer during immunosuppression with azathioprine. Latest reports show the increased incidence of malignant melanoma in immunosuppressed patients. Our case illustrates the necessity of close dermatological surveillance of allograft recipients, to assure an early recognition of any malignant skin tumor and to reduce the risk of systemic metastatic disease. PMID:19550360

  12. 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

  13. 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

  14. Inguinal or inguino-iliac/obturator lymph node dissection after positive inguinal sentinel lymph node in patients with cutaneous melanoma

    PubMed Central

    Glumac, Nebojsa; Hocevar, Marko; Zadnik, Vesna; Snoj, Marko

    2012-01-01

    Background The aim of the study was to determine whether the presence of inguinal sentinel lymph node (SLN) metastases smaller than 2 mm (micrometastases) subdivided according to the number of micrometastases predicts additional, non-sentinel inguinal, iliac or obturator lymph node involvement in completion lymph node dissection (CLND). Patients and methods. Positive inguinal SLN was detected in 58 patients (32 female, 26 male, median age 55 years) from 743 consecutive and prospectively enrolled patients with primary cutaneous melanoma stage I and II who were treated with SLN biopsy between 2001 and 2007. Results Micrometastases in inguinal SLN were detected in 32 patients, 14 were single, 2 were double, and 16 were multiple. Twenty-six patients had macrometastases. Conclusions No patient with any micrometastases or a single SLN macrometastasis in the inguinal region had any iliac/obturator non-sentinel metastases after CLND in our series. Furthermore, no patient with single SLN micrometastasis in the inguinal region had any non-sentinel metastases at all after CLND in our series. In these cases respective CLND might be omitted. PMID:23077465

  15. Spotlight on pembrolizumab in the treatment of advanced melanoma.

    PubMed

    Rajakulendran, Thanashan; Adam, David N

    2015-01-01

    Metastatic melanoma is an aggressive cancer with a poor prognosis. Many approved therapies often do not achieve durable responses in patients. This underscores the need for novel therapeutic strategies. Recruiting a robust immune response is an important antineoplastic treatment strategy. Immune checkpoints offer a molecular target for modulating the immune response and a promising therapeutic target in metastatic melanoma. Here we discuss the recent approval of pembrolizumab by the US Food and Drug Administration for the treatment of metastatic melanoma and its impact on future management of the disease.

  16. 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

  17. 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

  18. Integrating first-line treatment options into clinical practice: what's new in advanced melanoma?

    PubMed

    Dummer, Reinhard; Schadendorf, Dirk; Ascierto, Paolo A; Larkin, James; Lebbé, Celeste; Hauschild, Axel

    2015-12-01

    Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients. PMID:26426764

  19. 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

  20. 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.

  1. 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

  2. Clinicopathologic characteristics and management trends of cutaneous invasive and in situ melanoma in older patients: a retrospective analysis of the National Cancer Data Base

    PubMed Central

    Shrestha, Rajesh; Krishnamurthy, Jairam; Mosalpuria, Kailash; Loberiza, Fausto R.; Ganti, Apar Kishor; Silberstein, Peter T.

    2015-01-01

    Background: The incidence of melanoma in older patients is on the rise. Prior studies have shown disparities in surgical management and poor survival of older patients with melanoma. Methods: This is a retrospective study of adult patients diagnosed with cutaneous invasive and in situ melanoma between 2000 and 2011 in the National Cancer Data Base. Characteristics and management of older patients (≥60 years) were compared with younger patients (20–59 years) using χ2 testing. Results: Of 476,623 total cases, 54% (n = 258,153) were diagnosed among older patients. The reported cases in the older patients increased by 1.74-fold between 2000 and 2011. The majority were white (96%), men (65%), with early-stage disease (76% stage 0-II), and superficial spreading melanoma histology (39%). Older patients, compared with younger patients, were more likely to be men (65% versus 49%, p < 0.0001), and have in situ melanoma (28% versus 21%, p < 0.0001); less likely to have nodal metastases (7% versus 9%, p < 0.0001), receive care in academic centers (30% versus 35%, p < 0.0001), undergo wide excision or major amputation for stage I–III disease (68% versus 72%, p < 0.0001) and systemic therapy for stage III (18% versus 45%, p < 0.0001) and IV disease (30% versus 50%, p < 0.0001). Conclusion: Older patients with melanoma are less likely to receive care in academic centers, undergo wide excision for stage I–III disease and receive systemic therapy for stage III–IV disease. Particularly, the utilization of systemic therapy is markedly low. This disparity is particularly important with the availability of less intense more effective therapies. PMID:25553079

  3. Recent advances in cytokines in cutaneous and systemic lupus erythematosus.

    PubMed

    Mikita, Naoya; Ikeda, Takaharu; Ishiguro, Mariko; Furukawa, Fukumi

    2011-09-01

    Lupus erythematosus (LE) includes a broad spectrum of diseases from a cutaneous-limited type to a systemic type. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which affects multiple organs. Cutaneous lupus erythematosus (CLE) includes skin symptoms seen in SLE and cutaneous-limited LE. Although immune abnormalities, as well as heritable, hormonal and environmental factors, are involved in the pathology of LE, the actual pathogenesis is still unclear. Recently, the involvement of various cytokines has been shown in the pathogenesis of LE. Moreover, some trials with biological agents targeted specific cytokines are also ongoing for SLE. In this article, we review the contributions of major cytokines such as interferon, tumor necrosis factor-α and interleukin-18 to LE, especially SLE and CLE.

  4. Seasonal variation in the occurrence of cutaneous melanoma in Europe: influence of latitude. An analysis using the EUROCARE group of registries.

    PubMed

    Boniol, Mathieu; De Vries, Esther; Coebergh, Jan Willem; Doré, Jean-François

    2005-01-01

    The aim of our study was to analyse seasonal variations in melanoma incidence in Europe. Data from 28117 cutaneous melanoma cases reported during 1978-1993 to the EUROCARE group of registries were analysed. There is a clear summer peak in incidence in Western countries (summer-winter ratio: 1.31 P < 0.0001; Nam's test), which was not observed in Central Europe (ratio: 1.06; P = 0.0699). The amplitude of seasonality is higher for females (ratio = 1.38, 95% Confidence Interval (CI) [1.31-1.44]) than for males (ratio = 1.21 95%CI [1.14-1.29]). It is also higher for upper and lower limbs (1.44 and 1.46, respectively), than for head and neck or trunk regions (1.09 and 1.20, respectively). The amplitude of seasonality also varies with latitude and increases with time: in a linear regression adjusting for age, gender and anatomical localisation, the date of diagnosis was significantly closer to summer solstice with decreasing latitude (P = 0.0005) and for more recent year of diagnosis (P = 0.0123). The effect of latitude on the amplitude of the seasonal variation in melanoma incidence in Europe may be an indicator of ultraviolet B (UVB) exposure. Furthermore, an increase in intentional sun exposure could lead to an increase in melanoma promotion and thus to an increase in the amplitude of seasonal variation.

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

    PubMed

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

    2016-04-01

    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. Multivariate 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 (P(trend)=0.003). Further analysis explored a multiplicative interaction between the sensitivity to 4-NQO and a family history of skin cancer (P(interaction)=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 chromotid breaks.

  6. 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

  7. Sun exposure, pigmentary traits, and risk of cutaneous malignant melanoma: a case-control study in a Mediterranean population.

    PubMed

    Ródenas, J M; Delgado-Rodríguez, M; Herranz, M T; Tercedor, J; Serrano, S

    1996-03-01

    The main objective of this study was to assess the influence of sun exposure and pigmentary traits on the risk of cutaneous malignant melanoma (CMM) in a Mediterranean population (Andalusia, southern Spain). Cases and controls were selected from 1988 to 1993. The study population included 105 incident cases with non-familial CMM (ICD-9 code 172) and 138 controls aged 20 to 79 years. Data were collected by personal interview, and melanocytic nevi were counted over the entire body surface. Crude, and multiple-risk factor adjusted, odds ratios (OR) and their 95 percent confidence intervals (CI) were computed. After adjustment, the major constitutional risk factor was skin type I-II (OR = 29.8, CI = 8.9-100) compared with skin type V. Statistically significant and positive trends were observed between the risk of CMM and occupational sun exposure of the skin (P = 0.003), recreational exposure (P < 0.001), and cumulative lifetime sun exposure (P < 0.001). Several characteristics related to sun exposure during summer increased the CMM risk, e.g., episodes of blistering sunburns and the number of sunbaths in childhood. Use of sunscreens and spending summer holidays in places other than beach were associated with a lower risk of CMM. Regarding pigmentary traits, CMM significantly occurred with more frequency in individuals with a high degree of freckling and quoted numbers of melanocytic nevi. In conclusion, the results support sun exposure and pigmentary traits (skin type, melanocytic nevi, and freckles) as main risk factors for CMM in this population.

  8. 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.

  9. Treatment patterns in advanced melanoma: findings from a survey of European oncologists.

    PubMed

    Jones, C; Zhao, Z; Barber, B; Bagijn, M; Corrie, P; Saltman, D

    2015-11-01

    With the emergence of new therapies, established patterns of treating advanced melanoma are changing. The aim of this study was to understand how advanced melanoma is treated in clinical practice in Europe following the introduction of ipilimumab and vemurafenib. An online survey was conducted between August and November 2012 with 150 oncologists and dermatologists, from France, Germany, Italy, Spain and the U.K.; respondents reported treating the majority of patients with one or two lines of therapy. For BRAF mutant melanoma, the most frequently used first-line treatments were vemurafenib and dacarbazine. For BRAF wild-type melanoma, the most frequently used first-line treatment was dacarbazine. There was no single preferred agent for the second-line treatment of BRAF mutant or BRAF wild-type disease. Most sequencing from first- to second-line was from conventional dacarbazine to newer agents such as ipilimumab and vemurafenib. The treatment of advanced melanoma is rapidly evolving due to the introduction of new agents. This study presents an early insight into access to the new agents, ipilimumab and vemurafenib, and clinical practice in several European countries.

  10. 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

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

    PubMed

    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

    2015-02-01

    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 with 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.

  12. 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

  13. DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice.

    PubMed

    Ojima, Ayako; Matsui, Takanori; Maeda, Sayaka; Takeuchi, Masayoshi; Inoue, Hiroyoshi; Higashimoto, Yuichiro; Yamagishi, Sho-ichi

    2014-04-01

    Epidemiological studies have suggested that diabetes is associated with an increased risk of cancer. However, the underlying molecular mechanism remains unclear. We investigated here whether DNA aptamer directed against advanced glycation end products (AGE-aptamer) inhibited melanoma growth in nude mice. G361 melanoma cells were injected intradermally into the upper flank of athymic nude mice. Mice received continuous intraperitoneal infusion (0.136 μg/day) of either AGE-aptamer (n=9) or Control-aptamer (n=8) by an osmotic mini pump. Tumor volume was measured at 4-day interval, and G361 melanoma was excised at day 43 after the aptamer treatment. We further examined the effects of AGE-aptamer on proliferation of AGE-exposed endothelial cells and G361 cells. AGE-aptamer significantly inhibited the in vivo-tumor growth of G361 melanoma. Immunohistochemical and western blotting analyses of G361 melanoma revealed that AGE-aptamer decreased expression levels of proliferating nuclear antigen, CD31 and Mac-3, markers of endothelial cells and macrophages, respectively. AGE-aptamer significantly decreased the number of tumor-associated vessels. AGE, receptor for AGE (RAGE) and vascular endothelial growth factor levels were also reduced in AGE-aptamer-treated G361 melanoma. AGE-aptamer inhibited the AGE-induced proliferation and tube formation of endothelial cells as well as the growth of G361 cells in vitro. The present findings suggest that AGE-aptamer could inhibit the AGE-RAGE axis in G361 melanoma and resultantly suppress the tumor growth in nude mice by blocking the angiogenesis. AGE-aptamer might be a novel therapeutic strategy for preventing the progression of malignant melanoma in diabetes.

  14. 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

  15. 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

  16. Prognostic significance of in situ and plasma levels of transforming growth factor β1, -2 and -3 in cutaneous melanoma.

    PubMed

    Tang, Ming-Rui; Wang, Yu-Xin; Guo, Shu; Han, Si-Yuan; Li, He-Huan; Jin, Shi-Feng

    2015-06-01

    Melanoma is an aggressive type of cutaneous malignancy. Transforming growth factor (TGF)‑β has been demonstrated to be an important mediator of tumor progression. However, to the best of our knowledge, the systemic roles of plasma TGF‑β and TGF‑β in situ have not been investigated in Han Chinese melanoma patients. The results of the present study demonstrated that the in situ and plasma levels of TGF‑β1, TGF‑β2 and TGF‑β3 protein and messenger RNA were significantly elevated in tumor tissues compared with those of normal tissues. The survival rates of the patients which were triple‑positive (TGF‑β1+, TGF‑β2+ and TGF‑β3+) were found to be markedly decreased compared to those which were single‑ (TGF‑β1+, TGF‑β2+ or TGF‑β3+) or double‑positive (TGF‑β1+, TGF‑β2+; TGF‑β2+, TGF‑β3+; or TGF‑β1+, TGF‑β3+). These results may therefore contribute to the use of TGF‑β as a prognostic biomarker, and to the development of novel therapies for melanoma treatment.

  17. Abnormal responses to the carcinogen 4-nitroquinoline 1-oxide of cultured fibroblasts from patients with dysplastic nevus syndrome and hereditary cutaneous malignant melanoma

    SciTech Connect

    Smith, P.J.; Greene, M.H.; Adams, D.; Paterson, M.C.

    1983-01-01

    The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). A putative role of host-environmental interactions in the etiology of hereditary melanoma has been strengthened by the recent finding that fibroblasts derived from HCMM/DNS patients demonstrated enhanced sensitivity to u.v.-irradiation in vitro. An extension of these studies is reported in which we have examined the invitro responses to a model environmental carcinogen, 4-nitroquinoline 1-oxide (4NQO), of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. Three of the six HCMM/DNS strains showed enhanced cell killing with sensitivities greater than that of a xeroderma pigmentosum (XP) variant strain but less than those of ataxia telangiectasia and XP Group D cell strains. The inhibition and recovery of de novo DNA synthesis, together with the expression of repair synthesis, following 4NQO exposure appeared to be normal in HCMM/DNS strains, irrespective of their subsequent clonogenic potential. The data point to a metabolic anomaly which may contribute to the carcinogenic risk of the melanoma prone preneoplastic state presented by some DNS patients.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. Of Mice and Melanoma: PDX System for Modeling Personalized Medicine.

    PubMed

    Hartsough, Edward J; Aplin, Andrew E

    2016-04-01

    Targeted therapies have advanced the treatment options for cutaneous melanoma, but many patients will progress on drug. Patient-derived xenografts (PDX) can be used to recapitulate therapy-resistant tumors. Furthermore, PDX modeling can be utilized in combination with targeted sequencing and phosphoproteomic platforms, providing preclinical basis for second-line targeted inhibitor strategies. See related article by Krepler et al., p. 1592.

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. Genome-wide association study identifies nidogen 1 (NID1) as a susceptibility locus to cutaneous nevi and melanoma risk

    PubMed Central

    Nan, Hongmei; Xu, Mousheng; Zhang, Jiangwen; Zhang, Mingfeng; Kraft, Peter; Qureshi, Abrar A.; Chen, Constance; Guo, Qun; Hu, Frank B.; Rimm, Eric B.; Curhan, Gary; Song, Yiqing; Amos, Christopher I.; Wang, Li-E; Lee, Jeffrey E.; Wei, Qingyi; Hunter, David J.; Han, Jiali

    2011-01-01

    We conducted a genome-wide association study on the number of melanocytic nevi reported by 9136 individuals of European ancestry, with follow-up replication in 3581 individuals. We identified the nidogen 1 (NID1) gene on 1q42 associated with nevus count (two linked single nucleotide polymorphisms with r2 > 0.9: rs3768080 A allele associated with reduced count, P = 6.5 × 10−8; and rs10754833 T allele associated with reduced count, P = 1.5 × 10−7). We further determined that the rs10754833 [T] was associated with a decreased melanoma risk in 2368 melanoma cases and 7432 controls [for CT genotype: odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.75–0.99, P = 0.04; for TT genotype: OR = 0.84, 95% CI = 0.71–0.98, P = 0.03]. Expression level of the NID1 locus was 2-fold higher for the rs10754833 T allele carriers than that with the CC genotype (P = 0.017) in the 87 HapMap CEU cell lines. The NID1 gene is a biologically plausible locus for nevogenesis and melanoma development, with decreased expression levels of NID1 in benign nevi (P = 3.5 × 10−6) and in primary melanoma (P = 4.6 × 10−4) compared with the normal skin. PMID:21478494

  10. Fully Regressive Melanoma: A Case Without Metastasis.

    PubMed

    Ehrsam, Eric; Kallini, Joseph R; Lebas, Damien; Khachemoune, Amor; Modiano, Philippe; Cotten, Hervé

    2016-08-01

    Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. AH of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis. PMID:27672418

  11. 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

  12. 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

  13. Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib

    PubMed Central

    Sosman, Jeffrey A.; Kim, Kevin B.; Schuchter, Lynn; Gonzalez, Rene; Pavlick, Anna C.; Weber, Jeffrey S.; McArthur, Grant A.; Hutson, Thomas E.; Moschos, Stergios J.; Flaherty, Keith T.; Hersey, Peter; Kefford, Richard; Lawrence, Donald; Puzanov, Igor; Lewis, Karl D.; Amaravadi, Ravi K.; Chmielowski, Bartosz; Lawrence, H. Jeffrey; Shyr, Yu; Ye, Fei; Li, Jiang; Nolop, Keith B.; Lee, Richard J.; Joe, Andrew K.; Ribas, Antoni

    2013-01-01

    BACKGROUND Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann–La Roche; ClinicalTrials.gov number, NCT00949702.) PMID:22356324

  14. Melanoma with gastric metastases

    PubMed Central

    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

  15. 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

  16. 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.

  17. New developments in the management of advanced melanoma - role of pembrolizumab.

    PubMed

    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.

  18. New developments in the management of advanced melanoma - role of pembrolizumab.

    PubMed

    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

  19. 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

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

    PubMed

    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

  1. 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

  2. Recombinant interferon alfa-2a, an active agent in advanced cutaneous T-cell lymphomas.

    PubMed

    Bunn, P A; Ihde, D C; Foon, K A

    1987-01-01

    The cutaneous T-cell lymphomas including mycosis fungoides and the Sézary syndrome, are indolent lymphomas with early systemic dissemination. Like the indolent B-cell lymphomas, they cannot be cured by currently available systemic chemotherapy so new systemic therapies need to be developed. A study of very high-dose recombinant interferon alfa-2a was, therefore, initiated in 20 patients with advanced cutaneous T-cell lymphoma (5 in stage II, 2 in stage III and 13 in stage IV). All patients were refractory to at least 2 standard therapies, including topical nitrogen mustard (18 patients), psoralens and ultraviolet A light (12 patients), total skin electron irradiation (14 patients) and systemic chemotherapy (16 patients). Nine out of 20 patients (45%; 95% confidence interval 25-69%) had either objective partial or complete responses within 3 months of starting treatment. Maximal response, however, often did not occur for at least one year. The median duration of response was 5.5 months and all complete responses lasted more than 2 years. Response frequencies were equal at both cutaneous and extracutaneous sites and in patients with or without prior chemotherapy. Toxicity was exhibited primarily as a flu-like syndrome consisting of fever, malaise, fatigue, anorexia and weight loss which necessitated dose reductions in all patients. Transient elevations in liver function and decreases in renal function and granulocyte counts occurred in some patients. It is concluded that interferon alfa-2a is highly active against advanced cutaneous T-cell lymphomas and that it should be studied in its early stages. It should also be evaluated in combination with other biological agents and with chemotherapy.

  3. 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

  4. Country of origin, age at migration and risk of cutaneous melanoma: a migrant cohort study of 1,100,000 Israeli men.

    PubMed

    Levine, Hagai; Afek, Arnon; Shamiss, Ari; Derazne, Estela; Tzur, Dorit; Astman, Nadav; Keinan-Boker, Lital; Mimouni, Daniel; Kark, Jeremy D

    2013-07-15

    Cutaneous melanoma (CM) is a common cancer with increasing incidence in many parts of the world where light-skinned populations live. We conducted a large-scale nationally representative migrant cohort study to assess country of origin and age at migration as predictors of CM, controlling for possible confounders. Data on 1,086,569 Israeli Jewish males, who underwent a general health examination before compulsory military service at ages 16-19 between the years 1967-2005, were linked to Israel National Cancer Registry to obtain incident CM up to 2006. Cox proportional hazards was used to model time to event. Overall, 1562 incident cases were detected during 19.3 million person-years of follow-up. Origin was a strong independent predictor of CM. Incidence was higher for European (hazard ratio [HR] = 4.08, 95% confidence interval [CI]: 3.55-4.67) and Israeli origin (HR = 2.92, 95% CI: 2.25-3.79) compared to N. African/Asian origin, adjusted for year of birth, years of education, residential socio-economic position, rural residence and body surface area (or height). Among those of European origin, the adjusted risk was significantly lower for those who immigrated after the age of 10 years (HR = 0.58, 95% CI: 0.45-0.73) but not for younger ages (HR = 1.02, 95% CI 0.84-1.23) compared to Israeli born. The high rates of CM among men of European origin and the almost twofold lower risk among those immigrating after age 10 provide solid support for the deleterious role of childhood sun exposure as a risk factor for melanoma. These findings will serve in directing public health and research efforts.

