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Sample records for melanomas uveales posteriores

  1. 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.

  2. Iodine-125 radiation of posterior uveal melanoma

    SciTech Connect

    Packer, S.

    1987-12-01

    Twenty-eight cases of posterior choroidal melanoma were treated with iodine-125 in gold eye plaques. Eleven cases were located within 3.0 mm of the optic nerve (group A), nine were within 3.0 mm of the fovea (group B), and eight were within 3.0 mm of the optic nerve and fovea (group C). The mean follow-up of group A was 46.3 months; group B, 25.5 months; and group C, 42.7 months. Complications included macular edema, cataract and tumor growth. Visual acuity remained within two lines of that tested preoperatively for 4 of 11 patients in group A, 4 of 9 in group B, and 5 of 8 in group C. These results with iodine-125 suggest it as an appropriate treatment for patients with choroidal melanoma located near optic nerve and/or macula.

  3. Cobalt plaque therapy of posterior uveal melanomas

    SciTech Connect

    Shields, J.A.; Augsburger, J.J.; Brady, L.W.; Day, J.L.

    1982-10-01

    One hundred patients with choroidal melanomas who were treated by the authors with cobalt plaque radiotherapy were analyzed with regard to tumor regression, visual results, complications, and mortality rate. The follow-up period at the time of this writing ranged from one to five years. These preliminary observations indicate that cobalt plaque radiotherapy induces tumor regression in 96% of cases, preserves useful vision in many cases and has fewer complications during the one- to five-year follow-up period than previously believed.

  4. 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

  5. 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

  6. Culturing Uveal Melanoma Cells.

    PubMed

    Angi, Martina; Versluis, Mieke; Kalirai, Helen

    2015-04-01

    A major challenge in cancer research is the use of appropriate models with which to study a specific biological question. Cell lines have long been used to study cellular processes and the effects of individual molecules because they are easy to use, grow rapidly, produce reproducible results and have a strong track record in research. In uveal melanoma in particular, the absence of animal models that faithfully replicate the behavior of the human disease has propagated the generation and use of numerous cell lines by individual research groups. This in itself, however, can be viewed as a problem due to the lack of standardization when characterizing these entities to determine how closely they reflect the genetic and phenotypic characteristics of this disease. The alternative is to use in vitro primary cultures of cells obtained directly from uveal melanoma patient samples, but this too has its difficulties. Primary cell cultures are difficult to use, hard to obtain and can show considerable heterogeneity. In this article, we review the following: (1) the uveal melanoma cell lines that are currently available, discussing the importance of establishing a bank of those that represent the molecular heterogeneity of uveal melanoma; (2) the methods used to isolate and perform short-term cultures of primary uveal melanoma cells, and (3) the establishment of 3D tissue culture models that bridge the gap between 2D in vitro systems and in vivo models with which to dissect cancer biology and perform therapeutic screens. PMID:27171555

  7. Malignant melanoma of the eye: treatment of posterior uveal lesions by Co-60 plaque radiotherapy versus enucleation

    SciTech Connect

    Markoe, A.M.; Brady, L.W. Jr.; Shields, J.A.; Augsburger, J.J.; Micaily, B.; Damsker, J.I.; Day, J.L.; Gamel, J.W.

    1985-09-01

    Survival rates and visual acuity of 100 patients treated for posterior uveal malignant melanoma by cobalt-60 plaque radiotherapy were compared with 150 patients treated by enucleation for the same disease. Life-table comparisons of the entire group showed significant differences in survival rates, with plaque radiotherapy patients appearing to fare better. However, when patients with small or medium tumors were compared, only slight differences were seen, implying that criteria used to select patients for treatment may affect interpretation. The two groups were also compared using the Cox proportional hazards model, which predicts survival based on the impact of clinical variables. In this analysis, the survival rates of the plaque radiotherapy group were no worse than those of the enucleation group. The advantage of conservative therapy lies in the potential to preserve useful vision over a considerable time.