  5. Targeting KIT in Melanoma: A Paradigm of Molecular Medicine and Targeted Therapeutics

    PubMed Central

    Woodman, Scott E.; Davies, Michael A.

    2014-01-01

    Despite multiple clinical trials utilizing a spectrum of therapeutic modalities, melanoma remains a disease with dismal outcomes in patients with advanced disease. However, it is now clear that melanoma is not a single entity, but can be molecularly divided into subtypes that generally correspond to the anatomical location of the primary melanoma. Melanomas from acral lentiginous, mucosal, and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in the more common cutaneous tumors. Multiple case reports and early observations from clinical trials suggest that targeting mutant KIT with tyrosine kinase inhibitors is efficacious in KIT mutant melanoma. This review recounts what is known about the role of KIT in melanocyte maturation, our current understanding of KIT genetic aberrations in melanoma, and how this knowledge is being translated into clinical oncology. PMID:20457136

  6. 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

  7. 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

  8. 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

  9. 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.

  10. Novel approaches in melanoma prevention and therapy.

    PubMed

    Grimaldi, Antonio M; Cassidy, Pamela B; Leachmann, Sancy; Ascierto, Paolo A

    2014-01-01

    The incidence of cutaneous melanoma has risen at a rate significantly higher than that for other malignancies. This increase persists despite efforts to educate the public about the dangers of excess exposure to UV radiation from both the sun and tanning beds. Melanoma affects a relatively younger population and is notorious for its propensity to metastasize and for its poor response to current therapeutic regimens. These factors make prevention an integral component to the goal of decreasing melanoma-related mortality. Transformation of melanocytes into malignant melanoma involves the interplay between genetic factors, UV exposure, and the tumor microenvironment. The roles of UV radiation in the etiology of melanoma are mediated by both direct damage of DNA through formation of photoproducts and production of reactive oxygen species (ROS). Many of the promising antioxidant agents under development for the prevention of melanoma are derived from foodstuffs. B-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases that plays a role in regulating the MAP kinase/ERKs signaling pathway. About 50 % of melanomas harbor activating BRAF mutations. BRAF mutations are found in 59 % of the melanomas arising in skin with intermittent sun exposure, such as trunk and arms, as compared with only 23 % of the acral melanomas, 11 % of mucosal melanomas, and 0 % of uveal melanomas. Two new agents, ipilimumab and vemurafenib, have been shown to improve outcome of advanced melanoma as presented at the plenary session of the 2011 annual meeting of the American Society of Clinical Oncology. Vemurafenib is the first personalized compound which demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in metastatic melanoma harboring the BRAFV600 mutation and represents the first drug of a class that exerts its anti-proliferative activity through inhibition of a highly specific molecular target. GSK2118436 (dabrafenib), the

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. Genomic investigations of posterior uveal melanoma.

    PubMed

    Hovland, Peter G; Trempe, Clement

    2005-01-01

    The specific genetic mechanisms responsible for the malignant behavior of uveal melanoma are not known. Unlike cutaneous melanoma, epidemiologic studies have not demonstrated a definitive germline form of uveal melanoma, though familial melanoma and racial predilections occur. Molecular cytogenetic characterization of uveal melanoma suggests that somatic deletions of chromosome 3 are associated with a worse prognosis. Microarray technology has been used to characterize uveal melanoma gene expression and may provide tests useful for determining prognosis. As an improved understanding of the cellular mechanisms used by uveal melanoma is gained, new opportunities to adapt or design therapeutic approaches may emerge.

  18. 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

  19. 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.

  20. Uveal Melanoma

    PubMed Central

    Papastefanou, Vasilios P.; Cohen, Victoria M. L.

    2011-01-01

    Uveal melanoma is the most common primary intraocular malignancy and the leading primary intraocular disease which can be fatal in adults. In this paper epidemiologic, pathogenetic, and clinical aspects of uveal melanoma are discussed. Despite the advance in local ocular treatments, there has been no change in patient survival for three decades. Development of metastases affects prognosis significantly. Current survival rates, factors predictive of metastatic potential and metastatic screening algorithms are discussed. Proposed and emerging treatments for uveal melanoma metastases are also overviewed. Current advances in genetics and cytogenetics have provided a significant insight in tumours with high metastatic potential and the molecular mechanisms that underlie their development. Biopsy of those lesions may prove to be important for prognostication and to allow further research into genetic mutations and potential new therapeutic targets in the future. PMID:21773036

  1. Inclusion of populations at risk of advanced melanoma in an opportunistic targeted screening project involving general practitioners

    PubMed Central

    Rat, Cédric; Quereux, Gaelle; Grimault, Charlotte; Fernandez, Jérémy; Poiraud, Mickael; Gaultier, Aurélie; Chaslerie, Anicet; Pivette, Jacques; Khammari, Amir; Dreno, Brigitte; Nguyen, Jean-Michel

    2016-01-01

    Objective The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. Design This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. Setting Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. Patients Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. Main outcome measures Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. Results A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61–0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60–0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55–0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17–0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77–0.98]; p < 0.028). Conclusion This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. Key Points Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities.• Despite the involvement of general practitioners, the

  2. 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

  3. 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

  4. Conditional survival estimates improve over time for patients with advanced melanoma: results from a population-based analysis

    PubMed Central

    Xing, Yan; Chang, George J.; Hu, Chung-Yuan; Askew, Robert L.; Ross, Merrick I.; Gershenwald, Jeffrey E.; Lee, Jeffrey E.; Mansfield, Paul F.; Lucci, Anthony; Cormier, Janice N.

    2009-01-01

    Background Conditional survival (CS) has emerged as a clinically relevant measure of prognosis for cancer survivors. The objective of this analysis was to provide melanoma-specific CS estimates to help clinicians promote more informed patient decision-making. Methods Patients with melanoma and at least 5 years of follow-up were identified from the Surveillance Epidemiology and End Results (SEER) registry (1988–2000). Using the methods of Kaplan and Meier, stage-specific 5-year CS estimates were independently calculated for survivors for each year following diagnosis. Stage-specific multivariate Cox regression models including baseline survivor functions were used to calculate adjusted melanoma-specific CS for different subgroups of patients further stratified by age, gender, race, marital status, anatomic tumor location, and tumor histology. Results Five-year CS estimates for stage I patients remained constant at 97% annually, while for patients with stages II, III and IV disease, 5-year CS estimates from time 0 (diagnosis) to 5 years improved from 72% to 86%, 51% to 87%, and 19% to 84%, respectively. Multivariate CS analysis revealed that differences in stages II through IV CS based on age, gender and race decreased over time. Conclusions Five-year melanoma-specific CS estimates improve dramatically over time for survivors with advanced stages of disease. These prognostic data are critical to patients for both treatment and non-treatment related life decisions. PMID:20187100

  5. The receptor for advanced glycation end products influences the expression of its S100 protein ligands in melanoma tumors.

    PubMed

    Meghnani, Varsha; Wagh, Anil; Indurthi, Venkata S K; Koladia, Mohit; Vetter, Stefan W; Law, Benedict; Leclerc, Estelle

    2014-12-01

    Recent studies have suggested that the receptor for advanced glycation end products (RAGE) participates in melanoma progression by promoting tumor growth. However, the mechanisms of RAGE activation in melanoma tumors are not clearly understood. To get deeper insights into these mechanisms, we transfected a melanoma cell line, which was established from a human melanoma primary tumor, with RAGE, and studied the effect of RAGE overexpression on cell proliferation and migration in vitro. We observed that overexpression of RAGE in these cells not only resulted in significantly increased migration rates compared to control cells, but also in decreased proliferation rates (Meghnani et al., 2014). In the present study, we compared the growth of xenograft tumors established from RAGE overexpressing WM115 cells, to that of control cells. We observed that when implanted in mice, RAGE overexpressing cells generated tumors faster than control cells. Analysis of protein tumor extracts showed increased levels of the RAGE ligands S100B, S100A2, S100A4, S100A6 and S100A10 in RAGE overexpressing tumors compared to control tumors. We show that the tumor growth was significantly reduced when the mice were treated with anti-RAGE antibodies, suggesting that RAGE, and probably several S100 proteins, were involved in tumor growth. We further demonstrate that the anti-RAGE antibody treatment significantly enhanced the efficacy of the alkylating drug dacarbazine in reducing the growth rate of RAGE overexpressing tumors. PMID:25310905

  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. 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

  8. 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

  9. New Perspectives of “omics” Applications in Melanoma Research

    PubMed Central

    Rodríguez-Cerdeira, Carmen; Molares-Vila, Alberto

    2011-01-01

    Background: Oncoproteomics is the study of proteins and their interactions in a cancer cell by proteomic technologies and has the potential to revolutionize clinical practice, including cancer diagnosis. Recent technological advances in the analysis of the human genome have opened the door to improving our primitive understanding of the gene expression patterns in cancer. The examination of the phenotypic and (epi) genetic changes in cutaneous melanoma has identified several genes deemed central to the development and progression of melanoma. Methods: A review of the literature was performed to determine the role of epigenetic modifications in human melanoma. The role of array-based high-throughput gene expression analysis in understanding the specific genes involved as well as the pathways and the comparative gene expression patterns of primary and metastatic melanoma. The development and clinical application of selective pharmacologic agents are also discussed. Results: We identified several articles that have extensively studied the role of epigenetics in melanoma, further elucidating the complex processes involved in gene regulation and expression. Other studies utilizing gene microarray analysis and other whole genome approaches reveal a wide array of genes and expression patterns in human melanoma. Several genes have been identified as potential prognostic markers of tumor progression and overall clinical outcome. Conclusions: High-throughput gene expression analysis has had a major impact in melanoma research. Several gene expression platforms have provided insight into the gene expression patterns in melanoma. Such data will provide foundations for the future development of prognostic markers and improved targeted therapies for patients with melanoma. PMID:22253648

  10. Unusual clinical presentation of cutaneous malignant melanoma metastatic to the parotid gland; initially discovered by fine needle aspiration: case report and review of literature.

    PubMed

    Elshenawy, Yasmin; Youngberg, George; Al-Abbadi, Mousa A

    2011-05-01

    We report a case of malignant melanoma (MM) metastatic to the parotid gland, initially discovered on fine needle aspiration (FNA). The patient presented with a mass in the parotid gland area with previous history only significant for prostatic carcinoma. The initial FNA impression was melanoma. The smears were hypercellular with bloody necrotic background. The cells were epithelioid with mild nuclear atypia. Discrete cytoplasmic pigmentation was seen. No lymphoglandular bodies were noticed. Fragments of benign salivary gland were also identified. The cytological diagnosis of MM triggered onsite thorough physical examination for potential primary, where a scalp pigmented lesion was discovered hidden by overlying covering hair. Our differential diagnosis included melanoma, metastatic carcinoma, and lymphoma. Further work up for melanoma with S100, HMB45, and Mart 1 confirmed our top differential diagnosis. We emphasize thorough physical examination in such circumstances, and the importance of onsite evaluation guiding clinicians looking for primary.

  11. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma.

    PubMed

    Stanojevic, Ivan; Miller, Karolina; Kandolf-Sekulovic, Lidija; Mijuskovic, Zeljko; Zolotarevski, Lidija; Jovic, Milena; Gacevic, Milomir; Djukic, Mirjana; Arsenijevic, Nebojsa; Vojvodic, Danilo

    2016-02-01

    Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3(-), CD19(-), CD56(-)), HLA-DR(-/low), CD11b(+) and CD33(+). Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) < 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI. PMID:26391013

  12. 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

  13. 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

  14. Golgi-Related Proteins GOLPH2 (GP73/GOLM1) and GOLPH3 (GOPP1/MIDAS) in Cutaneous Melanoma: Patterns of Expression and Prognostic Significance

    PubMed Central

    Donizy, Piotr; Kaczorowski, Maciej; Biecek, Przemyslaw; Halon, Agnieszka; Szkudlarek, Teresa; Matkowski, Rafal

    2016-01-01

    GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 primary melanoma tissue samples and evaluated their expression in three compartments: cancer cells, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). High levels of both proteins in melanoma cells were associated with characteristics of aggressive disease, and shorter disease-free survival (DFS) and cancer-specific overall survival (CSOS). On the contrary, increased numbers of GOLPH2-positive and GOLPH3-positive TAMs were observed in thinner, non-ulcerated tumors, with brisk lymphocytic reaction and absent lymphangioinvasion. Distant metastases were not observed among patients with high numbers of GOLPH2-positive TAMs. Increased expression of either protein in TAMs was related to prolonged CSOS and DFS. Similarly, GOLPH3-expressing CAFs were more frequent in thin melanomas with low mitotic rate, without ulceration and lymphangioinvasion. Moreover, increased GOLPH3-positive CAFs correlated with the absence of regional or distant metastases, and with longer CSOS and DFS. GOLPH2 expression was not observed in CAFs. Our results suggest that GOLPH2 and GOLPH3 play a role in melanoma progression and are potential targets for molecular-based therapies. PMID:27706081

  15. NM23 deficiency promotes metastasis in a UV radiation-induced mouse model of human melanoma.

    PubMed

    Jarrett, Stuart G; Novak, Marian; Harris, Nathan; Merlino, Glenn; Slominski, Andrezj; Kaetzel, David M

    2013-01-01

    Cutaneous malignant melanoma is the most lethal form of skin cancer, with 5-year survival rates of <5 % for patients presenting with metastatic disease. Mechanisms underlying metastatic spread of UVR-induced melanoma are not well understood, in part due to a paucity of animal models that accurately recapitulate the disease in its advanced forms. We have employed a transgenic mouse strain harboring a tandem deletion of the nm23-m1 and nm23-m2 genes to assess the combined contribution of these genes to suppression of melanoma metastasis. Crossing of the nm23-h1/nm23-h2 knockout in hemizygous-null form ([m1m2](+/-)) to a transgenic mouse strain (hepatocyte growth factor/scatter factor-overexpressing, or HGF(+) strain) vulnerable to poorly-metastatic, UVR-induced melanomas resulted in UVR-induced melanomas with high metastatic potential. Metastasis to draining lymph nodes was seen in almost all cases of back skin melanomas, while aggressive metastasis to lung, thoracic cavity, liver and bone also occurred. Interestingly, no differences were observed in the invasive characteristics of primary melanomas of HGF(+) and HGF(+) × [m1m2](+/-) strains, with both exhibiting invasion into the dermis and subcutis, indicating factors other than simple invasive activity were responsible for metastasis of HGF(+) × [m1m2](+/-) melanomas. Stable cell lines were established from the primary and metastatic melanoma lesions from these mice, with HGF(+) × [m1m2](+/-) lines exhibiting increased single cell migration and genomic instability. These studies demonstrate for the first time in vivo a potent metastasis suppressor activity of NM23 in UVR-induced melanoma, and have provided new tools for identifying molecular mechanisms that underlie melanoma metastasis.

  16. [Melanoma secondary prevention].

    PubMed

    Suppa, M; Daxhelet, M; del Marmol, V

    2015-09-01

    Melanoma represents a major public health problem. Its incidence is constantly rising and the mortality rate can be frightfully important if the diagnosis is delayed. Melanoma also exerts a significant economical burden on the society. Therefore there is a need of concrete and pragmatic public health strategies in order to enhance melanoma prevention. Primary prevention of melanoma consists in avoiding excessive exposure to ultraviolet rays,'which represent the main risk factor for the disease occurrence. Secondary prevention is a synonym of melanoma early diagnosis and can be obtained by means of two methods : patients' self-examination and medical examination. Both these examinations must be routinely and thoroughly performed, must be based on the ABCDE rule and the ugly duckling sign, and ideally must be aided by the use of total-body photography. Current international guidelines suggest that all cutaneous screenings should be performed using dermoscopy, a non-invasive imaging technique that allows improving considerably the diagnostic performance. More sophisticated imaging techniques, such as confocal microscopy, are also available in specialised centres. The current scientific evidence supports the efficacy of melanoma primary and secondary prevention programs as a tool to decrease melanoma mortality. Many skin cancer prevention campaigns have been organised worldwide. The most famous and successful in Europe is Euromelanoma.

  17. Melanoma immunotherapy.

    PubMed

    Sivendran, Shanthi; Glodny, Bradley; Pan, Michael; Merad, Miriam; Saenger, Yvonne

    2010-01-01

    Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies.

  18. Translational research in melanoma.

    PubMed

    Ray, Madhury; Farma, Jeffrey M; Hsu, Cary

    2013-10-01

    Recent breakthroughs in the fundamental understanding of the cellular and molecular basis of melanoma have culminated in new therapies with unquestionable efficacy. Immunotherapy and targeted therapy strategies have completely transformed the contemporary management of advanced melanoma. The translational research behind these developments is discussed, with an emphasis on immune checkpoint blockade and inhibition of the mitogen-activated protein kinase signaling pathway.

  19. Epidermotropic Metastatic Melanoma with Perilesional Depigmentation in an Indian Male

    PubMed Central

    Doshi, Bhavana; Mahajan, Sunanda; Khopkar, Uday S; Kharkar, Vidya; Agarwal, Prachi

    2013-01-01

    Melanoma is a rare form of cutaneous malignancy encountered in the dark skin population. Epidermotropic metastatic melanoma is a rare form of cutaneous metastatic melanoma which can mimic primary melanoma on histopathology. Hence its differentiation is of immense prognostic importance. The occurrence of rim of depigmentation around the primary cutaneous melanoma has previously been reported to portend a bad prognosis. The occurrence of vitiligo like lesions in patients with metastatic melanoma in comparison has a better prognosis. However the occurrence of depigmentation around the secondaries is rare and its importance is not well known. Hence we wish to report a case of epidermotropic metastatic melanoma with perilesional depigmentation in a 78 year old Indian male. PMID:24082190

  20. 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.

  1. 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

  2. An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study

    PubMed Central

    Davies, John R; Field, Sinead; Randerson-Moor, Juliette; Harland, Mark; Kumar, Rajiv; Anic, Gabriella M; Nagore, Eduardo; Hansson, Johan; Höiom, Veronica; Jönsson, Göran; Gruis, Nelleke A; Park, Jong Y; Guan, Jian; Sivaramakrishna Rachakonda, P; Wendt, Judith; Pjanova, Dace; Puig, Susana; Schadendorf, Dirk; Okamoto, Ichiro; Olsson, Håkan; Affleck, Paul; García-Casado, Zaida; Puig-Butille, Joan Anton; Stratigos, Alexander J; Kodela, Elizabeth; Donina, Simona; Sucker, Antje; Hosen, Ismail; Egan, Kathleen M; Barrett, Jennifer H; van Doorn, Remco; Bishop, D Timothy; Newton-Bishop, Julia

    2014-01-01

    An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization. PMID:24219834

  3. Restoration of tumor equilibrium after immunotherapy for advanced melanoma: three illustrative cases.

    PubMed

    Wilgenhof, Sofie; Pierret, Lauranne; Corthals, Jurgen; Van Nuffel, An M T; Heirman, Carlo; Roelandt, Truus; De Coninck, Arlette; Verfaillie, Guy; Vandenbroucke, Frederik; Van Riet, Ivan; Bonehill, Aude; Thielemans, Kris; Neyns, Bart

    2011-04-01

    Metastatic melanoma runs a predictable detrimental course in the vast majority of patients. New modalities of immunotherapy, such as melanoma antigen-specific therapeutic vaccination and cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blockade by monoclonal antibodies (mAbs), have been associated with atypical kinetics of tumor response that differ from those observed during cytotoxic treatment. Recently, new tumor response criteria have been proposed based on the tumor response characteristics observed in clinical studies with ipilimumab (the so-called 'immune-related response criteria'). We report three illustrative cases of the American Joint Committee on Cancer stage IV-M1c melanoma patients who experienced atypical kinetics of tumor response to the treatment with the CTLA-4-blocking mAb, ipilimumab (case 1), or an autologous dendritic cell vaccine in combination with interferon α-2b (cases 2 and 3). These cases show that atypical response patterns not only relate to the outcome of CTLA-4-blocking mAb therapy but also to the treatment with therapeutic vaccines and interferon α-2b.

  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. 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

  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.

  8. 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

  9. 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

  10. Melanoma Disparities among US Hispanics: Use of the Social Ecological Model to Contextualize Reasons for Inequitable Outcomes and Frame a Research Agenda.

    PubMed

    Harvey, Valerie M; Oldfield, Charlene W; Chen, Jarvis T; Eschbach, Karl

    2016-01-01

    Cutaneous melanoma is a significant public health concern, accounting for thousands of deaths annually in the US. Early detection and diagnosis are critical given the poor prognosis and limited treatment options of advanced-stage disease. While non-Hispanic whites have higher incidence rates of melanoma, Hispanics are typically diagnosed at later disease stages and suffer higher morbidity and mortality. Currently, there is a paucity of literature investigating the root causes underlying these trends among Hispanics. Given that Hispanics are the most rapidly expanding demographic segment in the US, it is essential for cancer control efforts to elucidate the major determinants of their poor melanoma outcomes. Herein, we use the social ecological model as a framework to explore the multitude of influences on melanoma disparities among Hispanics and provide recommendations for planning future studies and interventions. PMID:27651954

  11. Melanoma Disparities among US Hispanics: Use of the Social Ecological Model to Contextualize Reasons for Inequitable Outcomes and Frame a Research Agenda

    PubMed Central

    Oldfield, Charlene W.; Chen, Jarvis T.; Eschbach, Karl

    2016-01-01

    Cutaneous melanoma is a significant public health concern, accounting for thousands of deaths annually in the US. Early detection and diagnosis are critical given the poor prognosis and limited treatment options of advanced-stage disease. While non-Hispanic whites have higher incidence rates of melanoma, Hispanics are typically diagnosed at later disease stages and suffer higher morbidity and mortality. Currently, there is a paucity of literature investigating the root causes underlying these trends among Hispanics. Given that Hispanics are the most rapidly expanding demographic segment in the US, it is essential for cancer control efforts to elucidate the major determinants of their poor melanoma outcomes. Herein, we use the social ecological model as a framework to explore the multitude of influences on melanoma disparities among Hispanics and provide recommendations for planning future studies and interventions.

  12. Melanoma Disparities among US Hispanics: Use of the Social Ecological Model to Contextualize Reasons for Inequitable Outcomes and Frame a Research Agenda

    PubMed Central

    Oldfield, Charlene W.; Chen, Jarvis T.; Eschbach, Karl

    2016-01-01

    Cutaneous melanoma is a significant public health concern, accounting for thousands of deaths annually in the US. Early detection and diagnosis are critical given the poor prognosis and limited treatment options of advanced-stage disease. While non-Hispanic whites have higher incidence rates of melanoma, Hispanics are typically diagnosed at later disease stages and suffer higher morbidity and mortality. Currently, there is a paucity of literature investigating the root causes underlying these trends among Hispanics. Given that Hispanics are the most rapidly expanding demographic segment in the US, it is essential for cancer control efforts to elucidate the major determinants of their poor melanoma outcomes. Herein, we use the social ecological model as a framework to explore the multitude of influences on melanoma disparities among Hispanics and provide recommendations for planning future studies and interventions. PMID:27651954

  13. 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

  14. Unexpected reduction of mortality rates from melanoma in males living in central Italy.

    PubMed

    Crocetti, E; Carli, Paolo

    2003-04-01

    A registry-based study has been carried out in central Italy to investigate cutaneous melanoma incidence and mortality trends. The incidence of invasive (1492 cases analysed) and in situ (224 cases) cutaneous melanomas increased significantly from 1985 to 1997, in both genders. The increase of invasive tumours was mainly due to 'thin' (melanoma make this finding largely unexpected, and difficult to understand assuming that in the last decade no 'clear-cut' improvements in survival have been documented as a result of new treatments in advanced melanomas.

  15. 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.

  16. Parotid involvement by desmoplastic melanoma.

    PubMed

    Jennings, T A; Okby, N T; Schroer, K R; Wolf, B C; Mihm, M C

    1996-08-01

    Desmoplastic malignant melanoma often arises in sun damaged skin of the head and neck and shows frequent neurotropism. Although metastatic melanoma frequently involve the parotid, direct spread to the parotid has been rarely reported. We evaluated five cases of desmoplastic malignant melanoma involving the parotid gland with clinical and pathological evidence of precursor cutaneous lesions in four of the five cases. The parotid involvement in four cases was tumoural, and three of these were not clinically suspected to be melanoma. The histological appearance in all five cases was that of a sarcomatoid tumour. Immunohistochemistry and electronmicroscopy performed on three of the cases showed only evidence of schwannian differentiation: the tumour cells were positive for S-100 protein and vimentin, and negative for cytokeratin and HMB-45. Electronmicroscopy showed no evidence of melanogenesis. All five tumours showed histological evidence of prominent neurotropism with one case demonstrating extension from overlying skin along cutaneous nerves to the superficial parotid. Thus, desmoplastic malignant melanoma may involve the parotid by neurotropic spread and can be pathologically indistinguishable from malignant schwannoma, a diagnosis which may be made erroneously in the absence of clinical information. PMID:8872151

  17. Melanoma Prevention Using Topical PBISe

    PubMed Central

    Chung, Chin-Ying; Madhunapantula, SubbaRao V.; Desai, Dhimant; Amin, Shantu; Robertson, Gavin P.

    2012-01-01

    Malignant melanoma is the deadliest form of skin cancer, known for its drug resistance and high metastatic potential. Deregulated PI3 and MAP kinase pathways promote early melanocytic lesion development and confer drug resistance. No agent exists to target these deregulated pathways to prevent cutaneous non-invasive melanocytic cells or invasive melanomas from developing into more aggressive widely disseminated metastatic disease. In this study, a selenium containing isosteric analogue of PBIT [S,S′-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea] called PBISe [Se,Se′-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea] is shown to moderate these two major signaling pathways to prevent cutaneous melanocytic lesion or melanoma development. Topical application of PBISe retarded melanocytic lesion development in laboratory-generated skin by 70-80% and in animal skin by ∼50%. Mechanistically, prevention of lesion development occurred due to decreased Akt3 signaling, which increased MAP kinase pathway activity to inhibitory levels. The combined effect of targeting these pathways led to decreased cell proliferation and increased apoptotic cell death thereby preventing melanoma development. Thus, topically applied PBISe treatment has potential to prevent non-invasive melanocytic lesion and invasive metastatic melanoma development in skin. PMID:21367959

  18. 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.

  19. 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

  20. A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma.

    PubMed

    Ebert, Lisa M; MacRaild, Sarah E; Zanker, Damien; Davis, Ian D; Cebon, Jonathan; Chen, Weisan

    2012-01-01

    Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX™ cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.

  1. 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

  2. [Hyperthermic-antiblastic isolation perfusion for advanced melanoma of the limbs. The technic, immediate results and a review of the literature].

    PubMed

    Decian, F; Balletto, N; Camerini, G; Depaoli, M; D'Aniello, R; Ameri, A; Brisighella, A; Bonalumi, U; Bachi, V; Civalleri, D

    1990-10-15

    Hyperthermic antiblastic isolated perfusion is a method largely used for the treatment of locally advanced limb melanoma. The method requires vascular isolation and hyperthermic perfusion of the limb using an extracorporeal circuit and administering the melphalan as antiblastic drug. Twenty-six patients with primary or recurrent melanoma of the limbs have undergone this treatment at our Institute. There were no cases of operative mortality and systemic toxicity was negligible. The local complications were transitory and no patient showed symptoms of nervous toxicity or permanent functional damage. Two cases of deep thrombophlebitis and two of lymphocele were documented a few months after treatment. Four clinically complete responses, 3 partial and 2 cases of stable disease were observed in the 9 patients treated with unexcised lesions. Our data like the totality of the present experience points to the safety of this method in the therapy of locally advanced limb melanoma. Nevertheless further controlled studies are required to define its role in order to improve survival.

  3. 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

  4. Loss of heterozygosity on 10q and microsatellite instability in advanced stages of primary cutaneous T-cell lymphoma and possible association with homozygous deletion of PTEN.

    PubMed

    Scarisbrick, J J; Woolford, A J; Russell-Jones, R; Whittaker, S J

    2000-05-01

    Previous cytogenetic studies of primary cutaneous T-cell lymphoma (CTCL) were based on limited numbers of patients and seldom showed consistent nonrandom chromosomal abnormalities. In this study, 54 tumor DNA samples from patients with CTCL were analyzed for loss of heterozygosity on 10q. Allelic loss was identified in 10 samples, all of which were from the 44 patients with mycosis fungoides (10/44 patients; 23%). Of the patients with allelic loss, 3 were among the 29 patients with early-stage myosis fungoides (T(1) or T(2)) (3/29 patients; 10%), whereas the other 7 were among the 15 patients with advanced cutaneous disease (T(3) or T(4)) (7/15 patients; 47%). The overlapping region of deletion was between 10q23 and 10q24. In addition, microsatellite instability (MSI) was present in 13 of the 54 samples (24%), 12 from patients with mycosis fungoides and 1 from a patient with Sezary syndrome. There was also an association between MSI and disease progression in patients with mycosis fungoides, with 6 of 15 (40%) patients with MSI having advanced cutaneous disease and only 6 of 29 (21%) having early-stage disease. Samples with allelic loss on 10q were analyzed for abnormalities of the tumor suppressor gene PTEN (10q23.3). No tumor-specific mutations were detected, but homozygous deletion was found in 2 patients. Thus, we found loss of heterozygosity on 10q and MSI in advanced cutaneous stages of mycosis fungoides. These findings indicate that a tumor suppressor gene or genes in this region may be associated with disease progression. Furthermore, abnormalities of PTEN may be important in the pathogenesis of mycosis fungoides, but our data imply that this gene is rarely inactivated by small deletions or point mutations. (Blood. 2000;95:2937-2942)

  5. Dabrafenib for Treating Unresectable, Advanced or Metastatic BRAF V600 Mutation-Positive Melanoma: An Evidence Review Group Perspective.

    PubMed

    Fleeman, Nigel; Bagust, Adrian; Beale, Sophie; Boland, Angela; Dickson, Rumona; Dwan, Kerry; Richardson, Marty; Dundar, Yenal; Davis, Helen; Banks, Lindsay

    2015-09-01

    The National Institute for Health and Care Excellence (NICE) invited GlaxoSmithKline, the manufacturer of dabrafenib, to submit evidence for the clinical and cost effectiveness of dabrafenib for the treatment of unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the company and provides a summary of the Appraisal Committee's (AC) final decision in October 2014. The clinical evidence for dabrafenib was derived from an ongoing phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BREAK-3) involving 230 patients randomized 2:1 to receive either dabrafenib or dacarbazine. A significant improvement in median progression-free survival (PFS) but not overall survival (OS) was reported in the dabrafenib arm compared with dacarbazine. Vemurafenib is considered a more appropriate comparator than is dacarbazine. The clinical evidence for vemurafenib was derived from a completed phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BRIM-3) involving 675 patients randomized 1:1 to receive either vemurafenib or dacarbazine. A significant improvement in median PFS and OS was reported in the vemurafenib arm compared with dacarbazine. As there is no direct evidence comparing dabrafenib versus vemurafenib, the company presented an indirect treatment comparison (ITC) that demonstrated no statistical differences between dabrafenib and vemurafenib for PFS or OS. The ERG expressed concerns with the ITC, mainly in relation to the validity of the assumptions underpinning the methodology; the ERG concluded this resulted in findings that are unlikely to be robust or reliable. Dabrafenib and

  6. 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

  7. 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.

  8. Frontline approach to metastatic BRAF-mutant melanoma diagnosis, molecular evaluation, and treatment choice.

    PubMed

    Chapman, Paul B; Hauschild, Axel; Sondak, Vernon K

    2014-01-01

    An estimated 76,100 patients will be diagnosed with invasive melanoma in the United States in 2014, and 9,710 patients will die from the disease. In almost all cases, the cause of death is related to the development of widespread metastatic disease. Although death rates from most types of cancer have steadily decreased in the United States--a 20% decrease during two decades from a peak of 215.1 deaths per 100,000 population in 1991 to 171.8 in 2010--death rates from melanoma have steadily increased during the same time, especially among males. The news regarding melanoma is far from all bad. Increases in our understanding of the human immune system have led to the development of new immunotherapeutic drugs such as ipilimumab, which has been shown to improve survival in phase III trials in metastatic melanoma, and anti-programmed death 1 (anti-PD1) antibodies, recently hailed by ASCO as one of the past year's most noteworthy clinical cancer advances. However, no discovery has influenced and, indeed, transformed the management of metastatic melanoma more than the identifıcation of activating mutations in the BRAF gene in the mitogen-activated protein kinase (MAPK) pathway, which occur in about half of cutaneous melanomas and can be targeted with small molecule inhibitors of the BRAF protein, the downstream MEK protein, or both. This article will address how patients with metastatic melanoma are evaluated for their mutation status and how the presence of a targetable mutation influences therapeutic decisions regarding systemic therapy and even surgery.

  9. Chemotherapy for Melanoma.

    PubMed

    Wilson, Melissa A; Schuchter, Lynn M

    2016-01-01

    Prior to the recent therapeutic advances, chemotherapy was the mainstay of treatment options for advanced-stage melanoma. A number of studies have investigated various chemotherapy combinations in order to expand on the clinical responses achieved with single-agent dacarbazine, but these have not demonstrated an improvement in overall survival. Similar objective responses were observed with the combination of carboplatin and paclitaxel as were seen with single-agent dacarbazine. The combination of chemotherapy and immunotherapy, known as biochemo-therapy, has shown high clinical responses; however, biochemo-therapy has not been shown to improve overall survival and resulted in increased toxicities. In contrast, palliation and long-term responses have been observed with localized treatment with isolated limb perfusion or infusion in limb-isolated disease. Although new, improved therapeutic options exist for first-line management of advanced-stage melanoma, chemotherapy may still be important in the palliative treatment of refractory, progressive, and relapsed melanoma. We review the various chemotherapy options available for use in the treatment and palliation of advanced-stage melanoma, discuss the important clinical trials supporting the treatment recommendations, and focus on the clinical circumstances in which treatment with chemotherapy is useful.

  10. 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

  11. 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

  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. Phase I clinical study with multiple peptide vaccines in combination with tetanus toxoid and GM-CSF in advanced-stage HLA-A*0201-positive melanoma patients.

    PubMed

    Bins, Adriaan; Mallo, Henk; Sein, Johan; van den Bogaard, Colette; Nooijen, Willem; Vyth-Dreese, Florry; Nuijen, Bastiaan; de Gast, Gijsbert C; Haanen, John B A G

    2007-01-01

    Successful induction of functional tumor-specific T cells by peptide vaccination in animal models has resulted in many clinical trials to test this approach in advanced-stage melanoma patients. In this phase I clinical trial, 11 end-stage melanoma patients were vaccinated intradermally with 3 peptides: MART-1(26-35) E27L (ELAGIGILTV), tyrosinase(368-376) N375Q (YMDGTMSQV), and gp100(209-217) T210M (IMQVPFSV), admixed with tetanus toxoid and granulocyte-monocyte colony stimulating factor. The peptide vaccine was well tolerated at all tested doses, and led to grade 1-2 toxicity only. Although all patients did show a rise in antitetanus IgG titers, in only 3 patients peptide-specific CD8 T-cells were induced. In 2 cases, the response was directed against MART-1(26-35) and consisted of 0.2% and 3.3% of the CD8 population; however, in both instances these cells did not produce interferon-gamma on stimulation with the unmodified peptide. The third patient mounted a small (0.1%) response against gp100. In a fourth patient, a nonfunctional tyrosinase-specific response (0.6%) was found that was present before vaccination, but was not affected in size nor in function by the vaccine. None of the 11 patients responded clinically according to response evaluation criteria in solid tumors criteria. Although this study is a small scale phase I clinical trial, the efficacy that was observed was disappointingly low. In accordance with previously published peptide vaccination studies, these results add to the increasing evidence that peptide vaccination in itself is not potent enough as an effective melanoma immunotherapy in advanced-stage patients.

  14. Reduced Intensity Conditioning Before Partially Matched Donor Stem Cell Transplant in Treating Patients With Advanced Cutaneous T Cell Lymphoma

    ClinicalTrials.gov

    2016-10-19

    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

  15. 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

  16. 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

  17. 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

  18. New developments in the treatment of metastatic melanoma - role of dabrafenib-trametinib combination therapy.

    PubMed

    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.

  19. [Choroidal melanoma].

    PubMed

    Desjardins, Laurence

    2016-03-01

    Choroidal melanoma is the most common form of eye cancer in adults. Treatments enabling the tumour to be destroyed or removed while preserving the eye socket are mainly based on surgery, proton therapy and brachytherapy. PMID:26944641

  20. Spectrum of p53 gene mutations suggests a possible role for ultraviolet radiation in the pathogenesis of advanced cutaneous lymphomas.

    PubMed

    McGregor, J M; Crook, T; Fraser-Andrews, E A; Rozycka, M; Crossland, S; Brooks, L; Whittaker, S J

    1999-03-01

    There is evidence that the incidence of primary cutaneous lymphoma, like other forms of non-Hodgkin's lymphoma, is increasing, yet little is known of the pathogenetic events involved in this group of disorders. In this study we examine the frequency and spectrum of P53 gene mutations in a large series of primary cutaneous lymphomas, with particular emphasis on tumor stage mycosis fungoides, as it is in these cases that p53 overexpression has previously been reported. Sixty-six samples from 55 patients with primary cutaneous B cell and T cell lymphomas were analyzed for mutations in exons 5-9 of the P53 gene using polymerase chain reaction/single strand conformational polymorphism, and subsequent cloning and sequencing of genomic DNA. Fourteen separate P53 mutations were identified in blood, skin, and lymph node samples in 13 patients (24%). Twelve of 14 mutations occurred at dipyrimidine sites, eight resulting in C-->T transitions and one in a CC-->TT tandem base transition, a mutation spectrum strikingly similar to that reported in nonmelanoma skin cancer and characteristic of DNA damage caused by ultraviolet B radiation. In the subset of patients with mycosis fungoides, P53 mutations were identified in six of 17 patients with tumor-stage but in none of 12 patients with plaque-stage disease (Fisher's exact test p = 0.027). These data suggest a role for ultraviolet radiation in the pathogenesis of primary cutaneous lymphomas and a possible ultraviolet B-related step in the progression of mycosis fungoides from plaque to tumor-stage disease.

  1. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.

    PubMed

    Yuan, Jianda; Adamow, Matthew; Ginsberg, Brian A; Rasalan, Teresa S; Ritter, Erika; Gallardo, Humilidad F; Xu, Yinyan; Pogoriler, Evelina; Terzulli, Stephanie L; Kuk, Deborah; Panageas, Katherine S; Ritter, Gerd; Sznol, Mario; Halaban, Ruth; Jungbluth, Achim A; Allison, James P; Old, Lloyd J; Wolchok, Jedd D; Gnjatic, Sacha

    2011-10-01

    Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

  2. [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.

  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. Stable synthetic bacteriochlorins overcome the resistance of melanoma to photodynamic therapy

    PubMed Central

    Mroz, Pawel; Huang, Ying-Ying; Szokalska, Angelika; Zhiyentayev, Timur; Janjua, Sahar; Nifli, Artemissia-Phoebe; Sherwood, Margaret E.; Ruzié, Christian; Borbas, K. Eszter; Fan, Dazhong; Krayer, Michael; Balasubramanian, Thiagarajan; Yang, Eunkyung; Kee, Hooi Ling; Kirmaier, Christine; Diers, James R.; Bocian, David F.; Holten, Dewey; Lindsey, Jonathan S.; Hamblin, Michael R.

    2010-01-01

    Cutaneous malignant melanoma remains a therapeutic challenge, and patients with advanced disease have limited survival. Photodynamic therapy (PDT) has been successfully used to treat many malignancies, and it may show promise as an antimelanoma modality. However, high melanin levels in melanomas can adversely affect PDT effectiveness. Herein the extent of melanin contribution to melanoma resistance to PDT was investigated in a set of melanoma cell lines that markedly differ in the levels of pigmentation; 3 new bacteriochlorins successfully overcame the resistance. Cell killing studies determined that bacteriochlorins are superior at (LD50≈0.1 μM) when compared with controls such as the FDA-approved Photofrin (LD50≈10 μM) and clinically tested LuTex (LD50≈1 μM). The melanin content affects PDT effectiveness, but the degree of reduction is significantly lower for bacteriochlorins than for Photofrin. Microscopy reveals that the least effective bacteriochlorin localizes predominantly in lysosomes, while the most effective one preferentially accumulates in mitochondria. Interestingly all bacteriochlorins accumulate in melanosomes, and subsequent illumination leads to melanosomal damage shown by electron microscopy. Fluorescent probes show that the most effective bacteriochlorin produces significantly higher levels of hydroxyl radicals, and this is consistent with the redox properties suggested by molecular-orbital calculations. The best in vitro performing bacteriochlorin was tested in vivo in a mouse melanoma model using spectrally resolved fluorescence imaging and provided significant survival advantage with 20% of cures (P<0.01).—Mroz, P., Huang, Y.-Y., Szokalska, A., Zhiyentayev, T., Janjua, S., Nifli, A.-P., Sherwood, M. E., Ruzié, C., Borbas, K. E., Fan, D., Krayer, M., Balasubramanian, T., Yang, E., Kee, H. L., Kirmaier, C., Diers, J. R., Bocian, D. F., Holten, D., Lindsey, J. S., Hamblin, M. R. Stable synthetic bacteriochlorins overcome the

  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. 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

  7. Increasing radiation dose improves immunotherapy outcome and prolongation of tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma.