  8. General Information about Intraocular (Uveal) Melanoma

    MedlinePlus

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

  9. Animal Eye Models for Uveal Melanoma

    PubMed Central

    Cao, Jinfeng; Jager, Martine J.

    2015-01-01

    Animal models play an important role in understanding tumor growth and may be used to develop novel therapies against human malignancies. The significance of the results from animal experiments depends on the selection of the proper model. Many attempts have been made to create appropriate animal models for uveal melanoma and its characteristic metastatic behavior. One approach is to use transgenic animal models or to implant tumor cells. A variety of tumor types have been used for this purpose: tumor cells, such as Greene melanoma, murine B16 melanoma, and human uveal melanoma cells, may be implanted in the eyes of hamsters, rats, rabbits, and mice, among others. Various inoculation routes, including into the anterior chamber and posterior compartment, and retro-orbitally, have been applied to obtain tumor growth mimicking ocular uveal melanoma. However, when we choose animal models, we must be conscious of many disadvantages, such as variable tumor growth, or the need for immunosuppression in xenogeneic grafts. In this paper, we will discuss the various eye models. PMID:27172424

  10. Animal Eye Models for Uveal Melanoma.

    PubMed

    Cao, Jinfeng; Jager, Martine J

    2015-04-01

    Animal models play an important role in understanding tumor growth and may be used to develop novel therapies against human malignancies. The significance of the results from animal experiments depends on the selection of the proper model. Many attempts have been made to create appropriate animal models for uveal melanoma and its characteristic metastatic behavior. One approach is to use transgenic animal models or to implant tumor cells. A variety of tumor types have been used for this purpose: tumor cells, such as Greene melanoma, murine B16 melanoma, and human uveal melanoma cells, may be implanted in the eyes of hamsters, rats, rabbits, and mice, among others. Various inoculation routes, including into the anterior chamber and posterior compartment, and retro-orbitally, have been applied to obtain tumor growth mimicking ocular uveal melanoma. However, when we choose animal models, we must be conscious of many disadvantages, such as variable tumor growth, or the need for immunosuppression in xenogeneic grafts. In this paper, we will discuss the various eye models. PMID:27172424

  11. [Surgical treatment modalities in uveal melanomas].

    PubMed

    Bechrakis, N E; Petousis, V; Krause, L; Wachtlin, J; Willerding, G; Foerster, M H

    2009-11-01

    The treatment of large uveal melanomas poses a therapeutic challenge, due to the expected treatment-related side-effects. After sole radiotherapy the majority of patients are faced with radiogenic complications secondary to the large amount of tumour necrosis. Alternative treatment modalities addressing this issue are transscleral resection in arterial hypotension in anteriorly located tumours and endoresection via pars plana vitrectomy in posteriorly located tumours. A surgical resection treatment was applied in 292 patients with large uveal melanomas. In 150 patients the tumour was treated by transscleral resection and postoperative adjuvant (106)ruthenium brachytherapy and 142 patients were treated by primary proton beam irradiation and secondary endoresection. The mean follow-up time was 3.8 and 2.5 years, respectively. Local tumour control was achieved in 76 % and 98 %, respectively. The 5-year metastatic rates were 28 % and 21 % and eye retention was achieved in 82 % and 97 %, respectively. Surgical resection of uveal melanomas with adjuvant radiotherapy is the treatment of choice in cases of large tumours, avoiding enucleation in the vast majority of cases in the long term, without increasing the incidence of tumour-related risks.

  12. CDX-1401 and Poly-ICLC Vaccine Therapy With or Without CDX-301in Treating Patients With Stage IIB-IV Melanoma

    ClinicalTrials.gov

    2016-06-21

    Carcinoma of Unknown Primary Origin; Iris Melanoma; Medium/Large Size Posterior Uveal Melanoma; Mucosal Melanoma; Ocular Melanoma With Extraocular Extension; Small Size Posterior Uveal Melanoma; Stage IIB Skin Melanoma; Stage IIB Uveal Melanoma; Stage IIC Skin 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