    PubMed

    Smilowitz, Henry M; Micca, Peggy L; Sasso, Daniel; Wu, Qian; Dyment, Nathanial; Xue, Crystal; Kuo, Lynn

    2016-02-01

    Previously, we developed a clinically relevant therapy model for advanced intracerebral B16 melanomas in syngeneic mice combining radiation and immunotherapies. Here, 7 days after B16-F10-luc2 melanoma cells were implanted intracerebrally (D7), syngeneic mice with bioluminescent tumors that had formed (1E10(5) to 7E10(6) photons per minute (>1E10(6), large; <1E10(6), small) were segregated into large-/small-balanced subgroups. Then, mice received either radiation therapy alone (RT) or radiation therapy plus immunotherapy (RT plus IT) (single injection of mAbPC61 to deplete regulatory T cells followed by multiple injections of irradiated granulocyte macrophage colony stimulating factor transfected B16-F10 cells) (RT plus IT). Radiation dose was varied (15, 18.75 or 22.5 Gy, given on D8), while immunotherapy was provided similarly to all mice. The data support the hypothesis that increasing radiation dose improves the outcome of immunotherapy in a subgroup of mice. The tumors that were greatly delayed in beginning their progressive growth were bioluminescent in vivo-some for many months, indicating prolonged tumor "dormancy," in some cases presaging long-term cures. Mice bearing such tumors had far more likely received radiation plus immunotherapy, rather than RT alone. Radiotherapy is a very important adjunct to immunotherapy; the greater the tumor debulking by RT, the greater should be the benefit to tumor immunotherapy.

  8. 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.

  9. Novel mechanisms and therapeutic approaches in melanoma: targeting the MAPK pathway.

    PubMed

    Grimaldi, Antonio Maria; Simeone, Ester; Festino, Lucia; Vanella, Vito; Palla, Marco; Ascierto, Paolo Antonio

    2015-06-01

    The development of novel treatments that selectively inhibit the RAS-RAF-MAPK pathway represents a milestone in the history of melanoma treatment. BRAF mutations occur in approximately 45% of cutaneous melanomas, while mutations in NRAS occur in 15-25%. Vemurafenib was the first BRAF inhibitor to be approved in 2011, based on the results of a phase III trial (BRIM-3) that showed higher progression-free survival and overall survival compared with dacarbazine chemotherapy in metastatic BRAF-mutated melanoma. Dabrafenib, another BRAF inhibitor, has shown similar results and was approved in 2013. Preclinical studies suggested that another novel group of agents, the MEK inhibitors, showed stronger inhibition of both mutated BRAF and NRAS cell cultures than vemurafenib. Trametinib was the first MEK inhibitor approved in 2014, both as a single agent and in combination with dabrafenib for the treatment of advanced BRAF-mutated melanoma. Other MEK inhibitors are also in development. Concomitant inhibition of both MEK and BRAF has shown more durable and greater tumor response than BRAF monotherapy, by overcoming the multiple genetic mechanisms of escape. Combined therapy prevents the development of acquired resistance as well as decreasing cutaneous toxicity secondary to paradoxical activation of the MAPK pathway induced by BRAF inhibitors. Various combinations of BRAF and MEK inhibitors have shown promising results. Moreover, triple combination therapies involved other agents with novel mechanisms of action are also being evaluated. These and other combination strategies involving immunotherapies and targeted therapies offer the hope of improving outcomes beyond those already achieved with anti-BRAF treatments.

  10. Cutaneous zygomycosis.

    PubMed

    Bonifaz, Alexandro; Vázquez-González, Denisse; Tirado-Sánchez, Andrés; Ponce-Olivera, Rosa María

    2012-01-01

    Cutaneous zygomycosis is a fungal infection caused by zygomycetes that affects the skin. It occurs in uncontrolled diabetic patients and immunosuppressed individuals. It has 2 clinical forms: primary cutaneous zygomycosis and secondary cutaneous zygomycosis. The first is characterized by necrotic lesions and the fungus is usually inoculated by trauma. If diagnosed early, it generally has a good prognosis. Secondary zygomycosis is usually a complication and extension of the rhinocerebral variety that starts as a palpebral fistula and progresses to a necrotic lesion with a poor prognosis. The diagnosis is made by identification of the fungus by direct KOH examination, culture, and biopsy. Treatment for the primary disease is surgical debridement plus amphotericin B. The secondary type is treated with amphotericin B and/or posaconazole.

  11. 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

  12. 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.

  13. The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial

    PubMed Central

    Rutkowski, Piotr; Mackiewicz, Jacek; Krzemieniecki, Krzysztof; Nawrocki, Sergiusz; Wasilewska-Teśluk, Ewa; Kwinta, Łukasz; Wysocki, Piotr; Koseła-Paterczyk, Hanna; Świtaj, Tomasz

    2015-01-01

    Aim of the study The BRAF inhibitor vemurafenib has improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. Here we present the results of an open-label safety study with vemurafenib in patients with metastatic melanoma enrolled in Polish oncological centres. Material and methods Patients with untreated or previously treated Stage IIIC/IV BRAFV600 mutation-positive melanoma were treated with oral vemurafenib in an initial dose of 960 mg twice daily. Assessments for safety and efficacy were made every 28 days. For the survival analysis the Kaplan-Meier estimator was used with the log-rank tests for bivariate comparisons. Results In total, 75 Polish patients were enrolled in the safety study across four centres. At data cut-off, 28 patients died (37%), mainly (26) due to disease progression; 33 (44%) patients continued vemurafenib after disease progression. The objective response rate was 46%, including two patients with a complete response and 29 with a partial response. Median progression-free survival was 7.4 months. The one-year overall survival rate was 61.9% (median overall survival was not reached). Seventy-three (97.3%) patients reported adverse events (AEs), and grade 3–5 toxicity was reported in 49.4% (37) patients. The most common AEs were: skin lesions (including rash and photosensitivity), arthralgia, and fatigue. Conclusions The overall safety profile and response rate of vemurafenib were comparable to those reported in previous studies of this drug. Our study confirmed the value of well-established prognostic features for overall survival, such as initial LDH (lactate dehydrogenase) level and AJCC staging. PMID:26557775

  14. Effective Treatment of Multiple Unresectable Skin Melanoma Metastases by Electrochemotherapy

    PubMed Central

    Snoj, Marko; Cemazar, Maja; Slekovec Kolar, Breda; Sersa, Gregor

    2007-01-01

    Multiple unresectable melanoma skin metastases pose a treatment problem, especially in centers where isolated limb perfusion is not available. We report the case of a 59-year-old woman who developed multiple small unresectable cutaneous melanoma metastases on the thigh after her lower limb was amputated. Electrochemotherapy with bleomycin resulted in good local control of the disease, with a complete response of the treated melanoma nodules (224 tumor nodules) after 4 treatment sessions. Comparison between electrochemotherapy using repetition frequency of the applied electric pulses of 1 Hz and 5 kHz demonstrated equal antitumor effectiveness. Electrochemotherapy with intravenous bleomycin can also be used as a treatment of choice for local control of multiple unresectable cutaneous melanoma skin metastases. PMID:17589984

  15. Cutaneous sarcoidosis.

    PubMed

    Wilson, N J; King, C M

    1998-11-01

    Sarcoidosis is a multi-organ granulomatous disorder of unknown cause. Skin sarcoidosis occurs in about 25% of patients with systemic disease and may also arise in isolation. A wide range of clinical presentations of cutaneous sarcoidosis is recognised. The diagnosis rests on the presence of non-caseating granulomas on skin biopsy and the exclusion of other granulomatous skin disease. The treatment and overall prognosis of cutaneous sarcoidosis is primarily dependent on the degree of systemic involvement. In patients with aggressive disease limited to the skin immunosuppressive therapy may be indicated.

  16. Are some melanomas caused by artificial light?

    PubMed

    Kvaskoff, Marina; Weinstein, Philip

    2010-09-01

    The incidence rate of cutaneous melanoma has been increasing faster than that of any other cancer in white-skinned populations over the past decades. The main risk factors for melanoma (i.e. exposure to sunlight, naevus count, phototype, and family history of melanoma) may not wholly explain the epidemiological trends observed for this cancer. The light-at-night theory postulates that increasing use of artificial light-at-night may contribute to the increasing breast cancer incidence through suppressed secretion of melatonin (a hormone produced in the dark and inhibited by light, which regulates circadian rhythms). Here, we postulate that this theory may also apply to melanoma and that it may explain a part of this cancer burden. Consistent with our hypothesis is evidence from experimental studies suggesting a lightening effect of melatonin on frog skin and mammal hair during seasonal changes, its antioxidant and anti-carcinogenic effects in skin melanocytes, as well as the expression of melatonin receptors in melanocytes. Also, epidemiological data suggest lower melatonin concentrations in melanoma patients compared with controls; a potential therapeutic effect of melatonin in patients with metastatic disease; a higher prevalence of melanoma in pilots and aircrews, with increased risks with higher time zones travelled; and increased melanoma risks in office workers exposed to fluorescent lighting. Moreover, melanoma incidence and seasonal patterns are consistent with a reduction of melatonin secretion with intensity of exposure to light, although it remains difficult to distinguish the effect of melatonin disruption from that of sun exposure on the basis of ecological studies. Finally, the reported associations between hormonal factors and melanoma are consistent with melatonin inhibition increasing the risk of melanoma by increasing circulating oestrogen levels. Despite the existing suggestive evidence, the light-at-night hypothesis has never been directly tested

  17. 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.

  18. Immunohistochemical Expression of Leptin in Non Melanoma Skin Cancer

    PubMed Central

    Farag, Azza G.A.; El-Dien, Marwa Mohammed Serag

    2016-01-01

    Introduction Obesity in adults is associated with numerous health disorders including some forms of cancer. Various epidemiological studies have found a link between excess adiposity and malignant melanoma; however, the association with non melanoma skin cancer is questionable. Leptin is a hormone produced mainly by the adipose tissue and its serum level may reflect body mass index. Leptin is reported to promote proliferation and angiogenesis and deregulate apoptosis, therefore facilitates the process of carcinogenesis. Aim The current study tried to assess leptin localization and expression in non melanoma skin cancer to verify its possible role in pathogenesis of this cancer. Materials and Methods This study was carried out on 13 Basal Cell Carcinoma (BCC) cases and 14 Squamous Cell Carcinoma (SCC) cases together with 19 normal skin biopsies as a control group using immunohistochemical method. Results Leptin was expressed in 52.6% of the normal epidermis with pure cytoplasmic and both cytoplasmic and nuclear staining patterns. All cases of SCC (100%) and two cases of BCC (15.4%) showed leptin expression in tumour cells whereas nuclear expression was in favour of SCC. Stromal expression of leptin was seen in both SCC (57.1%) and BCC (38.5%) without significant differences. Percentage of leptin expression by tumour cells in SCC showed positive linear correlation with tumour size (p=0.02) and microvessel density (p=0.000). Stromal expression of leptin in SCC was associated with large tumour size (p=0.04), advanced stage (p=0.01) and tumours arising in sites other than head and neck (p=0.01). Conclusion Leptin could have a more important role in pathogenesis of cutaneous SCC rather than BCC that may reflect the trivial role of obesity in induction of BCC. The expression of leptin by tumour and stromal cells of SCC could co-operate in its progression by promoting angiogenesis with subsequently acquiring large tumour size and then advanced stage. PMID:27656540

  19. 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.

  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. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma

    PubMed Central

    Thomas, Nancy E.; Edmiston, Sharon N.; Alexander, Audrey; Groben, Pamela A.; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; From, Lynn; Busam, Klaus J.; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A.; Luo, Li; Reiner, Anne S.; Paine, Susan; Frank, Jill S.; Bramson, Jennifer I.; Marrett, Lorraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E.; Ollila, David W.; Begg, Colin B.; Berwick, Marianne; Conway, Kathleen

    2015-01-01

    Importance NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. Objective To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. Design, Setting, and Participants A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Main Outcomes and Measures Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. Results The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8–3.4) or BRAF (HR, 1.5, 95% CI, 0.8–2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1–7.7) or BRAF (HR 3.1; 95% CI 1.2–8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center

  2. 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 ...

  3. 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

  4. 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

  5. Cutaneous sarcoidosis.

    PubMed Central

    Wilson, N. J.; King, C. M.

    1998-01-01

    Sarcoidosis is a multi-organ granulomatous disorder of unknown cause. Skin sarcoidosis occurs in about 25% of patients with systemic disease and may also arise in isolation. A wide range of clinical presentations of cutaneous sarcoidosis is recognised. The diagnosis rests on the presence of non-caseating granulomas on skin biopsy and the exclusion of other granulomatous skin disease. The treatment and overall prognosis of cutaneous sarcoidosis is primarily dependent on the degree of systemic involvement. In patients with aggressive disease limited to the skin immunosuppressive therapy may be indicated. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:10197194

  6. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound.

    PubMed

    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.

  7. 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.

  8. 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

  9. Cutaneous ectoparasites.

    PubMed

    Nordlund, James J

    2009-01-01

    Parasites inhabit many places in the world. Some of these can inhabit the human skin or body. Many of these have been eradicated in the developed countries but persist in some tropical environments that are fun places to visit. Visitors can bring such parasites home with them such as scabies, cutaneous larva migrans, tungiasis and myiasis. Their clinical manifestations and treatment are presented for physicians evaluating and treating travelers from exotic places. PMID:19889135

  10. Pembrolizumab superior to ipilimumab in melanoma.

    PubMed

    2015-06-01

    In the first randomized trial to compare FDA-approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab.

  11. Cutaneous metastasis from gastrointestinal adenocarcinoma of unknown primary origin.

    PubMed

    Junqueira, Ana Lucia Ariano; Corbett, Ana Maria França; Oliveira Filho, Jayme de; Nasser, Kassila da Rosa; Haddad, Natalie Nejem; Tebet, Ana Carolina Franco

    2015-01-01

    Cutaneous metastasis is a rare manifestation of visceral malignancies that indicates primarily advanced disease. Due to its low incidence and similarity to other cutaneous lesions, it is not uncommon to have a delayed diagnosis and a shortened prognosis. We describe the case of a patient who presented with a cutaneous nodule in the sternal region as a first sign of malignancy.

  12. 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

  13. 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

  14. 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

  15. 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

  16. Genetic Testing in the Multidisciplinary Management of Melanoma.

    PubMed

    Rashid, Omar M; Zager, Jonathan S

    2015-10-01

    Melanoma is increasing in incidence and represents an aggressive type of cancer. Efforts have focused on identifying genetic factors in melanoma carcinogenesis to guide prevention, screening, early detection, and targeted therapy. This article reviews the hereditary risk factors associated with melanoma and the known molecular pathways and genetic mutations associated with this disease. This article also explores the controversies associated with genetic testing and the latest advances in identifying genetic targets in melanoma, which offer promise for future application in the multidisciplinary management of melanoma.

  17. 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

  18. Malignant melanoma in a Eurasian otter (Lutra lutra).

    PubMed

    Weber, H; Mecklenburg, L

    2000-03-01

    An 11-yr-old female Eurasian otter (Lutra lutra) presented with multiple cutaneous nodules identified histologically as malignant melanomas of spindle cell and epithelioid cell type. Metastases were detected in lymph nodes and liver, and the tumor, which was derived from melanocytes, showed aggressive biological behavior. Only occasional reports exist of neoplastic disease in otters. PMID:10884131

  19. 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

  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. Iridociliary melanoma – Clinical case

    PubMed Central

    Schmitzer, S; Butea-Simionescu, C; Gheorghe, A; Zemba, M; Cioboata, M

    2016-01-01

    Abstract Iris and ciliary body melanoma is an aggressive tumor, which, unfortunately, presents symptoms only in advanced stages and is often discovered accidentally during a routine eye examination. There are several treatment options, ranging from in time monitorization in order to observe the tumor’s evolution to more aggressive methods such as radiotherapy and enucleation. We present a case of iridociliary melanoma, who underwent conservative surgery, iridocyclectomy under scleral flap, with good results, and maintenance of the function and integrity of the eyeball. PMID:27713771

  2. Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma

    PubMed Central

    Hong, David S.; Kurzrock, Razelle; Falchook, Gerald S.; Andresen, Corina; Kwak, Jennifer; Ren, Min; Xu, Lucy; George, Goldy C.; Kim, Kevin B.; Nguyen, Ly M.; O'Brien, James P.; Nemunaitis, John

    2015-01-01

    Objective and Methods In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1–5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. Results Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) ≥ 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD ≥ 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. Conclusion Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1–5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group. PMID:26503473

  3. Arginine deprivation therapy for malignant melanoma

    PubMed Central

    Yoon, Jung-Ki; Frankel, Arthur E; Feun, Lynn G; Ekmekcioglu, Suhendan; Kim, Kevin B

    2013-01-01

    Despite recent development of promising immunotherapeutic and targeted drugs, prognosis in patients with advanced melanoma remains poor, and a cure for this disease remains elusive in most patients. The success of melanoma therapy depends on a better understanding of the biology of melanoma and development of drugs that effectively target the relevant genes or proteins essential for tumor cell survival. Melanoma cells frequently lack argininosuccinate synthetase, an essential enzyme for arginine synthesis, and as a result they become dependent on the availability of exogenous arginine. Accordingly, a therapeutic approach involving depletion of available arginine has been shown to be effective in preclinical studies. Early clinical studies have demonstrated sufficient antitumor activity to give rise to cautious optimism. In this article, the rationale for arginine deprivation therapy is discussed. Additionally, various strategies for depleting arginine are discussed and the preclinical and clinical investigations of arginine deprivation therapy in melanoma are reviewed. PMID:23293541

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

    PubMed

    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.

  9. 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.

  10. 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

  11. 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

  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. 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.

  14. The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

    PubMed

    Hanaizi, Zahra; van Zwieten-Boot, Barbara; Calvo, Gonzalo; Lopez, Arantxa Sancho; van Dartel, Maaike; Camarero, Jorge; Abadie, Eric; Pignatti, Francesco

    2012-01-01

    On 13 July 2011 the European Commission issued a marketing authorisation valid throughout the European Union (EU) for ipilimumab for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy. Ipilimumab is a monoclonal antibody that specifically blocks the inhibitory signal of cytotoxic T lymphocyte antigen 4 (CTLA-4), resulting in T cell activation, proliferation and lymphocyte infiltration into tumours, leading to tumour cell death. The recommended induction regimen of ipilimumab is 3mg/kg administered intravenously over a 90 min period every 3 weeks for a total of four doses. In a phase 3 trial in patients with advanced melanoma, median overall survival for ipilimumab was 10 months versus 6 months for gp100, an experimental melanoma vaccine (Hazard ratio (HR) 0.66; 95% confidence interval (CI): 0.51, 0.87; p = 0.0026). Ipilimumab was most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab. The most common side-effects (affecting more than 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. The objective of this paper is to summarise the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the European Medicines Agency (EMA) website (www.ema.europa.eu).

  15. Black Pleural Effusion: A Unique Presentation of Metastatic Melanoma

    PubMed Central

    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

  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. 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

  18. 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 of skin cancer with 75% of all skin cancer deaths within the US attributed to it. Risk factors for melanoma include ultraviolet exposure, genetic predisposition, and phenotypic characteristics (eg, fair skin and blond hair). Whites have a 27-fold higher incidence of melanoma than African-Americans (AA), but the 5-year survival is 17.8% lower for AA than Whites. It is reported continuously that AA have more advanced melanomas at diagnosis, and overall lower survival rates. This minority melanoma paradox is not well understood or studied. Objective To explore further, the possible explanations for the difference in melanoma severity and survival in AA within the US. Methods Qualitative review of the literature. Results Lack of minority-targeted public education campaigns, low self-risk perception, low self-skin examinations, intrinsic virulence, vitamin D differences, and physician mistrust may play a role in the melanoma survival disparity among AA. Conclusion Increases in public awareness of melanoma risk among AA through physician and media-guided education, higher index of suspicion among individuals and physicians, and policy changes can help to improve early detection and close the melanoma disparity gap in the future. PMID:26346576

  19. Cutaneous angiomyolipoma.

    PubMed

    Val-Bernal, J F; Mira, C

    1996-08-01

    Extrarenal angiomyolipomas are rare lesions. An angiomyolipoma located on the right ear lobe in a 49-year-old man is reported. Pathologic examination showed a well-circumscribed subcutaneous nodule, 2 cm in diameter. The components of the tumor were confirmed by immunohistochemistry. Reactivity for HMB-45 was negative. A review of the twelve published cases, including the present, reveals that the patients age ranged from 33 to 77 years (mean 53.6), the male/female ratio was 11.1. The tumors were solitary, asymptomatic, noninvasive, located most commonly in acral skin or on the ear. The clinical impression is that of a cyst, a lipoma or a vascular tumor. Signs of tuberous sclerosis were absent in all cases. In contrast to the renal form, the cutaneous angiomyolipoma is a tumor differing in sex predominance, clinical associations, circumscription, solitariness, and HMB-45 immunoreactivity. Distinction from other mesenchymal lesions depends on recognition of traditional histologic criteria.

  20. Axitinib in Treating Patients With Melanoma That is Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-05-31

    Extraocular Extension Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIA Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIB Melanoma; Stage IIIC Intraocular Melanoma; Stage IIIC Melanoma; Stage IV Intraocular Melanoma; Stage IV Melanoma

  1. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine.

    PubMed

    Kircher, David A; Silvis, Mark R; Cho, Joseph H; Holmen, Sheri L

    2016-01-01

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

  2. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

    PubMed Central

    Kircher, David A.; Silvis, Mark R.; Cho, Joseph H.; Holmen, Sheri L.