  13. Uveal Melanoma: Current Trends in Diagnosis and Management

    PubMed Central

    Tarlan, Berçin; Kıratlı, Hayyam

    2016-01-01

    Uveal melanoma, which is the most common primary intraocular malignancy in adults, arises from melanocytes within the iris, ciliary body and choroid. The diagnosis is based principally on clinical examination of the tumor with biomicroscopy and indirect ophthalmoscopy and confirmed by diagnostic techniques such as ultrasonography, fundus fluorescein angiography and optical coherence tomography. The clinical diagnosis of posterior uveal melanomas can be made when the classical appearance of a pigmented dome-shaped mass is detected on dilated fundus exam. Uveal melanomas classically show low to medium reflectivity on A-scan ultrasonography and on B-scan ultrasonography the tumor appears as a hyperechoic, acoustically hollow intraocular mass. Management of a suspicious pigmented lesion is determined by its risk factors of transforming into a choroidal melanoma, such as documentation of growth, thickness greater than 2 mm, presence of subretinal fluid, symptoms and orange pigment, margin within 3 mm of the optic disc, and absence of halo and drusen. Advances in the diagnosis and local and systemic treatment of uveal melanoma have caused a shift from enucleation to eye-conserving treatment modalities including transpupillary thermotherapy and radiotherapy over the past few decades. Prognosis can be most accurately predicted by genetic profiling of fine needle aspiration biopsy of the tumor before the treatment, and high-risk patients can now be identified for clinical trials that may lead to target-based therapies for metastatic disease and adjuvant therapy which aims to prevent metastatic disease. PMID:27800275

  14. Proton beam radiotherapy of uveal melanoma

    PubMed Central

    Damato, Bertil; Kacperek, Andrzej; Errington, Doug; Heimann, Heinrich

    2013-01-01

    Proton beam radiotherapy of uveal melanoma can be administered as primary treatment, as salvage therapy for recurrent tumor, and as neoadjuvant therapy prior to surgical resection. The physical properties of proton beams make it possible to deliver high-doses of radiation to the tumor with relative sparing of adjacent tissues. This form of therapy is effective for a wider range of uveal melanoma than any other modality, providing exceptionally-high rates of local tumor control. This is particularly the case with diffuse iris melanomas, many of which are unresectable. The chances of survival, ocular conservation, visual preservation and avoidance of iatrogenic morbidity depend greatly on the tumor size, location and extent. When treating any side-effects and/or complications, it is helpful to consider whether these are the result of collateral damage or persistence of the irradiated tumor (‘toxic tumor syndrome’). PMID:24227980

  15. Uveal melanoma in children and teenagers

    PubMed Central

    Shields, Carol L.; Kaliki, Swathi; Arepalli, Sruthi; Atalay, Hatice Tuba; Manjandavida, Fairooz P.; Pieretti, Guilia; Shields, Jerry A.

    2013-01-01

    Purpose To review the features and prognosis of uveal melanoma in children. Methods Retrospective case series. Results Of 122 children with uveal melanoma, there were 53 (43%) male and 69 (57%) female patients. In this group, the mean age at presentation was 15 years (median 16 years, range 3–20 years). Age at presentation was 0 to 5 years in 4 (3%), 5.1 to 10 years in 14 (11%), 10.1 to 15 years in 43 (35%), and 15.1 to ⩽20 in 61 (50%). Associated ocular melanocytosis was present in 4 (3%). The melanoma was primarily located in the iris (n = 30, 25%), ciliary body (n = 10, 8%), or choroid (n = 82, 67%). The mean tumor basal dimension was 9.8 mm and mean thickness was 5.0 mm. The tumor color was pigmented (brown) (n = 102, 84%), nonpigmented (yellow) (n = 19, 16%), or mixed (n = 25, 21%). Subretinal fluid (n = 66, 54%) and hemorrhage (n = 9, 7%) were noted. Primary treatment involved laser photocoagulation (n = 3, 2%), transpupillary thermotherapy (n = 17, 14%), local tumor resection (n = 26, 21%), plaque radiotherapy (n = 42, 34%), or enucleation (n = 54, 44%). Kaplan Meier 5, 10, and 20-year estimates for uveal melanoma-related metastasis were 9%, 9%, and 20%, respectively, for children compared to 15%, 25%, and 36% for all ages. Conclusion Uveal melanoma in children tends to occur most often in the teenage years as a pigmented tumor involving the choroid or iris and with mean thickness of 5 mm. Prompt treatment is advised. PMID:24227986

  16. Malignant uveal melanoma and similar lesions studied by computed tomography

    SciTech Connect

    Mafee, M.F.; Peyman, G.A.; McKusick, M.A.