    2016-01-01

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

  3. 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

  4. 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

  5. Cixutumumab in Treating Patients With Metastatic Melanoma of the Eye

    ClinicalTrials.gov

    2015-06-25

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Iris Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Stage IV Intraocular Melanoma

  6. Transmission of donor melanoma to multiple organ transplant recipients.

    PubMed

    Morris-Stiff, G; Steel, A; Savage, P; Devlin, J; Griffiths, D; Portman, B; Mason, M; Jurewicz, W A

    2004-03-01

    Malignant melanoma represents the most common tumour responsible for donor-derived post transplantation malignancies. We report the varied presentation and outcome of three graft recipients (two kidney and hepatic) who developed metastatic melanoma following cadaveric organ transplantation from a single multiorgan donor. Two of the recipients presented with symptomatic metastatic lesions and the third patient, despite being carefully monitored, developed evidence of metastatic cutaneous melanoma. Two of the patients died as a direct result of their melanomas. The recipients of corneal and cardiac grafts remain disease-free. We conclude that despite careful screening, donor-derived tumours remain a not uncommon clinical entity. The identification of a lesion in one recipient should prompt immediate examination and investigation of the remaining recipients of multiorgan donations.

  7. Primary glottic malignant melanoma of the larynx (PGMML): a very rare entity.

    PubMed

    Aggarwal, Sumeet; Kaushal, Vivek; Singla, Sujata; Sen, Rajeev

    2015-11-20

    Primary glottic malignant melanoma of the larynx (PGMML) is a very rare clinical entity with less than 20 cases reported in the literature so far. The most frequently reported subsite in primary malignant melanomas of the larynx is the supraglottic larynx. The vocal cord as a subsite for primary malignant melanoma is very rare. The present case is a primary glottic malignant melanoma involving both vocal cords. PGMML may present early due to associated hoarseness of voice, unlike other non-cutaneous melanomas in the head and neck. Non-cutaneous malignant melanomas in the head and neck are historically very aggressive in nature and known for poor outcomes and survival. Most non-cutaneous melanomas described in the literature have been superficial spreading or ulcerative in nature, unlike the present case, in which proliferative, polypoidal growth was seen. No associated risk factor was present in this case. Every reported case of this rare entity further adds to the better understanding of tumour biology and expression.

  8. Influence of sun exposures during childhood and during adulthood on melanoma risk. EPIMEL and EORTC Melanoma Cooperative Group. European Organisation for Research and Treatment of Cancer.

    PubMed

    Autier, P; Doré, J F

    1998-08-12

    Sun exposure in both childhood and adult life represents the main environmental risk determinant for cutaneous melanoma. However, little is known about the joint effects of sun exposure during early and later life on melanoma risk. A case-control study in Belgium, Germany and France conducted in 1991-1992 suggests that the melanoma risks attached to indicators related to sun exposure appear to combine their effects in an additive way. We therefore constructed composite indices of sun exposure during childhood and during adulthood, assuming additive combinations of melanoma risk associated with each indicator of sun exposure. Logistic regression modeling showed that the melanoma risk associated with a given level of sun exposure during adulthood increased with higher sun exposure during childhood, but the increase in risk was higher than the simple addition of melanoma risk associated with sun exposure during childhood or adulthood. In turn, high sun exposure during childhood constituted a significant risk factor for melanoma only if there was substantial sun exposure during adult life. We thus suggest that sun exposure during childhood and during adulthood would be interdependent as far as their impact on melanoma risk is concerned. Our results support the hypothesis by which the important contribution of sun exposure during childhood in melanoma occurrence is not properly assessed by retrospective epidemiologic studies. Sun avoidance during childhood would have a greater impact on melanoma risk than sun avoidance during adulthood.

  9. Primary Malignant Melanoma of Maxilla: Report of a Case with Discussion

    PubMed Central

    Rani, G. Shirisha; Kumar, T. Vinay; Begum, Md Rezwana; Priya Srinivasan, Anu

    2014-01-01

    Primary oral malignant melanoma, very rare neoplasm of melanocytic origin, usually presents as a bluish black to tan-brown colored lesion Which is accounting for 0.2 to 8% of all melanomas, 1.6% of all head and neck malignancies, and 0.5% of all oral neoplasia. In general, the prognosis of oral melanoma is poor and worse than that of cutaneous melanoma. Here a case of oral malignant melanoma is presented, which was undetected during the first visit to a dental clinic. When a simple oral surgical treatment was carried out in that region, it resulted in the appearance of a massive pigmented lesion which was histopathologically diagnosed as malignant melanoma. This paper is presented to reemphasize the fact that any pigmented lesion in the oral cavity should be viewed with suspicion and proper investigation (biopsy) should be carried out to rule out any untoward experiences later. PMID:25642350

  10. [Mucosal melanomas of the head and neck: State of the art and current controversies].

    PubMed

    Troussier, Idriss; Baglin, Anne-Catherine; Marcy, Pierre-Yves; Even, Caroline; Moya-Plana, Antoine; Krengli, Marco; Thariat, Juliette

    2015-06-01

    Mucosal melanomas of the head and neck (sinonasal and oral cavity) account for 1% of neoplasms, 4% of all melanomas and over 50% of all mucosal melanomas. They have a high metastatic potential. Five-year overall survival does not exceed 30%. Diagnosis may be difficult and includes adequate immunohistochemical staining. Risk factors, presentation and molecular biology are different from those of cutaneous melanomas. The mainstay of treatment is surgery and postoperative radiotherapy. Endoscopic surgery should be evaluated prospectively. Neck dissection is recommended for N0 oral cavity melanomas, while it can generally be omitted for sinonasal melanomas. Inoperable tumors can be treated with exclusive radiotherapy. Molecular guidance for metastatic cases is a relevant option despite low level of evidence, based on the rarity of disease and low response rates to chemotherapy. c-KIT inhibitors and immunotherapy appear promising.

  11. AC-93253 triggers the downregulation of melanoma progression markers and the inhibition of melanoma cell proliferation.

    PubMed

    Karwaciak, Iwona; Gorzkiewicz, Michal; Ryba, Katarzyna; Dastych, Jaroslaw; Pulaski, Lukasz; Ratajewski, Marcin

    2015-07-01

    A major challenge in anti-melanoma therapy is to develop treatments that are effective for advanced melanoma patients. Unfortunately, the currently used regimens are not efficient and have unsatisfactory effects on disease progression, thus increasing the pressure to develop new, profitable drugs and to identify new molecular targets. Here, we show for the first time that AC-93253, a SIRT2 inhibitor, exerts a negative effect on the expression of a set of genes involved in the progression and chemoresistance (e.g., oncogenes, apoptosis-related genes, ABC transporter genes, and cell cycle control genes) of melanoma cells. Furthermore, melanoma cells exposed to AC-93253 and doxorubicin displayed altered biological responses, including apoptosis and proliferation, compared to cells exposed to single treatments. Taken together, we conclude that the usage of AC-93253 in combined therapy could be a promising strategy for melanoma patients.

  12. Molecular Classification of Melanoma

    Cancer.gov

    Tissue-based analyses of precursors, melanoma tumors and metastases within existing study populations to further understanding of the heterogeneity of melanoma and determine a predictive pattern of progression for dysplastic nevi.

  13. General Information about Melanoma

    MedlinePlus

    ... Screening Research Melanoma Treatment (PDQ®)–Patient Version General Information About Melanoma Go to Health Professional Version Key ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  14. 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

  15. CTGF is a therapeutic target for metastatic melanoma.

    PubMed

    Finger, E C; Cheng, C-F; Williams, T R; Rankin, E B; Bedogni, B; Tachiki, L; Spong, S; Giaccia, A J; Powell, M B

    2014-02-27

    Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.

  16. Melanoma to the heart

    PubMed Central

    Hall, James A.; Fidone, Erica J.; Mack, Ryan; Metting, Austin L.

    2016-01-01

    Malignant melanoma is the third most common skin cancer yet has the highest mortality rate due to its predilection for metastasis. While the diagnosis of antemortem melanoma with cardiac metastasis is relatively uncommon, diagnosing malignant melanoma itself by first identifying a cardiac metastasis is even more rare. This vignette describes an antemortem diagnosis of melanoma in a 50-year-old woman through identification of metastasis to multiple sites, including the tricuspid valve. PMID:27695188

  17. Melanoma to the heart

    PubMed Central

    Hall, James A.; Fidone, Erica J.; Mack, Ryan; Metting, Austin L.

    2016-01-01

    Malignant melanoma is the third most common skin cancer yet has the highest mortality rate due to its predilection for metastasis. While the diagnosis of antemortem melanoma with cardiac metastasis is relatively uncommon, diagnosing malignant melanoma itself by first identifying a cardiac metastasis is even more rare. This vignette describes an antemortem diagnosis of melanoma in a 50-year-old woman through identification of metastasis to multiple sites, including the tricuspid valve.

  18. 18F-FDG PET/CT Reveals Disease Remission in a Patient With Ipilimumab-Refractory Advanced Melanoma Treated With Pembrolizumab.

    PubMed

    Sachpekidis, Christos; Hassel, Jessica C; Dimitrakopoulou-Strauss, Antonia

    2016-02-01

    Pembrolizumab is an anti-programmed cell death receptor 1 (anti-PD-1) antibody, recently approved for the treatment of ipilimumab-refractory metastatic melanoma. We report on a 49-year-old patient with unresectable metastatic melanoma initially treated with 4 cycles of ipilimumab. Because of demonstration of progressive disease on PET/CT, the patient was enrolled into a clinical trial of pembrolizumab. After completion of 4 cycles of pembrolizumab, the follow-up PET/CT scans performed early after and 7 months after the end of treatment exhibited complete disease remission, reflecting the potential role of the modality in treatment response evaluation of melanoma patients receiving anti-PD-1 therapy.

  19. Sun exposure and melanoma prognostic factors

    PubMed Central

    GANDINI, SARA; MONTELLA, MAURIZIO; AYALA, FABRIZIO; BENEDETTO, LUCIA; ROSSI, CARLO RICCARDO; VECCHIATO, ANTONELLA; CORRADIN, MARIA TERESA; DE GIORGI, VINCENZO; QUEIROLO, PAOLA; ZANNETTI, GUIDO; GIUDICE, GIUSEPPE; BORRONI, GIOVANNI; FORCIGNANÒ, ROSACHIARA; PERIS, KETTY; TOSTI, GIULIO; TESTORI, ALESSANDRO; TREVISAN, GIUSTO; SPAGNOLO, FRANCESCO; ASCIERTO, PAOLO A.

    2016-01-01

    Previous studies have reported an association between sun exposure and the increased survival of patients with cutaneous melanoma (CM). The present study analyzed the association between ultraviolet (UV) light exposure and various prognostic factors in the Italian Clinical National Melanoma Registry. Clinical and sociodemographic features were collected, as well as information concerning sunbed exposure and holidays with sun exposure. Analyses were performed to investigate the association between exposure to UV and melanoma prognostic factors. Between December 2010 and December 2013, information was obtained on 2,738 melanoma patients from 38 geographically representative Italian sites. A total of 49% of the patients were >55 years old, 51% were men, 50% lived in the north of Italy and 57% possessed a high level of education (at least high school). A total of 8 patients had a family history of melanoma and 56% had a fair phenotype (Fitzpatrick skin type I or II). Of the total patients, 29% had been diagnosed with melanoma by a dermatologist; 29% of patients presented with a very thick melanoma (Breslow thickness, >2 mm) and 25% with an ulcerated melanoma. In total, 1% of patients had distant metastases and 13% exhibited lymph node involvement. Holidays with sun exposure 5 years prior to CM diagnosis were significantly associated with positive prognostic factors, including lower Breslow thickness (P<0.001) and absence of ulceration (P=0.009), following multiple adjustments for factors such as sociodemographic status, speciality of doctor performing the diagnosis and season of diagnosis. Sunbed exposure and sun exposure during peak hours of sunlight were not significantly associated with Breslow thickness and ulceration. Holidays with sun exposure were associated with favorable CM prognostic factors, whereas no association was identified between sunbed use and sun exposure during peak hours of sunlight with favorable CM prognostic factors. However, the results of the

  20. [Malignant melanoma coexisting with pregnancy].

    PubMed

    Krasomski, G; Broniarczyk, D; Gładysiak, A

    1992-09-01

    An extremely rare case of melanoma amelanoticum coexisting with pregnancy has been discussed. Pregnant A. Ch., age 42, was admitted to the Polish Mother's Health Centre Memorial Hospital on the 22nd of August, 1990 with a diagnosis of the 5th pregnancy, the 2nd delivery, the 30th week of gestation, state after cesarean section. Suspected malignant melanoma. Stomach ulceration. Thrombophlebitis of left lower extremity. General condition--medium hard. For the last three days she did not report fetal movements, fetal heartbeat was not detected either. Us examination confirmed fetal death. On the 24th of August, 1990, spontaneous vaginal delivery terminated the pregnancy, giving a dead, macerated female fetus, body weight of 1500 g. On the 3rd day after delivery the patient died with growing circulation-respiratory insufficiency. Autopsy revealed melanoma malignum amelanoticum disseminatum. Neither an autopsy of the fetus nor histopathological examinations of the secundines were performed for the advanced maceration. The coexistence of pregnancy with malignant melanoma in this case brought a tragic end both for the mother and the fetus. PMID:1305602

  1. Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

    ClinicalTrials.gov

    2016-10-31

    Mucosal Melanoma; Recurrent Melanoma; Recurrent Uveal Melanoma; Stage IIIA Skin Melanoma; Stage IIIA Uveal Melanoma; Stage IIIB Skin Melanoma; Stage IIIB Uveal Melanoma; Stage IIIC Skin Melanoma; Stage IIIC Uveal Melanoma; Stage IV Skin Melanoma; Stage IV Uveal Melanoma

  2. The genetics of uveal melanoma: current insights

    PubMed Central

    Helgadottir, Hildur; Höiom, Veronica

    2016-01-01

    Uveal melanoma (UM) is the most common malignant eye tumor in adults affecting ~7,000 individuals per year worldwide. UM is a rare subtype of melanoma with distinct clinical and molecular features as compared to other melanoma subtypes. UMs lack the most typical cutaneous melanoma-associated mutations (BRAF, NRAS, and NF1) and are instead characterized by a different set of genes with oncogenic or loss-of-function mutations. By next-generation sequencing efforts on UM tumors, several driver genes have been detected. The most frequent ones are BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. In many cases, mutations in these genes appear in a mutually exclusive manner, have different risk of metastasis, and are consequently of prognostic importance. The majority of UM cases are sporadic but a few percentage of the cases occurs in families with an inherited predisposition for this malignancy. In recent years, germline mutations in the BAP1 gene have been found to segregate in an autosomal dominant pattern with numerous different cancer types including UM in cancer-prone families. This cancer syndrome has been denoted as the tumor predisposition syndrome.

  3. The genetics of uveal melanoma: current insights

    PubMed Central

    Helgadottir, Hildur; Höiom, Veronica

    2016-01-01

    Uveal melanoma (UM) is the most common malignant eye tumor in adults affecting ~7,000 individuals per year worldwide. UM is a rare subtype of melanoma with distinct clinical and molecular features as compared to other melanoma subtypes. UMs lack the most typical cutaneous melanoma-associated mutations (BRAF, NRAS, and NF1) and are instead characterized by a different set of genes with oncogenic or loss-of-function mutations. By next-generation sequencing efforts on UM tumors, several driver genes have been detected. The most frequent ones are BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. In many cases, mutations in these genes appear in a mutually exclusive manner, have different risk of metastasis, and are consequently of prognostic importance. The majority of UM cases are sporadic but a few percentage of the cases occurs in families with an inherited predisposition for this malignancy. In recent years, germline mutations in the BAP1 gene have been found to segregate in an autosomal dominant pattern with numerous different cancer types including UM in cancer-prone families. This cancer syndrome has been denoted as the tumor predisposition syndrome. PMID:27660484

  4. The genetics of uveal melanoma: current insights.

    PubMed

    Helgadottir, Hildur; Höiom, Veronica

    2016-01-01

    Uveal melanoma (UM) is the most common malignant eye tumor in adults affecting ~7,000 individuals per year worldwide. UM is a rare subtype of melanoma with distinct clinical and molecular features as compared to other melanoma subtypes. UMs lack the most typical cutaneous melanoma-associated mutations (BRAF, NRAS, and NF1) and are instead characterized by a different set of genes with oncogenic or loss-of-function mutations. By next-generation sequencing efforts on UM tumors, several driver genes have been detected. The most frequent ones are BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. In many cases, mutations in these genes appear in a mutually exclusive manner, have different risk of metastasis, and are consequently of prognostic importance. The majority of UM cases are sporadic but a few percentage of the cases occurs in families with an inherited predisposition for this malignancy. In recent years, germline mutations in the BAP1 gene have been found to segregate in an autosomal dominant pattern with numerous different cancer types including UM in cancer-prone families. This cancer syndrome has been denoted as the tumor predisposition syndrome. PMID:27660484

  5. Vaccine Therapy in Treating Patients With Stage IIC-IV Melanoma

    ClinicalTrials.gov

    2014-05-20

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Iris Melanoma; Metastatic Intraocular Melanoma; Mucosal Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage IIC Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIA Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIB Melanoma; Stage IIIC Intraocular Melanoma; Stage IIIC Melanoma; Stage IV Intraocular Melanoma; Stage IV Melanoma

  6. 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

  7. Xeroderma pigmentosum with melanoma of face and its prosthetic management.

    PubMed

    Sadaf, Ayesha; Yazdanie, Nazia

    2013-10-01

    Xeroderma pigmentosum is a rare genetic disorder, characterized by cutaneous, ocular and neurological symptoms. Squamous cell carcinoma and melanoma are also its secondary characters. This case report is about maxillofacial prosthetic management of a 10 years old child presented with xeroderma pigmentosum. The nose of the patient was excised surgically due to melanoma. This case report elaborates the role of prosthodontist and the whole procedure of constructing the nasal prosthesis via conventional technique by using the patient's sibling nasal form as template. Regular follow up revealed marked improvement in esthetics, function and ultimately patient's quality of life.

  8. Melanoma never says die.

    PubMed

    Haass, Nikolas K; Schumacher, Udo

    2014-07-01

    Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Targeting apoptosis regulators is thus considered a promising approach to sensitizing melanoma to therapy. In the previous issue of Experimental Dermatology, Plötz and Eberle discuss the role that apoptosis plays in melanoma progression and drug resistance and the utility of apoptosis-inducing BH3-mimetics as targeted therapy. There are a number of compounds in clinical development and the field seems close to translating recent findings into benefits for patients with melanoma. Thus, this viewpoint is timely and achieves a valuable summary of the current state of apoptosis-inducing therapy of melanoma.

  9. Delayed reaction to suture material simulating melanoma.

    PubMed

    Frumkin, A; Gorbacz, S; Lifschitz-Mercer, B

    1992-01-01

    A twenty-one-year-old woman who had been involved in an accident sustained severe trauma to the left side of her face and scalp. Because of deterioration in her neurologic condition, a number of exploratory burr holes were drilled in her skull. Fifteen years later, a 6 mm black tender nodule was noted on the left temple, close to one of the burr holes. Nodular melanoma was suspected, but results of microscopic examination proved the lesion to be a granuloma with transepidermal elimination of exogenous filamentous material. The relationship between foreign bodies and cutaneous neoplasia, genuine or simulated, is noted briefly. PMID:1733661

  10. Pembrolizumab for the treatment of melanoma.

    PubMed

    Kumar, Sanjeev Srinivas; McNeil, Catriona Mairi

    2015-01-01

    The immune system plays a vital role in regulating tumor growth, and the oncology community has witnessed an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. The utility of these strategies in advanced melanoma has been at the forefront of these developments. In particular, blockade of programmed cell death protein 1 (PD-1) in advanced melanoma has proven to be a most promising new anticancer strategy. Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. Its effect has been most convincingly demonstrated in the setting of advanced melanoma, with growing evidence of clinical responses across a broad spectrum of other solid and hematological malignancies.

  11. Cutaneous pancreatic metastasis: a case report and review of literature.

    PubMed

    Hafez, H Z Abdel

    2008-01-01

    Pancreatic cancer is one of the most dangerous human cancers and will continue to be a major unsolved health problem as we enter the 21(st) century. This is the case despite advances in imaging technology and surgical management. Indeed, 80% to 90% of pancreatic cancers are diagnosed either at the locally advanced or metastatic stage. Cutaneous metastases originating from pancreatic cancer are relatively rare. The most common site of cutaneous metastasis is the umbilicus, and this is known as the Sister Joseph's nodule. Very few patients have been reported with cutaneous lesions disclosing a pancreatic carcinoma at sites other than the umbilical area. To the best of our knowledge, there have been no previous reports on cutaneous pancreatic metastasis in Egypt. This is a report on a patient with cutaneous pancreatic metastases at the neck and review of reported non-umbilical cutaneous metastases from pancreatic carcinoma in the literatures.

  12. Cutaneous pancreatic metastasis: a case report and review of literature.

    PubMed

    Hafez, Hza

    2007-01-01

    Pancreatic cancer is one of the most lethal human cancers and continues to be a major unsolved health problem as we enter the 21st century. This is the case despite advances in imaging technology and surgical management. Indeed, 80-90% of pancreatic cancers are diagnosed either at the locally advanced stage or metastatic stage. Cutaneous metastases originating from pancreatic cancer are relatively rare. The most common site of cutaneous metastasis is the umbilicus, and it is known as the Sister Joseph's nodule. Very few patients have been reported with cutaneous lesions disclosing pancreatic carcinoma at sites other than the umbilical area. To our knowledge, there were no previous reports on cutaneous pancreatic metastasis in Egypt. This is a report of a patient with cutaneous pancreatic metastases at the neck, followed by a review of reported non-umbilical cutaneous metastases from pancreatic carcinoma in the literature.