    1985-08-01

    Forty-four patients with intraocular disease were studied by computed tomography (CT); in 19 cases malignant uveal melanoma was considered the likely diagnosis. CT proved to be accurate in determining the location and size of uveal melanomas, demonstrating scleral invasion, and differentiating melanoma from choroidal detachment or angioma, toxocariasis, and senile macular degeneration. On CT, uveal melanomas appeared as hyperdense lesions with slight to moderate contrast enhancement. Tumors thinner than 2 mm could not be seen. Using dynamic CT, the authors noted moderate peak amplitude, normal or delayed tissue transit time, and persistently elevated washout phase (downslope), indicating increased permeability as the result of an impaired tumor blood barrier. Histological types of uveal melanoma could not be differentiated on the basis of circulatory patterns. Dynamic CT may be useful in distinguishing uveal melanoma from choroidal hemangioma or hematoma.

  17. 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

  18. Upcoming translational challenges for uveal melanoma.

    PubMed

    Amirouchene-Angelozzi, Nabil; Schoumacher, Marie; Stern, Marc-Henri; Cassoux, Nathalie; Desjardins, Laurence; Piperno-Neumann, Sophie; Lantz, Olivier; Roman-Roman, Sergio

    2015-11-01

    The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients. PMID:26505679

  19. Upcoming translational challenges for uveal melanoma

    PubMed Central

    Nabil, Amirouchene-Angelozzi; Marie, Schoumacher; Marc-Henri, Stern; Nathalie, Cassoux; Laurence, Desjardins; Sophie, Piperno-Neumann; Olivier, Lantz; Sergio, Roman-Roman

    2015-01-01

    The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients. PMID:26505679

  20. Proteomics of Uveal Melanoma: A Minireview

    PubMed Central

    Abildgaard, Søren K. O.; Vorum, Henrik

    2013-01-01

    Uveal melanoma (UM) continues to be associated with a high mortality rate of up to 50% due to metastatic spread primarily to the liver. Currently there are relatively effective treatments for the primary tumor, though the management of the metastatic disease remains inadequate. Conventional diagnostic tools have a low sensitivity for detecting metastasis, and early detection of metastatic spread would allow more treatment options that could ultimately increase survival of UM patients. Advanced proteomic methods have already helped to find potential biomarkers associated with UM pathogenesis and metastasis. In the present review we discuss the field of proteomics in relation to studies elucidating biomarkers of UM, where proteins such as S-100β, osteopontin (OPN), and melanoma inhibitory activity (MIA) have been shown to be associated with metastasis. PMID:24078811

  1. 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

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

    PubMed Central

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

    2016-01-01

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

  3. 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.

  4. 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

  5. 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

  6. Nanomedicine in the application of uveal melanoma

    PubMed Central

    You, Shuo; Luo, Jing; Grossniklaus, Hans E.; Gou, Ma-Ling; Meng, Ke; Zhang, Qing

    2016-01-01

    Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment. PMID:27588278

  7. Nanomedicine in the application of uveal melanoma.

    PubMed

    You, Shuo; Luo, Jing; Grossniklaus, Hans E; Gou, Ma-Ling; Meng, Ke; Zhang, Qing

    2016-01-01

    Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.

  8. Nanomedicine in the application of uveal melanoma.

    PubMed

    You, Shuo; Luo, Jing; Grossniklaus, Hans E; Gou, Ma-Ling; Meng, Ke; Zhang, Qing

    2016-01-01

    Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment. PMID:27588278

  9. Lipomatous Change in Uveal Melanoma: Histopathological, Immunohistochemical and Cytogenetic Analysis

    PubMed Central

    Yavuzyigitoglu, Serdar; Kilic, Emine; Vaarwater, Jolanda; de Klein, Annelies; Paridaens, Dion; Verdijk, Robert M.

    2016-01-01

    Purpose The aim of this study was to describe a case of lipomatous change in uveal melanoma. Procedures The patient presented with a 2-year history of blurry vision. A full examination of the right eye revealed a dome-shaped pigmented subretinal mass in the choroid with a thickness of 9 mm and a diameter of 15 mm. The eye was enucleated and prepared for histopathologic, genetic and molecular investigation. Results Histopathology revealed a small circumscribed area consisting of mature adipocytic appearing cells with abundant clear cytoplasm and small peripheral flattened nuclei within a spindle-cell melanoma of the uvea. The cytoplasm of the adipocytic cells stained negative for periodic acid-Schiff and Alcian blue and positive for Melan-A, HMB-45 and tyrosinase, confirming melanocytic lineage. Fluorescence in situ hybridization analysis confirmed trisomy of chromosome 6p22 and disomy of chromosome 3p13 in the nuclei of both the tumor spindle type B cells and in the nuclei of lipomatous tumor cells. Conclusions Lipomatous change can be added to the many histopathologic faces of uveal melanoma. To our knowledge, this is the first report of lipomatous change in uveal melanoma performed with cytogenetic investigations. PMID:27239451

  10. Long-term results of proton beam irradiated uveal melanomas

    SciTech Connect

    Gragoudas, E.S.; Seddon, J.M.; Egan, K.; Glynn, R.; Munzenrider, J.; Austin-Seymour, M.; Goitein, M.; Verhey, L.; Urie, M.; Koehler, A.

    1987-04-01

    The first 128 consecutive patients with uveal melanomas treated with proton beam irradiation were studied in order to evaluate survival and visual acuity status of patients with relatively long-term follow-up. The median follow-up was 5.4 years, and no patient was lost to follow-up. All tumors showed regression. The most recent visual acuity was 20/40 or better in 35% and 20/100 or better in 58%. Eight eyes were enucleated because of complications. Metastasis developed in 26 patients (20.5%) from 3 months to 7 years after treatment. Results indicate that proton irradiation is quite successful for achieving local control of uveal melanomas. A large proportion of the treated eyes maintained useful vision. Five-year follow-up data indicate that proton irradiation has no deleterious effect on the likelihood of the development of metastasis.

  11. Prognosis of uveal melanoma based on race in 8100 patients: The 2015 Doyne Lecture.

    PubMed

    Shields, C L; Kaliki, S; Cohen, M N; Shields, P W; Furuta, M; Shields, J A

    2015-08-01

    A retrospective, nonrandomized, interventional case series of 8100 patients with uveal melanoma were evaluated for melanoma-related metastasis based on patient race. The patient race was Caucasian (n=7918, 98%), Hispanic (n=105, 1%), Asian (n=44, <1%), or African American (n=33, <1%). On the basis of race (Caucasian, Hispanic, Asian, and African American), significant differences were noted in mean age at presentation (58, 48, 44, and 52 years; P<0.001), distance of posterior tumor margin to foveola (5, 5, 6, and 4 mm; P<0.001), distance of posterior tumor margin to optic disc (5, 5, 6, and 4 mm) (P<0.001), tumor base (11, 12, 12, and 13 mm; P<0.001), tumor thickness (5.4, 7.1, 6.5, and 7.5 mm; P<0.001), intraocular hemorrhage (10, 14, 11, and 24%; P=0.02), and rupture of Bruch's membrane (20, 27, 39, and 36%; P=0.001). On the basis of multivariate analysis, the rate of metastasis increased with increasing age (P<0.001), ciliary body location (P<0.001), increasing tumor base (P<0.001), increasing tumor thickness (P<0.001), pigmented tumor (P=0.001), subretinal fluid (P=0.001), intraocular hemorrhage (P=0.045), and extraocular extension (P=0.036). Kaplan-Meier estimates of metastasis at 3, 5, and 10 were 8, 15, and 25% in Caucasians; 13, 13, and 13% in Hispanics; 4, 4, and 36% in Asians; and 8, 8, and 8% in African Americans. Compared with Caucasians, despite relative risk for metastasis of 0.31 for African Americans, 0.73 for Hispanics, and 1.42 for Asians, there was no statistical difference in metastasis, or death from uveal melanoma based on race. In summary, uveal melanoma showed similar prognosis for all races.