  13. Genetics of familial melanoma: 20 years after CDKN2A.

    PubMed

    Aoude, Lauren G; Wadt, Karin A W; Pritchard, Antonia L; Hayward, Nicholas K

    2015-03-01

    Twenty years ago, the first familial melanoma susceptibility gene, CDKN2A, was identified. Two years later, another high-penetrance gene, CDK4, was found to be responsible for melanoma development in some families. Progress in identifying new familial melanoma genes was subsequently slow; however, with the advent of next-generation sequencing, a small number of new high-penetrance genes have recently been uncovered. This approach has identified the lineage-specific oncogene MITF as a susceptibility gene both in melanoma families and in the general population, as well as the discovery of telomere maintenance as a key pathway underlying melanoma predisposition. Given these rapid recent advances, this approach seems likely to continue to pay dividends. Here, we review the currently known familial melanoma genes, providing evidence that most additionally confer risk to other cancers, indicating that they are likely general tumour suppressor genes or oncogenes, which has significant implications for surveillance and screening. PMID:25431349

  14. Melanoma and occupation: results of a case-control study.

    PubMed Central

    Fritschi, L; Siemiatycki, J

    1996-01-01

    OBJECTIVES: Associations between occupational exposures and the occurrence of cutaneous melanoma were examined as part of a large population based case-control study of 19 cancer sites. METHODS: Cases were men aged 35 to 70 years old, resident in Montreal, Canada, with a new histologically confirmed cutaneous melanoma (n = 103). There were two control groups, a randomly selected population control group (n = 533), and a cancer control group (n = 533) randomly selected from among subjects with other types of cancer in the large study. Odds ratios for the occurrence of melanoma were calculated for each exposure circumstance for which there were more than four exposed cases (85 substances, 13 occupations, and 20 industries) adjusting for age, ethnicity, and number of years of schooling. RESULTS: Significantly increased risk of melanoma was found for exposure to four substances (fabric dust, plastic dust, trichloroethylene, and a group containing paints used on surfaces other than metal and varnishes used on surfaces other than wood), three occupations (warehouse clerks, salesmen, and miners and quarrymen), and two industries (clothing and non-metallic mineral products). CONCLUSIONS: Most of the occupational circumstances examined were not associated with melanoma, nor is there any strong evidence from previous research that any of those are risk factors. For the few occupational circumstances which were associated in our data with melanoma, the statistical evidence was weak, and there is little or no supporting evidence in the scientific literature. On the whole, there is no persuasive evidence of occupational risk factors for melanoma, but the studies have been too small or have involved too much misclassification of exposure for this conclusion to be definitive. PMID:8704857

  15. Melanoma in Maori, Asian, and Pacific peoples in New Zealand.

    PubMed

    Sneyd, Mary Jane; Cox, Brian

    2009-06-01

    New Zealand Maori, Pacific, and Asian people develop melanoma less frequently than New Zealand Europeans, but little is known about melanomas that develop in these people. We examined the characteristics of melanoma in these minority ethnic groups in New Zealand. In 2007, all first primary melanomas diagnosed from January 1996 to December 2006 were extracted from the New Zealand Cancer Registry database. Melanoma was more commonly diagnosed in Maori than Asian or Pacific peoples. Age-adjusted incidence rates increased annually from 1996 to 2006 by 0.37 per 100,000 in the total population and 0.20 per 100,000 in Maori, a 12% (from 30.9 to 34.6) and 90% (from 2.3 to 4.3) increase, respectively, over the 11 years. Nodular melanoma occurred more often in Maori (15.9%) and Pacific peoples (17.1%) compared with Asians (8.7%) and New Zealand Europeans (10.5%). In Pacific peoples, acral lentiginous melanoma (22.9%) was the most common subtype. The median thickness of melanoma was 0.78 mm in New Zealand Europeans, 1.2 mm in Maori, 2.5 mm in Pacific peoples, and 0.73 mm in Asians (P < 0.001, difference in medians). Thirty-seven percent of melanomas in Pacific peoples were >4 mm thick compared with 7.9% in New Zealand Europeans. About 13% of Asians and 11% of Pacific peoples, compared with 4% of New Zealand Europeans with melanoma, were diagnosed by histology of metastases rather than the primary lesion. Minority ethnicities in New Zealand have a higher than expected risk of thick and more advanced melanoma, with poorer prognosis. Melanoma campaigns should include messages that incorporate the unique features of melanoma in minorities.

  16. Metastatic malignant melanoma of the inguinal lymph node with unknown primary lesion.

    PubMed

    Eltawansy, Sherif Ali; Panasiti, Ryane; Hasanien, Samaa; Lourdusamy, Dennis; Sharon, David

    2015-01-01

    Background. Malignant melanoma could present with metastasis with unknown primary (MUP) and this happens in 2-3% according to the studies. Around 90% of melanomas have cutaneous origin, but still there are melanomas that could be found in visceral organs or lymph nodes with unknown primary site. Spontaneous regression of the primary site could be an explanation. Case Report. We report a 58-year-old Caucasian male who presented with a right sided swelling in the inguinal region. Surgery was performed and biopsy showed metastatic malignant melanoma. No cutaneous lesions were identified by history or physical examination. Work up could not detect the primary lesion and patient was started on radiotherapy and immunotherapy. Conclusion. We present a case of malignant melanoma of unknown primary presenting in an unusual place which is the inguinal lymph node. Theories try to explain the pathway of development of such tumors and one of the theories mentions that it could be a spontaneous regression of the primary cutaneous lesion. Another theory is that it could be from transformation of aberrant melanocyte within the lymph node. Prognosis is postulated to be better in this case than in melanoma with a known primary. PMID:25705230

  17. Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression

    PubMed Central

    Daud, Adil; Algazi, Alain; Gubens, Matthew; Luna, Sara Alcántara; Lin, Kevin; Quaglino, Pietro; Rappersberger, Klemens; Ortiz-Urda, Susana

    2016-01-01

    IMPORTANCE Immunomodulatory anticancer drugs, such as the anti–programmed death-1 drug pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response. OBJECTIVE To describe the frequency and spectrum of cutaneous AEs linked with pembrolizumab and their possible correlation with treatment response. DESIGN, SETTING, AND PARTICIPANTS A single-institution, retrospective medical record review was conducted of patients with cancer who were treated with pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83 consecutive patients who were enrolled in 2 clinical trials, received at least 1 dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped according to the following therapeutic regimen for pembrolizumab: 43 received 10 mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma. Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES Occurrence, severity, and type of cutaneous AEs, as well as disease progression and response to pembrolizumab treatment. RESULTS Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma. Survival analyses showed that patients who developed cutaneous AEs had significantly longer progression-free intervals in all 3 groups (pembrolizumab, 10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P = .003; pembrolizumab, 2 mg/kg, every 3

  18. Cutaneous lasers.

    PubMed

    Fedok, Fred G; Garritano, Frank; Portela, Antonio

    2013-02-01

    There has been a remarkable development and evolution of laser technology, leading to adaptation of lasers for medical use and the treatment of skin problems and disorders. Many treatments that required incisional surgery and other invasive methods are now preferentially treated with a laser. Although laser advances have resulted in the availability of some amazing tools, they require the clinical skill and judgment of the clinician for their optimal use. This article provides a clinically oriented overview of many of the lasers valuable in facial plastic surgery. Basic science, clinical adaptations, and patient management topics are covered.

  19. Current State of Animal (Mouse) Modeling in Melanoma Research

    PubMed Central

    Kuzu, Omer F.; Nguyen, Felix D.; Noory, Mohammad A.; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future. PMID:26483610

  20. Current State of Animal (Mouse) Modeling in Melanoma Research.

    PubMed

    Kuzu, Omer F; Nguyen, Felix D; Noory, Mohammad A; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future.

  1. Generation and analysis of zebrafish melanoma models.

    PubMed

    Wojciechowska, S; van Rooijen, E; Ceol, C; Patton, E E; White, R M

    2016-01-01

    The rapid emergence of the zebrafish as a cancer model has been aided by advances in genetic, chemical, and imaging technologies. Melanoma in particular highlights both the power and challenges associated with cancer modeling in zebrafish. This chapter focuses on the lessons that have emerged from the melanoma models as paradigmatic of what will apply to nearly all cancer models in the zebrafish system. We specifically focus on methodologies related to germline and mosaic transgenic melanoma generation, and how these can be used to deeply interrogate additional cooperating oncogenes or tumor suppressors. These transgenic tumors can in turn be used to generate zebrafish-specific, stable melanoma cell lines which can be fluorescently labeled, modified by cDNA/CRISPR techniques, and used for detailed in vivo imaging of cancer progression in real time. These zebrafish melanoma models are beginning to elucidate both cell intrinsic and microenvironmental factors in melanoma that have broader implications for human disease. We envision that nearly all of the techniques described here can be applied to other zebrafish cancer models, and likely expanded beyond what we describe here. PMID:27312504

  2. Melanoma resistance to photodynamic therapy: new insights

    PubMed Central

    Huang, Ying-Ying; Vecchio, Daniela; Avci, Pinar; Yin, Rui; Garcia-Diaz, Maria; Hamblin, Michael R.

    2012-01-01

    Melanoma is the most dangerous form of skin cancer, with a steeply rising incidence and a poor prognosis in its advanced stages. Melanoma is highly resistant to traditional chemotherapy and radiotherapy, although modern targeted therapies such as BRAF inhibitors are showing some promise. Photodynamic therapy (PDT, the combination of photosensitizing dyes and visible light) has been tested for melanoma with some promising results, but melanoma is generally considered to also be resistant to PDT. Optical interference by the highly-pigmented melanin, the anti-oxidant effect of melanin, the sequestration of photosensitizers inside melanosomes, defects in apoptotic pathways, and the efflux of photosensitizers by ATP-binding cassette (ABC) transporters have all been implicated in melanoma resistance to PDT. Approaches to overcoming melanoma resistance to PDT include: the discovery of highly active photosensitizers absorbing in the 700–800-nm near infrared spectral region; interventions that can temporarily reduce the amount or the pigmentation of the melanin; compounds that can reverse apoptotic defects or inhibit drug-efflux of photosensitizers; and immunotherapy approaches that can take advantage of the ability of PDT to activate the host immune system to the treated tumor. PMID:23152406

  3. Do sunscreens increase or decrease melanoma risk: an epidemiologic evaluation.

    PubMed

    Weinstock, M A

    1999-09-01

    Ultraviolet adiation is an important cause of melanoma, so the use of sunscreen lotions has been advocated for melanoma prevention. Several arguments have been raised in opposition to this inference. Sunscreen use may interfere with cutaneous vitamin D synthesis, which some have hypothesized may lower melanoma risk. Sunscreen users may compensate for their sunscreen use by staying out much longer in the sun, or may use sunscreen lotions inconsistantly. Published melanoma case-control studies have not consistantly demonstrated a protective effect of sunscreens; however, these studies do not provide strong evidence, ultraviolet radiation is a known cause of melanoma, and ultraviolet B may be particularly potent, so on balance the evidence supports continued advocacy of sunscreen lotion use as part of an overall sun-protection regimen. Uncertainty will remain, however, until the action spectrum of melanoma is convincingly demonstrated or the methodologic limitations of existing epidemiologic evidence are overcome. The latter may require another decade or more of experience with sunscreen use.

  4. Artificial ultraviolet radiation and ocular melanoma in Australia.

    PubMed

    Vajdic, Claire M; Kricker, Anne; Giblin, Michael; McKenzie, John; Aitken, Joanne F; Giles, Graham G; Armstrong, Bruce K

    2004-12-10

    We examined risk of ocular melanoma with exposure to artificial sources of exposure to ultraviolet radiation (UVR) in a population-based epidemiologic study of 290 cases of ocular melanoma and 893 controls aged 18-79 years in Australia in 1996-1998. Cases were identified through a prospective survey of all ophthalmologists and cancer registries in Australia; 91.8% participated. Controls were sourced from electoral rolls; 67.4% of those who were eligible and contactable participated, while 27.3% could not be contacted. Exposure to welding and use of sunlamps, including sunbeds and tanning booths, was measured by telephone interview. Analyses used unconditional logistic regression and included age, sex, region of birth, eye color, ocular and cutaneous sun sensitivity and personal sun exposure as covariates. Risk of choroid and ciliary body melanoma in 246 cases increased significantly with longer duration of use of sunlamps, first use before 21 years of age and first use after 1980. These effects were independent of personal sun exposure. Risk of these melanomas also increased with increasing duration of welding exposure, although the trend was not significant overall. There was no evidence that these exposures increased the risk of iris (n = 25) or conjunctival (n = 19) melanomas. Personal exposure to sunlamps and welding predicts risk of choroid and ciliary body melanoma in Australia.

  5. Dietary Antioxidants and Melanoma: Evidence from Cohort and Intervention Studies.

    PubMed

    Miura, Kyoko; Green, Adèle C

    2015-01-01

    Melanoma is the most serious form of skin cancer affecting mostly people of Caucasian origin and is associated with high exposure to solar ultraviolet (UV) radiation. Antioxidants in the diet are thought to prevent UV-induced DNA damage and oxidative stress and laboratory-based studies have shown that high antioxidant intakes inhibit melanoma development. Corresponding epidemiological evidence is inconsistent, however. We therefore reviewed results from prospective observational studies and randomized controlled trials (RCTs) to clarify whether consumption of antioxidant vitamin C, E (tocopherol), and A (retinol), carotenoids and selenium, as food, supplements, or both, or high fruit and vegetable intake, reduce the incidence of cutaneous melanoma. A total of 9 studies (2 cohort, 1 nested case-control, 6 RCTs) were included. Neither antioxidant nutrients, individually or combined, nor fruit and vegetable intake showed any strong and significant associations with melanoma, though the number of relevant studies was limited and several had methodological shortcomings. In particular, melanoma was not a primary disease outcome in any of the RCTs and therefore, none adequately accounted for potential confounding by sun exposure. In conclusion, available evidence is currently inadequate to assess possible beneficial effects of antioxidant intake on melanoma risk. PMID:26147450

  6. Relevance of in vivo models in melanoma skin cancer

    SciTech Connect

    Setlow, R.B.

    1995-12-31

    A discussion of possible wavelength dependence of induction of cutaneous malignant melanoma (CMM) is provided. Strengths and weaknesses of various experimental approaches to better understanding of the prevalence of CMM in different human populations including latitude effects are compared. Further the advantages and limitations of the use of the laboratory opossum (Monodelphis domestic), transgenic mice containing SV40 ongogene sequences under tyrosinase promoter control, and a backcross hybrid fish of the genus Xenophorus are contrasted.

  7. Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Stage IV Melanoma

    ClinicalTrials.gov

    2016-05-06

    Acral Lentiginous Malignant Melanoma; Lentigo Maligna Malignant Melanoma; Nodular Malignant Melanoma; Recurrent Melanoma; Solar Radiation-related Skin Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma

  8. Phase II Clinical Trial of Intratumoral Application of TG1042 (Adenovirus-interferon-γ) in Patients With Advanced Cutaneous T-cell Lymphomas and Multilesional Cutaneous B-cell Lymphomas

    PubMed Central

    Dummer, Reinhard; Eichmüller, Stefan; Gellrich, Sylke; Assaf, Chalid; Dreno, Brigitte; Schiller, Meinhard; Dereure, Olivier; Baudard, Marion; Bagot, Martine; Khammari, Amir; Bleuzen, Pascal; Bataille, Vincent; Derbij, Anna; Wiedemann, Nicole; Waterboer, Tim; Lusky, Monika; Acres, Bruce; Urosevic-Maiwald, Mirjana

    2010-01-01

    Cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative disorders that are manageable by immunotherapy. Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-γ] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy. Treatment was well tolerated with few adverse events including injection site reactions, chills, lymphopenia, and fever. Immune monitoring in the peripheral blood demonstrated systemic immune activation and the induction of antibodies against tumor antigens in some patients without clear association with clinical responses. CLs, in particular B-cell lymphomas with high objective response rates, seem to be excellent targets for this type of immunotherapy. PMID:20372104

  9. Primary malignant melanoma

    PubMed Central

    Mısır, A. Ferhat; Durmuşlar, Mustafa C.; Zerener, Tamer; Gün, Banu D.

    2016-01-01

    Malignant melanomas (MM) of the oral cavity are extremely rare, accounting for 0.2% to 8.0% of all malignant melanomas. Malignant melanomas is more frequently seen at the level of the hard palate and gingiva. Early diagnosis and treatment are important for reducing morbidity. Malignant melanoma cells stain positively with antibodies to human melanoma black 45, S-100 protein, and vimentin; therefore, immunohistochemistry can play an important role in evaluating the depth of invasion and the location of metastases. A 76-year-old man developed an oral malignant melanoma, which was originally diagnosed as a bluish reactive denture hyperplasia caused by an ill-fitting lower denture. The tumor was removed surgically, and histopathological examination revealed a nodular-type MM. There was no evidence of recurrence over a 4-year follow-up period. PMID:27052289

  10. Immune evasion by murine melanoma mediated through CC chemokine receptor-10.

    PubMed

    Murakami, Takashi; Cardones, Adela R; Finkelstein, Steven E; Restifo, Nicholas P; Klaunberg, Brenda A; Nestle, Frank O; Castillo, S Sianna; Dennis, Phillip A; Hwang, Sam T

    2003-11-01

    Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)-dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression. PMID:14581607

  11. Small Bowel Melanoma Metastasing to Inguinal Lymph Node - a Rare Case.

    PubMed

    Chisthi M, Meer; M, Rahul; A, Sreekumar

    2015-06-01

    Malignant Melanoma is one of the commonest cutaneous malignancies affecting human beings. The gastrointestinal tract is a common site for melanoma, both as primary and metastases. However it is rare for gastrointestinal melanoma to metastase oustide of the abdominal cavity. In the literature, there is no evidence about inguinal lymph node metastases from small bowel melanoma. Here we present a case report of an old lady who underwent laparoscopic resection of small bowel for melanoma and presented 4 years later with metastatic lymph node in inguinal lymph node. Though it could not be verified, we hypothesise that the tumour disseminated to the lymph node through a port-site metastases. Literature review shows several mechanisms which were put forward to explain the mechanism of port-site metastases.

  12. VEGF Trap in Treating Patients With Recurrent Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2015-02-02

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Extraocular Extension Melanoma; Iris Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage III Melanoma; Stage IV Melanoma

  13. Cutaneous Manifestations of Selected Parasitic Infections in Western Pacific and Southeast Asian Regions.

    PubMed

    Belizario, Vicente; Delos Trinos, John Paul Caesar; Garcia, Nikko Benjamin; Reyes, Maureen

    2016-09-01

    Cutaneous manifestations of parasitic infections often result in discomfort, debilitation, and even stigmatization. Data on cutaneous manifestations of parasitic infections, however, are limited. This article provides updates on the cutaneous manifestations of parasitic infections which are known to occur in Western Pacific and Southeast Asian regions, such as scabies, pediculosis, cutaneous larva migrans, larva currens, cutaneous schistosomiasis, cutaneous enterobiasis, cutaneous cysticercosis, acute dermatolymphangioadenitis (lymphatic filariasis), and cutaneous amoebiasis. The lack of epidemiological data on these conditions suggests the need for improvements in recording and reporting of cases. Utilization of advance diagnostic modalities and capacity building of health workers are important for proper case management. Cutaneous manifestations of parasitic infections are a topic rarely studied and thus represent an opportunity for further research. PMID:27447892

  14. Interferon-β gene transfer induces a strong cytotoxic bystander effect on melanoma cells.

    PubMed

    Rossi, Úrsula A; Gil-Cardeza, María L; Villaverde, Marcela S; Finocchiaro, Liliana M E; Glikin, Gerardo C

    2015-05-01

    A local gene therapy scheme for the delivery of type I interferons could be an alternative for the treatment of melanoma. We evaluated the cytotoxic effects of interferon-β (IFNβ) gene lipofection on tumor cell lines derived from three human cutaneous and four canine mucosal melanomas. The cytotoxicity of human IFNβ gene lipofection resulted higher or equivalent to that of the corresponding addition of the recombinant protein (rhIFNβ) to human cells. IFNβ gene lipofection was not cytotoxic for only one canine melanoma cell line. When cultured as monolayers, three human and three canine IFNβ-lipofected melanoma cell lines displayed a remarkable bystander effect. As spheroids, the same six cell lines were sensitive to IFNβ gene transfer, two displaying a significant multicell resistance phenotype. The effects of conditioned IFNβ-lipofected canine melanoma cell culture media suggested the release of at least one soluble thermolabile cytotoxic factor that could not be detected in human melanoma cells. By using a secretion signal-free truncated human IFNβ, we showed that its intracellular expression was enough to induce cytotoxicity in two human melanoma cell lines. The lower cytoplasmatic levels of reactive oxygen species detected after intracellular IFNβ expression could be related to the resistance displayed by one human melanoma cell line. As IFNβ gene transfer was effective against most of the assayed melanomas in a way not limited by relatively low lipofection efficiencies, the clinical potential of this approach is strongly supported.

  15. Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal.

  16. Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal. PMID:26892651

  17. Evolving Pharmacotherapies for the Treatment of Metastatic Melanoma

    PubMed Central

    Salama, April K.S.