  12. Tight Junction–Associated Signaling Pathways Modulate Cell Proliferation in Uveal Melanoma

    PubMed Central

    Jayagopal, Ashwath; Yang, Jin-Long; Haselton, Frederick R.; Chang, Min S.

    2011-01-01

    Purpose. To investigate the role of tight junction (TJ)–associated signaling pathways in the proliferation of uveal melanoma. Methods. Human uveal melanoma cell lines overexpressing the TJ molecule blood vessel epicardial substance (Bves) were generated. The effects of Bves overexpression on TJ protein expression, cell proliferation, and cell cycle distribution were quantified. In addition, localization and transcription activity of the TJ-associated protein ZO-1–associated nucleic acid binding protein (ZONAB) were evaluated using immunofluorescence and bioluminescence reporter assays to study the involvement of Bves signaling in cell proliferation-associated pathways. Results. Bves overexpression in uveal melanoma cell lines resulted in increased expression of the TJ proteins occludin and ZO-1, reduced cell proliferation, and increased sequestration of ZONAB at TJs and reduced ZONAB transcriptional activity. Conclusions. TJ proteins are present in uveal melanoma, and TJ-associated signaling pathways modulate cell signaling pathways relevant to proliferation in uveal melanoma. PMID:20861479

  13. Intraocular inflammation after proton beam irradiation for uveal melanoma

    PubMed Central

    Lumbroso, L.; Desjardins, L.; Levy, C.; Plancher, C.; Frau, E.; D'Hermies, F.; Schlienger, P.; Mammar, H.; Delacroix, S.; Nauraye, C.; Ferrand, R.; Desblancs, C.; Mazal, A.; Asselain, B.

    2001-01-01

    AIM—To describe the inflammatory reaction that can occur following proton beam irradiation of uveal melanomas based on a large series of patients and to try to determine the risk factors for this reaction.
METHODS—Data from a cohort of patients with uveal melanoma treated by proton beam irradiation between 1991 and 1994 were analysed. The presence of inflammation was recorded and evaluated. Kaplan-Meier estimates and statistical analysis of general and tumour related risk factors were performed.
RESULTS—28% of patients treated during this period presented with ocular inflammation (median follow up 62 months). Risks factors were essentially tumour related and were correlated with larger lesions (height > 5 mm, diameter > 12 mm, volume > 0.4 cm3). Multivariate analysis identified initial tumour height and irradiation of a large volume of the eye as the two most important risk factors. Ocular inflammation usually consisted of mild anterior uveitis, resolving rapidly after topical steroids and cycloplegics. The incidence of inflammation after proton beam irradiation of melanomas seems higher than previously reported and is related to larger lesions. Evidence of inflammation associated with uveal melanoma has been described and seems to be associated with tumour necrosis (spontaneous or after irradiation). The appearance of transient inflammation during the follow up of these patients may be related to the release of inflammatory cytokines during tumour necrosis.
CONCLUSION—Inflammation following proton beam irradiation is not unusual. It is correlated with larger initial tumours and may be related to tumour necrosis.

 PMID:11673294

  14. Neovascular glaucoma after helium ion irradiation for uveal melanoma

    SciTech Connect

    Kim, M.K.; Char, D.H.; Castro, J.L.; Saunders, W.M.; Chen, G.T.; Stone, R.D.