    2013-01-01

    Metastatic melanoma remains a difficult disease to treat, and long term survivors are rare. Over the past few years, however, breakthroughs in both immunotherapy as well as targeted agents have had a tremendous impact on patients diagnosed with this disease. This review summarizes recent advances in systemic therapies for melanoma, including immune modulators directed against cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), as well as a number of targeted agents. These approaches hold great promise as the landscape of therapeutic options for advanced melanoma continues to evolve. PMID:23843723

  18. Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013.

    PubMed

    Ascierto, Paolo A; Grimaldi, Antonio M; Anderson, Ana Carrizosa; Bifulco, Carlo; Cochran, Alistair; Garbe, Claus; Eggermont, Alexander M; Faries, Mark; Ferrone, Soldano; Gershenwald, Jeffrey E; Gajewski, Thomas F; Halaban, Ruth; Hodi, F Stephen; Kefford, Richard; Kirkwood, John M; Larkin, James; Leachman, Sancy; Maio, Michele; Marais, Richard; Masucci, Giuseppe; Melero, Ignacio; Palmieri, Giuseppe; Puzanov, Igor; Ribas, Antoni; Saenger, Yvonne; Schilling, Bastian; Seliger, Barbara; Stroncek, David; Sullivan, Ryan; Testori, Alessandro; Wang, Ena; Ciliberto, Gennaro; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

    2014-10-28

    The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers.

  19. First Oncolytic Viral Therapy for Melanoma.

    PubMed

    Poh, Alissa

    2016-01-01

    The FDA has approved talimogene laherparepvec, or T-VEC, to treat surgically unresectable skin and lymph node lesions in patients with advanced melanoma. T-VEC is the first oncolytic viral therapy to gain regulatory endorsement, based on data from the OPTiM study.

  20. Identification of differentially expressed microRNAs in metastatic melanoma using next-generation sequencing technology

    PubMed Central

    QI, MIN; HUANG, XIAOYUAN; ZHOU, LEI; ZHANG, JIANGLIN

    2014-01-01

    In this study, we investigated differentially expressed microRNAs (miRNAs or miRs) and their functions in metastatic melanoma using next-generation sequencing technology. The GSE36236 data set was downloaded from the Gene Expression Omnibus (GEO) database and 4 primary cutaneous melanoma samples (used as controls) and 3 metastatic melanoma samples were selected from 31 samples for further analysis. Firstly, the differentially expressed miRNAs were screened by limma package in R language. Secondly, the target genes of the miRNAs were retrieved with TargetScanHuman 6.2, and the interactions among these genes were identified by String and an interaction network was established. Finally, functional and pathway analyses were performed for the genes in the network using Expression Analysis Systematic Explorer (EASE). A total of 4 differentially expressed miRNAs (hsa-miR-146, hsa-miR-27, hsa-miR-877 and hsa-miR-186) were obtained between the metastatic melanoma and primary cutaneous melanoma samples. We predicted 101 high-confidence target genes of hsa-miR-27 and obtained a network with 41 interactions. Finally, functional and pathway analyses revealed that the genes in the network were significantly enriched at the transcriptional level. Differentially expressed miRNAs were identified in the metastatic melanoma compared with the primary cutaneous melanoma samples and the target genes of hsa-miR-27 were found to be significantly enriched at the transcriptional level. The results presented in our study may prove helpful in the diagnosis and treatment of metastatic melanoma. PMID:24573402

  1. Identification of differentially expressed microRNAs in metastatic melanoma using next-generation sequencing technology.

    PubMed

    Qi, Min; Huang, Xiaoyuan; Zhou, Lei; Zhang, Jianglin

    2014-05-01

    In this study, we investigated differentially expressed microRNAs (miRNAs or miRs) and their functions in metastatic melanoma using next-generation sequencing technology. The GSE36236 data set was downloaded from the Gene Expression Omnibus (GEO) database and 4 primary cutaneous melanoma samples (used as controls) and 3 metastatic melanoma samples were selected from 31 samples for further analysis. Firstly, the differentially expressed miRNAs were screened by limma package in R language. Secondly, the target genes of the miRNAs were retrieved with TargetScanHuman 6.2, and the interactions among these genes were identified by String and an interaction network was established. Finally, functional and pathway analyses were performed for the genes in the network using Expression Analysis Systematic Explorer (EASE). A total of 4 differentially expressed miRNAs (hsa-miR-146, hsa-miR-27, hsa-miR-877 and hsa-miR-186) were obtained between the metastatic melanoma and primary cutaneous melanoma samples. We predicted 101 high-confidence target genes of hsa-miR-27 and obtained a network with 41 interactions. Finally, functional and pathway analyses revealed that the genes in the network were significantly enriched at the transcriptional level. Differentially expressed miRNAs were identified in the metastatic melanoma compared with the primary cutaneous melanoma samples and the target genes of hsa-miR-27 were found to be significantly enriched at the transcriptional level. The results presented in our study may prove helpful in the diagnosis and treatment of metastatic melanoma.

  2. Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis.

    PubMed

    Jahn, Stephan W; Kashofer, Karl; Halbwedl, Iris; Winter, Gerlinde; El-Shabrawi-Caelen, Laila; Mentzel, Thomas; Hoefler, Gerald; Liegl-Atzwanger, Bernadette

    2015-07-01

    Desmoplastic malignant melanoma is a distinct melanoma entity histologically subtyped into mixed and pure forms due to significantly reduced lymph node metastases in the pure form. Recent reports investigating common actionable driver mutations have demonstrated a lack of BRAF, NRAS, and KIT mutation in pure desmoplastic melanoma. In search for alternative driver mutations next generation amplicon sequencing for hotspot mutations in 50 genes cardinal to tumorigenesis was performed and in addition the RET G691S polymorphism was investigated. Data from 21 desmoplastic melanomas (12 pure and 9 mixed) were retrieved. Pure desmoplastic melanomas were either devoid of mutations (50%) or displayed mutations in tumor suppressor genes (TP53, CDKN2A, and SMAD4) singularly or in combination with the exception of a PIK3CA double-mutation lacking established biological relevance. Mixed desmoplastic melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2). Separate analysis of morphologically heterogeneous tumor areas in four mixed desmoplastic malignant melanomas displayed no difference in mutation status and RET G691 status. GNAQ and GNA11, two oncogenes in BRAF and NRAS wild-type uveal melanomas, were not mutated in our cohort. The RET G691S polymorphism was found in 25% of pure and 38% of mixed desmoplastic melanomas. Apart from RET G691S our findings demonstrate absence of activating driver mutations in pure desmoplastic melanoma beyond previously investigated oncogenes (BRAF, NRAS, and KIT). The findings underline the therapeutic dichotomy of mixed versus pure desmoplastic melanoma with regard to activating mutations primarily of the mitogen-activated protein kinase pathway.

  3. Utility of BRAF V600E Immunohistochemistry Expression Pattern as a Surrogate of BRAF Mutation Status in 154 Patients with Advanced Melanoma.

    PubMed

    Tetzlaff, Michael T; Pattanaprichakul, Penvadee; Wargo, Jennifer; Fox, Patricia S; Patel, Keyur P; Estrella, Jeannelyn S; Broaddus, Russell R; Williams, Michelle D; Davies, Michael A; Routbort, Mark J; Lazar, Alexander J; Woodman, Scott E; Hwu, Wen-Jen; Gershenwald, Jeffrey E; Prieto, Victor G; Torres-Cabala, Carlos A; Curry, Jonathan L

    2015-08-01

    Successful BRAF inhibitor therapy depends on the accurate assessment of the mutation status of the BRAF V600 residue in tissue samples. In melanoma, immunohistochemical (IHC) analysis with monoclonal anti-BRAF V600E has emerged as a sensitive and specific surrogate of BRAF V600E mutation, particularly when BRAF V600E protein expression is homogeneous and strong. A subset of melanomas exhibit heterogeneous labeling for BRAF V600E, but our understanding of the significance of heterogeneous BRAF V600E IHC expression is limited. We used next-generation sequencing to compare BRAF V600E IHC staining patterns in 154 melanomas: 79 BRAF(WT) and 75 BRAF (including 53 V600E) mutants. Agreement among dermatopathologists on tumor morphology, IHC expression, and intensity was excellent (ρ = 0.99). A predominantly epithelioid cell phenotype significantly correlated with the BRAF V600E mutation (P = .0085). Tumors demonstrating either heterogeneous or homogeneous IHC expression were significantly associated with the BRAF V600E mutation (P < .0001), as was increased intensity of staining (P < .0001). The positive predictive value was 98% for homogenous IHC expression compared with 70% for heterogeneous labeling. Inclusion of both heterogeneous and homogeneous BRAF V600E IHC expression as a positive test significantly improved IHC test sensitivity from 85% to 98%. However, this reduced BRAF V600E IHC test specificity from 99% to 96%. Cautious evaluation of heterogeneous BRAF V600E IHC expression is warranted and comparison with sequencing results is critical, given its reduced test specificity and positive predictive value for detecting the BRAF V600E mutation.

  4. Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma

    PubMed Central

    Beasley, Georgia M.; Riboh, Jonathan C.; Augustine, Christina K.; Zager, Jonathan S.; Hochwald, Steven N.; Grobmyer, Stephen R.; Peterson, Bercedis; Royal, Richard; Ross, Merrick I.; Tyler, Douglas S.

    2011-01-01

    Purpose Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients and Methods Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). Conclusion To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study. PMID:21343562

  5. Pre-Appointment Testing for BRAF/KIT Mutation in Advanced Melanoma: A Model in Molecular Data Delivery for Individualized Medicine

    PubMed Central

    Mounajjed, Taofic; Brown, Char. L.; Stern, Therese K.; Bjorheim, Annette M.; Bridgeman, Andrew J.; Rumilla, Kandelaria M.; McWilliams, Robert R.; Flotte, Thomas J.

    2015-01-01

    The emergence of individualized medicine is driven by developments in precision diagnostics, epitomized by molecular testing. Because treatment decisions are being made based on such molecular data, data management is gaining major importance. Among data management challenges, creating workflow solutions for timely delivery of molecular data has become pivotal. This study aims to design and implement a scalable process that permits pre-appointment BRAF/KIT mutation analysis in melanoma patients, allowing molecular results necessary for treatment plans to be available before the patient's appointment. Process implementation aims to provide a model for efficient molecular data delivery for individualized medicine. We examined the existing process of BRAF/KIT testing in melanoma patients visiting our institution for oncology consultation. We created five working groups, each designing a specific segment of an alternative process that would allow pre-appointment BRAF/KIT testing and delivery of results. Data was captured and analyzed to evaluate the success of the alternative process. Over one year, 35 of 55 (59%) patients had prior BRAF/KIT testing. The remaining 20 patients went through the new process of pre-appointment testing; results were available at the time of appointment for 12 patients (overall pre-appointment results availability = 85.5%). The overall process averaged 13.4 ± 4.7 days. In conclusion, we describe successful implementation of a scalable workflow solution that permits pre-appointment BRAF/KIT mutation analysis and result delivery in melanoma patients. This sets the stage for further applications of this model to other conditions, answering an increasing demand for robust delivery of molecular data for individualized medicine. PMID:25179409

  6. An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma.

    PubMed

    Teh, Jessica L F; Purwin, Timothy J; Greenawalt, Evan J; Chervoneva, Inna; Goldberg, Allison; Davies, Michael A; Aplin, Andrew E

    2016-09-15

    Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Cancer Res; 76(18); 5455-66. ©2016 AACR. PMID:27488531

  7. A Matrix Metalloproteinase-1/Protease Activated Receptor-1 signaling axis promotes melanoma invasion and metastasis

    PubMed Central

    Blackburn, Jessica S.; Liu, Ingrid; Coon, Charles I.; Brinckerhoff, Constance E.

    2009-01-01

    Hallmarks of malignant melanoma are its propensity to metastasize and its resistance to treatment, giving patients with advanced disease a poor prognosis. The transition of melanoma from non-invasive radial growth phase (RGP) to invasive and metastatically competent vertical growth phase (VGP) is a major step in tumor progression, yet the mechanisms governing this transformation are unknown. Matrix Metalloproteinase-1 (MMP-1) is highly expressed by VGP melanomas, and is thought to contribute to melanoma progression by degrading type I collagen within the skin to facilitate melanoma invasion. Protease activated receptor-1 (PAR-1) is activated by MMP-1, and is also expressed by VGP melanomas. However, the effects MMP-1 signaling through PAR-1 have not been examined in melanoma. Here, we demonstrate that an MMP-1/PAR-1 signaling axis exists in VGP melanoma, and is necessary for melanoma invasion. Introduction of MMP-1 into RGP melanoma cells induced gene expression associated with tumor progression and promoted invasion in vitro, and enhanced tumor growth and conferred metastatic capability in vivo. This study demonstrates that both the type I collagenase and PAR-1 activating functions of MMP-1 are required for melanoma progression, and suggests that MMP-1 may be a major contributor to the transformation of melanoma from non-invasive to malignant disease. PMID:19734937

  8. Influence of loss of function MC1R variants in genetic susceptibility of familial melanoma in Spain.

    PubMed

    de Torre, Carlos; Garcia-Casado, Zaida; Martínez-Escribano, Jorge A; Botella-Estrada, Rafael; Bañuls, Jose; Oliver, Vicente; Mercader, Pedro; Azaña, Jose M; Frias, Javier; Nagore, Eduardo

    2010-08-01

    We explored the presence of germline alterations in CDK4 exon 2, CDKN2A and MC1R in a hospital-based study of 89 melanoma cases from 89 families with at least two members affected by cutaneous melanoma. A total of 30% of the melanoma kindreds studied were carriers of CDKN2A variants, and three of these variants were known predominant alleles that have been identified earlier in Mediterranean populations (p.G101W, p.V59G and c.358delG). We observed a higher frequency of nonsynonymous MC1R variants in these Spanish melanoma kindreds (72%) with respect to the general population (60%). We observed a higher frequency of nonsynonymous MC1R variants in this Spanish melanoma kindred (72%) respect to general population (60%). A new classification of MC1R variants based on their functional effects over melanocortin-1 receptor, including the dominant-negative effect of some of them in heterozygotes, suggested an association of loss of function MC1R variants and multiple primary melanoma cases from melanoma kindred (odds ratio: 6.07, 95% confidence interval: 1.35-27.20). This study proposes the relevance of loss of function MC1R variants in the risk of melanoma in multiple primary melanoma cases with family history from areas with low melanoma incidence rate. PMID:20539244

  9. Autophagy- An emerging target for melanoma therapy.

    PubMed

    Ndoye, Abibatou; Weeraratna, Ashani T

    2016-01-01

    Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression.  Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors.  This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation. PMID:27583134

  10. Autophagy- An emerging target for melanoma therapy

    PubMed Central

    Ndoye, Abibatou; Weeraratna, Ashani T.

    2016-01-01

    Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression.  Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors.  This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation. PMID:27583134

  11. Occupation and malignant melanoma: a study based on cancer registration data in England and Wales and in Sweden.

    PubMed Central

    Vågerö, D; Swerdlow, A J; Beral, V

    1990-01-01

    An analysis of the incidence of malignant melanoma according to occupation is presented using data from two national cancer registries. The data relate to 3991 cases of cutaneous malignant melanoma, 662 cases of ocular melanoma, and 179 cases of noncutaneous, non-ocular melanoma in subjects aged 15-64 in England and Wales diagnosed from 1971 to 1978 and to 5003 cases of cutaneous malignant melanoma diagnosed from 1961 to 1979 in Sweden in subjects born between 1896 and 1940. Professional workers of both sexes in both countries experienced an excess incidence of cutaneous malignant melanoma. An excess of ocular melanoma and of non-cutaneous, non-ocular melanoma also existed for this group in England and Wales. Pharmacists, medical doctors, and dentists had a high incidence of cutaneous melanoma in both countries and were represented three times when listing the top 20 occupations in both countries and both genders. Combining the data from cutaneous malignant melanoma over both sexes and both registries the occupations with the highest incidence ratios (expressed as a percentage) were: airline pilots, incidence ratio (IR) = 273, (95% confidence limits 118-538); finance and insurance brokers IR = 245 (140-398); professional accountants IR = 208 (134-307); dentists IR = 207 (133-309); inspectors and supervisors in transport IR = 206 (133-304); pharmacists IR = 198 (115-318); professionals not elsewhere classified IR = 196 (155-243); judges IR = 196 (126-289); doctors IR = 188 (140-248); university teachers IR = 188 (110-302); and chemists IR = 188 (111-296). No particular exposure in the workplace seemed to link these groups and only a few worked in high technology environments. Many of the highest risk groups have in common a high level of education. In England and Wales and in Sweden this might correlate particularly with foreign travel abroad was more unusual than it is now, but evidence on present and past exposure to sun by occupation is needed to clarify the

  12. Immunotherapy for Melanoma: Current Status and Perspectives

    PubMed Central

    Alexandrescu, Doru T.; Ichim, Thomas E.; Riordan, Neil H.; Marincola, Francesco M.; Nardo, Anna Di; Kabigting, Filamer D.; Dasanu, Constantin A.

    2012-01-01

    Summary Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease. PMID:20551839

  13. Targeting BRAF in melanoma: biological and clinical challenges.

    PubMed

    Mandalà, Mario; Voit, Christiane

    2013-09-01

    Melanoma is an aggressive form of skin cancer that causes the greatest number of skin cancer-related deaths worldwide. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal transduction pathway. The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. This review summarizes the critical role of BRAF in melanoma pathophysiology, the clinical and pathological determinants of BRAF mutation status and finally addresses the current state of the art of BRAF inhibitors. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape.

  14. [Melanomas of the female genital tract: state of the art].

    PubMed

    Trone, Jane-Chloé; Guy, Jean-Baptiste; Mery, Benoite; Langrand Escure, Julien; Lahmar, Rima; Moncharmont, Coralie; Rivoirard, Romain; Semay, Tiphaine; Chauleur, Céline; Collard, Olivier; Vignot, Stéphane; Magné, Nicolas

    2014-01-01

    Melanoma of the female genital tract is a rare location (less than 2% of melanomas all sites combined). These cancers have a very poor prognosis, due to the delay in diagnosis. Vulvar location is about 1% of melanomas then the vaginal location, uterine and ovarian. There is no consensus to date regarding their care, due to the rarity of the lesions. Their treatment must however be based on the current data concerning gynaecological cancers as well as standard management of cutaneous melanoma. The treatment is often based on conservative surgery, because radical resection does not improve survival. For the vulva and vagina, reconstructive surgery is possible. Treatment is sometimes supplemented by chemotherapy or radiotherapy, which could improve local control. The interest in the use of targeted therapy in these locations is not well known because of their rarity, but the study of genes c-Kit and BRAF provides new prospects for treatment. The objective of this review is to describe and report the current state of knowledge about gynaecologic melanomas.

  15. Vaccine Therapy With or Without Sargramostim in Treating Patients Who Have Undergone Surgery for Melanoma

    ClinicalTrials.gov

    2015-04-14

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Extraocular Extension Melanoma; Iris Melanoma; Stage IIB Melanoma; Stage IIC Melanoma; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma

  16. Porcine models of cutaneous wound healing.

    PubMed

    Seaton, Max; Hocking, Anne; Gibran, Nicole S

    2015-01-01

    Cutaneous wound healing in the pig is frequently used as a model for human cutaneous wound healing. In this review, we examine the appropriateness of this model for studying normal and pathological wound healing, and describe models for chronic nonhealing wounds, diabetic wounds, burns, and hypertrophic scars. In addition, we focus on studies that have used pigs to evaluate wound-healing therapies, and discuss genetic engineering technology in the pig that may advance our knowledge of wound healing. We conclude that, although not perfect, the pig offers a versatile model that can be adjusted to mimic a wide range of clinical scenarios.

  17. Romidepsin for cutaneous T-cell lymphoma.

    PubMed

    Prince, H Miles; Dickinson, Michael; Khot, Amit

    2013-12-01

    Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.

  18. [Issues around melanoma].

    PubMed

    Haanen, John

    2011-01-01

    Over the past 30 years little progress has been made in the treatment of patients with a metastatic melanoma. Recently there have been two new developments. One of these is ipilimumab, a monoclonal antibody that blocks the function of the protein cytotoxic T lymphocyte-associated antigen 4 (CTLA4) which inhibits activated T lymphocytes. This gives the immune system a chance to build up an immune response to the melanoma. The other development is vemurafenib, a small molecule that inhibits a mutated protein (BRAF) that occurs in many melanomas. The BRAF mutation leads to uninhibited proliferation.

  19. Intraoral malignant melanoma

    PubMed Central

    Babburi, Suresh; Subramanyam, R. V.; Aparna, V.; Sowjanya, P.

    2013-01-01

    Primary oral mucosal melanoma is a rare aggressive neoplasm and accounts for only 0.2-8% of all reported melanomas. It is a malignant neoplasm of melanocytes that may arise from a benign melanocytic lesion or de novo from melanocytes within normal skin or mucosa. It is considered to be the most deadly and biologically unpredictable of all human neoplasms, having the worst prognosis. In this article, we report a case of oral melanoma in a 52-year-old female patient with a chief complaint of black discolouration of the maxillary gingiva and palate. PMID:24249959

  20. [Primary cutaneous plasmacytoma].

    PubMed

    Dhouib Sellami, Rym; Sassi, Samia; Mrad, Karima; Abess, Imen; Driss, Maha; Ben Romdhane, Khaled

    2007-04-01

    Primary cutaneous plasmacytoma (PCP) is a rare cutaneous B cell lymphoma. We report a case of PCP in a 64 year old woman presenting with a nodular lesion of the left cheek. Histologically, the lesion was composed predominately of variably maturated plasma cells with monotypic expression of lambda chain. Extracutaneous localizations of the disease had been excluded. The prognosis of PCP is better than that of the metastatic cutaneous lesion of myeloma. The main prognosis factors are the size tumor and clinical presentation (solitary, versus multiple lesions). Solitary lesions of the PCP are treated by surgical excision and sometimes local radiotherapy. PMID:17909472

  1. Cutaneous lymphatic sporotrichosis.

    PubMed

    Anandi, V; Kurien, T; Jacob, M; Koshi, G

    1994-01-01

    The first case of cutaneous lymphatic sporotrichosis from Nagaland and a case of cutaneous sporotrichosis from Kerala who had acquired infection from Assam are reported. The diagnosis in both cases were established by isolating Sporothrix schenckii from multiple cutaneous lesions. The dimorphic nature of fungus was established in vitro by demonstrating the mycelial phase at 25-30 degrees C and yeast phase at 37 degrees C and pathogenicity to white mice. Both the patients were successfully treated with oral administration of potassium iodide for 3 months. PMID:8088907

  2. Cutaneous tuberculosis in children.

    PubMed

    Sethuraman, Gomathy; Ramesh, Venkatesh

    2013-01-01

    Cutaneous tuberculosis is a rare form of extrapulmonary tuberculosis that accounts for 1% to 2% of cases. Childhood skin tuberculosis represents 18% to 82% of all cutaneous tuberculosis cases. Scrofuloderma and lupus vulgaris are the two most common clinical forms in children. An increase in the number of tuberculids, especially lichen scrofulosorum, has been observed in the last several years. Cutaneous tuberculosis in children can be severe and have a protracted course. Multiplicity of lesions and multifocal disseminated involvement in scrofuloderma and lupus vulgaris is common. Scrofuloderma progressing to gummatous lesions (scrofulous gumma) is mostly described in children. Morbidities and deformities are more severe in children.

  3. Melanoma Risk Factors, Perceived threat and Intentional Tanning: An Online Survey

    PubMed Central

    Bränström, Richard; Chang, Yu-mei; Kasparian, Nadine; Affleck, Paul; Tibben, Aad; Aspinwall, Lisa G.; Azizi, Esther; Baron-Epel, Orna; Battistuzzi, Linda; Bruno, William; Chan, May; Cuellar, Francisco; Dębniak, Tadeusz; Dace, Pjanova; Ertmański, Sławomir; Figl, Adina; Gonzalez, Melinda; Hayward, Nicholas K.; Hocevar, Marco; Kanetsky, Peter A.; Leaf, Samantha L.; van Nieuwpoort, Frans A.; Olita, Heisele; Palmer, Jane; Peric, Barbara; Puig, Susana; Ruffin, Althea D.; Schadendorf, Dirk; Gruis, Nelleke A.; Brandberg, Yvonne; Newton-Bishop, Julia

    2013-01-01

    Background Cutaneous melanoma continues to increase in incidence in many countries, and intentional tanning is a risk factor for melanoma. The aim of this study was to understand how melanoma risk factors, perceived threat, and preferences for a suntan relate to intentional tanning. Methods Self-report data were collected on behalf of GenoMEL (www.genomel.org) from members of the general population using an online survey. A total of 8,178 individuals successfully completed at least 80% of the survey, with 72.8% of respondents from Europe, 12.1% from Australia, 7.1% from the USA, 2.5% from Israel, and 5.5% from other countries. Results Seven percent of respondents had previously been diagnosed with melanoma and 8% had at least one first-degree relative with a previous melanoma. Overall, 70% of the respondents reported some degree of intentional tanning during the past year, and 38% of respondents previously diagnosed with melanoma had intentionally tanned. Total number of objective risk factors was positively correlated with perceived risk of melanoma (correlation coefficient (ρ)=0.27), and negatively correlated with intentional tanning (ρ=−0.16). Preference for a dark suntan was the strongest predictor of intentional tanning (regression coefficient (β)=0.35, p<0.001), even in those with a previous melanoma (β=0.33, p<0.01). Conclusions A substantial proportion of participants reported having phenotypic and behavioural risk factors for melanoma. The preference regarding suntans seemed more important in the participants’ decision to intentionally tan than their perceived risk of developing melanoma, and this finding was consistent among respondents from different countries. The drive to sunbathe in order to tan appears to be a key psychological factor to be moderated if melanoma incidence is to be reduced. PMID:20093934

  4. Long-term Results of Carbon Ion Radiation Therapy for Locally Advanced or Unfavorably Located Choroidal Melanoma: Usefulness of CT-based 2-Port Orthogonal Therapy for Reducing the Incidence of Neovascular Glaucoma

    SciTech Connect

    Toyama, Shingo; Tsuji, Hiroshi; Mizoguchi, Nobutaka; Nomiya, Takuma; Kamada, Tadashi; Tokumaru, Sunao; Mizota, Atsushi; Ohnishi, Yoshitaka; Tsujii, Hirohiko

    2013-06-01

    Purpose: To determine the long-term results of carbon ion radiation therapy (C-ion RT) in patients with choroidal melanoma, and to assess the usefulness of CT-based 2-port irradiation in reducing the risk of neovascular glaucoma (NVG). Methods and Materials: Between January 2001 and February 2012, a total of 116 patients with locally advanced or unfavorably located choroidal melanoma received CT-based C-ion RT. Of these patients, 114 were followed up for more than 6 months and their data analyzed. The numbers of T3 and T2 patients (International Union Against Cancer [UICC], 5th edition) were 106 and 8, respectively. The total dose of C-ion RT varied from 60 to 85 GyE, with each dose given in 5 fractions. Since October 2005, 2-port therapy (51 patients) has been used in an attempt to reduce the risk of NVG. A dose-volume histogram analysis was also performed in 106 patients. Results: The median follow-up was 4.6 years (range, 0.5-10.6 years). The 5-year overall survival, cause-specific survival, local control, distant metastasis-free survival, and eye retention rates were 80.4% (95% confidence interval 89.0%-71.8%), 82.2% (90.6%-73.8%), 92.8% (98.5%-87.1%), 72.1% (81.9%-62.3%), and 92.8% (98.1%-87.5%), respectively. The overall 5-year NVG incidence rate was 35.9% (25.9%-45.9%) and that of 1-port group and 2-port group were 41.6% (29.3%-54.0%) and 13.9% (3.2%-24.6%) with statistically significant difference (P<.001). The dose-volume histogram analysis showed that the average irradiated volume of the iris-ciliary body was significantly lower in the non-NVG group than in the NVG group at all dose levels, and significantly lower in the 2-port group than in the 1-port group at high dose levels. Conclusions: The long-term results of C-ion RT for choroidal melanoma are satisfactory. CT-based 2-port C-ion RT can be used to reduce the high-dose irradiated volume of the iris-ciliary body and the resulting risk of NVG.

  5. Unpredictability of lymphatic drainage patterns in melanoma patients.

    PubMed

    Statius Muller, Markwin G; Hennipman, Feitse A; van Leeuwen, Paul A M; Pijpers, Rik; Vuylsteke, Ronald J; Meijer, Sybren

    2002-02-01

    We analysed the localisations of sentinel nodes (SN) found with the SN procedure to compare these sites with those that would have been predicted by conventional clinical descriptions of cutaneous lymphatic drainage. We assessed the surplus value of performing the SN procedure in melanoma patients who underwent regional nodal surgery. The SN procedure was performed in 348 patients with melanomas who were referred to our institute between 1993 and 1999. The localisations of the melanomas with the corresponding SNs were meticulously recorded on drawings of the human body and grouped according to the conventional descriptions. Predictability of lymph drainage was defined as the percentage of melanomas whose draining pattern was to the ipsilateral nearest basin, without simultaneous drainage to other basins or to an interval node. In all patients the SN procedure visualised at least one SN. We found 410 lymphatic basins in 347 patients. These basins included basins that could not have been predicted by the conventional clinical descriptions, such as multiple basins and contralateral drainage sites. For the head/neck region, SNs could be found in any of the basins described in the literature. The trunk's drainage predictability depended strongly on the melanoma localisation, ranging from 0% in the midline to 92% in one of the upper quadrants. The lower extremities had a high predictability of almost 100%, and predictability of drainage for the upper extremities ranged from 77% to 100%. In total, 34% of the patients had a cutaneous lymphatic drainage that was unpredictable, either totally or partially. We therefore conclude that an SN procedure is indispensable if the drainage site(s) are to be accurately identified. PMID:11930886

  6. A Phase 1 Study of a Vaccine Targeting Preferentially Expressed Antigen in Melanoma and Prostate-specific Membrane Antigen in Patients With Advanced Solid Tumors

    PubMed Central

    Weber, Jeffrey S.; Vogelzang, Nicholas J.; Ernstoff, Marc S.; Goodman, Oscar B.; Cranmer, Lee D.; Marshall, John L.; Miles, Sabrina; Rosario, Dar; Diamond, David C.; Qiu, Zhiyong; Obrocea, Mihail; Bot, Adrian

    2013-01-01

    Summary Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications. PMID:21760528

  7. Cell cycle arrest and apoptosis of melanoma cells by docosahexaenoic acid: association with decreased pRb phosphorylation.

    PubMed

    Albino, A P; Juan, G; Traganos, F; Reinhart, L; Connolly, J; Rose, D P; Darzynkiewicz, Z

    2000-08-01

    The incidence of cutaneous malignant melanoma is undergoing a dramatic increase in persons with light-color skin in all parts of the world. The prognosis for individuals with advanced disease is dismal due to the lack of effective treatment options. Thus, there is a need for new approaches to control tumor progression. Epidemiological, experimental, and mechanistic data implicate omega-6 polyunsaturated fatty acids (PUFAs) as stimulators and long-chain omega-3 PUFAs as inhibitors of development and progression of a range of human cancers, including melanoma. The aim of this study was to assess the mechanisms by which docosahexaenoic acid (DHA), an omega-3 PUFA, affects human melanoma cells. Exponentially growing melanoma cell lines were exposed in vitro to DHA and then assessed for (a) inhibition of cell growth; (b) expression of cyclins and cyclin-dependent kinase inhibitors in individual cells by flow cytometry and immunocytochemistry using specific monoclonal antibodies to cyclin D1, cyclin E, p21WAF1/CIP1, or p27(KIP1); and (c) expression of total pRb(T) independent of phosphorylation state and hypophosphorylated pRb(P-) in fixed cells by flow cytometry and immunocytochemistry using specific monoclonal antibodies to pRb(T) or pRb(P-), respectively. After treatment with increasing concentrations of DHA, cell growth in a majority of melanoma cell lines (7 of 12) was inhibited, whereas in 5 of 12 cell lines, cell growth was minimally affected. Two melanoma cell lines were examined in detail, one resistant (SK-Mel-29) and one sensitive (SK-Mel-110) to the inhibitory activity of DHA. SK-Mel-29 cells were unaffected by treatment with up to 2 microg/ml DHA whether grown in the absence or presence of 1% fetal bovine serum (FBS). No appreciable change was observed in cell growth, cell cycle distribution, the status of pRb phosphorylation, cyclin D1 expression, or the levels of the cyclin-dependent kinase inhibitors p21 and p27. In contrast, SK-Mel-110 cell growth was

  8. [Penile sporotrichoid cutaneous leishmaniasis].

    PubMed

    Masmoudi, A; Boudaya, S; Bouzid, L; Frigui, F; Meziou, T J; Akrout, F; Turki, H; Zahaf, A

    2005-12-01

    The localisation of the cutaneous leishmaniasis of L. major at the penis level is rare, we report here a new observation. Mr K. R aged of 41, without known pathological background presented for 20 days a nodular lesion of the anterior face of the neck, 2 juxtaposed ulcerated nodular lesions of the left wrist. He presented also subcutaneous nodules ranged linearly and extended to the root of the penis. Theses lesions were covered by an erythematous or ulcerated skin. The smear made from the genital lesions of the penis confirmed the diagnosis of a cutaneous leishmaniasis. The evolution was favourable after a 21 days treatment by doxycyclin after an interval of one week. Our observation was specific by the localisation of the cutaneous leishmaniasis and by the clinical form. This shows that in our region cutaneous leishmaniasis is characterised by different clinical symptoms. PMID:16425718

  9. Melanoma International Foundation

    MedlinePlus

    ... Exam Card Download a Patient Navigation Card Events, Webinars & Videos Events, Webinars & Videos Patient Experience Video Events Host an Event Past Webinars Upcoming Webinars Volunteer Blog Blog Melanoma? The Doctor ...

  10. Melanoma Epidemiology and Prevention.

    PubMed

    Berwick, Marianne; Buller, David B; Cust, Anne; Gallagher, Richard; Lee, Tim K; Meyskens, Frank; Pandey, Shaily; Thomas, Nancy E; Veierød, Marit B; Ward, Sarah

    2016-01-01

    The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as high-penetrant genes, moderate-risk genes, or low-risk genetic polymorphisms. Subtypes of tumors, such as BRAF-mutated tumors, have different risk factors as well as different therapies. Prevention of melanoma has been attempted using various strategies in specific subpopulations, but to date optimal interventions to reduce incidence have not emerged. PMID:26601858

  11. Anorectal melanoma. An update.

    PubMed

    Reina, Angel; Errasti, José; Espín, Eloy

    2014-10-01

    Anorectal melanoma is an uncommon and aggressive disease. Because the patients often present with non specific complaints, a high clinical suspicion is important to avoid a delayed diagnosis. Patients undergoing radical surgery have no significant survival difference compared to those undergoing wide local excision. Abdominoperineal resection should be reserved for selected patients in whom local excision is not technically possible or cannot obtain a clear margin. The indiscriminate use of groin dissection is not advisable in anorectal melanoma and should be use in selected cases. Systemic chemotherapy is generally a non effective treatment and continues be studied. Radiation therapy can be used as hypofractionated radiation therapy combined with local excision or in a palliative setting. The oncological outcomes in anorectal melanoma are very poor. The aim of the present study is to review clinicopathology features and management of anorectal melanoma.

  12. Germline MC1R status influences somatic mutation burden in melanoma

    PubMed Central

    Robles-Espinoza, Carla Daniela; Roberts, Nicola D.; Chen, Shuyang; Leacy, Finbarr P.; Alexandrov, Ludmil B.; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D.; Adams, David J.

    2016-01-01

    The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15–76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles. PMID:27403562

  13. Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.

    PubMed

    Khoja, L; Lorigan, P; Dive, C; Keilholz, U; Fusi, A

    2015-01-01

    Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.

  14. Post-menopausal bleeding: a rare presentation of metastatic uveal melanoma.

    PubMed

    Coutts, Michael A; Borthwick, Nicola J; Hungerford, John L; Cree, Ian A

    2006-01-01

    Uveal melanoma differs from cutaneous melanoma in many ways, including its pattern of metastasis, and exhibits latency with clinical evidence of metastasis sometimes appearing many years after primary diagnosis. Most patients develop metastasis within the liver, but some may present with metastasis to other sites. We report a case of uveal melanoma that presented with post-menopausal bleeding due to metastasis. Further investigation revealed widespread metastatic disease and the patient was not fit for chemotherapy. She died two months after presentation: autopsy revealed metastases in many sites, including the uterus, right ovarian fibroma, kidney, mesentery, liver, lung, thyroid, bone marrow and skin. The immediate cause of death was cardiac tamponade due to a malignant effusion secondary to cardiac metastasis. This case illustrates the widespread metastatic potential of uveal melanoma and highlights the potential for unusual presentation of metastatic disease from this eye tumor. PMID:16998600

  15. Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.

    PubMed

    Khoja, L; Lorigan, P; Dive, C; Keilholz, U; Fusi, A

    2015-01-01

    Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection. PMID:24907634

  16. Germline melanoma susceptibility and prognostic genes: a review of the literature.

    PubMed

    Ward, Katherine A; Lazovich, DeAnn; Hordinsky, Maria K

    2012-11-01

    In recent years, there have been increasing efforts to identify germline genetic variants that may alter melanoma susceptibility and prognosis. The findings of these studies have indicated the presence of rare, high-penetrance alleles with large effects, such as CDKN2A and CDK4, more common, moderately penetrant genes like MC1R, and very common, low-penetrance polymorphisms with small effects that are related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. The study of these low-penetrance single nucleotide polymorphisms is relatively new; thus many of them are termed 'candidate melanoma susceptibility or prognostic genes.' This review summarizes the research on germline polymorphisms that have been implicated in melanoma susceptibility and prognosis in order to provide a framework for additional studies to meet the ultimate goal of predicting a patient's risk of, and prognosis in, cutaneous malignant melanoma. PMID:22583682

  17. Germline MC1R status influences somatic mutation burden in melanoma.

    PubMed

    Robles-Espinoza, Carla Daniela; Roberts, Nicola D; Chen, Shuyang; Leacy, Finbarr P; Alexandrov, Ludmil B; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D; Adams, David J

    2016-07-12

    The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles.

  18. Germline MC1R status influences somatic mutation burden in melanoma.

    PubMed

    Robles-Espinoza, Carla Daniela; Roberts, Nicola D; Chen, Shuyang; Leacy, Finbarr P; Alexandrov, Ludmil B; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D; Adams, David J

    2016-01-01

    The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles. PMID:27403562

  19. Biflorin induces cytotoxicity by DNA interaction in genetically different human melanoma cell lines.

    PubMed

    Ralph, Ana Carolina Lima; Calcagno, Danielle Queiroz; da Silva Souza, Luciana Gregório; de Lemos, Telma Leda Gomes; Montenegro, Raquel Carvalho; de Arruda Cardoso Smith, Marília; de Vasconcellos, Marne Carvalho

    2016-08-01

    Cancer is a public health problem and the second leading cause of death worldwide. The incidence of cutaneous melanoma has been notably increasing, resulting in high aggressiveness and poor survival rates. Taking into account the antitumor activity of biflorin, a substance isolated from Capraria biflora L. roots that is cytotoxic in vitro and in vivo, this study aimed to demonstrate the action of biflorin against three established human melanoma cell lines that recapitulate the molecular landscape of the disease in terms of genetic alterations and mutations, such as the TP53, NRAS and BRAF genes. The results presented here indicate that biflorin reduces the viability of melanoma cell lines by DNA interactions. Biflorin causes single and double DNA strand breaks, consequently inhibiting cell cycle progression, replication and DNA repair and promoting apoptosis. Our data suggest that biflorin could be considered as a future therapeutic option for managing melanoma. PMID:27079618

  20. Booster Vaccination in Preventing Disease Recurrence in Previously Vaccinated Patients With Melanoma That Has Been Removed By Surgery

    ClinicalTrials.gov

    2015-01-23

    Recurrent Melanoma; 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

  1. Intravital Microscopy for Identifying Tumor Vessels in Patients With Stage IA-IV Melanoma That is Being Removed by Surgery

    ClinicalTrials.gov

    2016-01-13

    Recurrent Melanoma; 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

  2. A rat model for the treatment of melanoma metastatic to the brain by means of neutron capture therapy

    SciTech Connect

    Matalka, K.Z.; Bailey, M.Q.; Barth, R.F.; Staubus, A.E.; Adams, D.M.; Soloway, A.H.; James, S.M.; Goodman, J.H. ); Coderre, J.A.; Fairchild, R.G. ); Rofstad, E.K. )

    1991-01-01

    Melanoma metastatic to the brain is a serious clinical problem for which there currently is no satisfactory treatment. Boron neutron capture therapy (BNCT) has been shown by Mishima et al. to be clinically effective in the treatment of cutaneous melanoma using {sup 10}B-enriched boronophenylalaine (BPA) as the capture agent. In the present pilot study we have observed a significant prolongation in survival time of nude rats bearing intracerebral implants of the human melanoma cell line MRA 27 following administration of BPA and neutron irradiation. These findings suggest therapeutic efficacy, but unequivocal proof depends upon confirmation in a more definitive experiment using large numbers of animals with both solitary and multiple implants of melanoma. If our preliminary results are confirmed, then this will lay the groundwork for a clinical study of BNCT for the treatment of melanoma metastatic to the brain. 7 refs., 2 figs., 2 tabs.

  3. Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study.

    PubMed

    Thomas, Nancy E; Kricker, Anne; Waxweiler, Weston T; Dillon, Patrick M; Busman, Klaus J; From, Lynn; Groben, Pamela A; Armstrong, Bruce K; Anton-Culver, Hoda; Gruber, Stephen B; Marrett, Loraine D; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A; Orlow, Irene; Paine, Susan; Ollila, David W; Reiner, Anne S; Luo, Li; Hao, Honglin; Frank, Jill S; Begg, Colin B; Berwick, Marianne

    2014-12-01

    , anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

  4. Comparison of Clinicopathologic Features and Survival of Histopathologically Amelanotic and Pigmented Melanomas: A Population-Based Study

    PubMed Central

    Thomas, Nancy E.; Kricker, Anne; Waxweiler, Weston T.; Dillon, Patrick M.; Busam, Klaus J.; From, Lynn; Groben, Pamela A.; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; Marrett, Loraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; K