    1986-02-01

    Neovascular glaucoma developed in 22 of 169 uveal melanoma patients treated with helium ion irradiation. Most patients had large melanomas; no eyes containing small melanomas developed anterior segment neovascularization. The mean onset of glaucoma was 14.1 months (range, 7-31 months). The incidence of anterior segment neovascularization increased with radiation dosage; there was an approximately three-fold increase at 80 GyE versus 60 GyE of helium ion radiation (23% vs. 8.5%) (P less than 0.05). Neovascular glaucoma occurred more commonly in larger tumors; the incidence was not affected by tumor location, presence of subretinal fluid, nor rate of tumor regression. Fifty-three percent of patients had some response with intraocular pressures of 21 mmHg or less to a combination of antiglaucoma treatments.

  15. Uveal Melanoma Expression of Indoleamine 2, 3 Deoxygenase: Establishment of an Immune Privileged Environment by Tryptophan Depletion

    PubMed Central

    Chen, Peter W.; Mellon, Jessamee K.; Mayhew, Elizabeth; Wang, Shixuan; He, Yu Guang; Hogan, Nick; Niederkorn, Jerry Y.

    2009-01-01

    The enzyme indoleamine 2, 3-dioxygenase (IDO) catalyzes degradation of tryptophan, an essential amino acid required for lymphocyte activation and proliferation. Many tumors express IDO which implied that it acts as a mechanism to evade T cell-mediated immune attack, and also to establish an immunosuppressive tumor microenvironment. The purpose of this study was to determine whether primary and metastatic uveal melanoma expressed the IDO gene and whether uveal melanoma cells could deplete tryptophan. In situ expression of IDO in primary uveal melanoma from tumor bearing eyes and metastatic uveal melanoma liver tissues was determined by immunohistostaining with IDO-specific antibody. Reverse transcription PCR was used to assess IDO gene transcription by primary and metastatic uveal melanoma cell lines. IDO protein expression was determined by Western blot of uveal melanoma cell protein lysate. IDO catalytic activity was assessed by measuring the presence of kynurenine, a product generated by tryptophan degradation, in uveal melanoma culture supernatants. Primary uveal melanoma from tumor-bearing eyes and metastatic uveal melanoma from the liver did not express IDO in situ. IDO was not constitutively expressed in either primary or metastatic uveal melanoma cell lines. However, stimulation of primary and metastatic uveal melanoma cell cultures with interferon-gamma (IFN-γ) universally upregulated both IDO gene and protein expression. Culture supernatants from IFN-γ treated primary and metastatic uveal melanoma cell cultures contained elevated levels of kynurenine. Addition of the IDO inhibitor 1-methyl DL-tryptophan significantly diminished kynurenine levels in IFN-γ treated uveal melanoma cell cultures. The results from this study suggest that IFN-γ inducible IDO upregulation by primary and metastatic uveal melanoma may generate a local immune privileged microenvironment to promote escape from T cell-mediated immune surveillance. PMID:17870068

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma

    SciTech Connect

    Muller, Karin; Nowak, Peter; Pan, Connie de; Marijnissen, Johannes P.; Paridaens, Dion A.; Levendag, Peter; Luyten, Gre P.M. . E-mail: g.p.m.luyten@erasmusmc.nl

    2005-09-01

    Purpose: To study the effectiveness and acute side effects of fractionated stereotactic radiation therapy (fSRT) for uveal melanoma. Methods and Materials: Between 1999 and 2003, 38 patients (21 male, 17 female) were included in a prospective, nonrandomized clinical trial (mean follow-up of 25 months). A total dose of 50 Gy was given in 5 consecutive days. A blinking light and a camera (to monitor the position of the diseased eye) were fixed to a noninvasive relocatable stereotactic frame. Primary end points were local control, best corrected visual acuity, and toxicity at 3, 6, 12, and 24 months, respectively. Results: After 3 months (38 patients), the local control was 100%; after 12 months (32 patients) and 24 months (15 patients), no recurrences were seen. The best corrected visual acuity declined from a mean of 0.21 at diagnosis to 0.06 2 years after therapy. The acute side effects after 3 months were as follows: conjunctival symptoms (10), loss of lashes or hair (6), visual symptoms (5), fatigue (5), dry eye (1), cataract (1), and pain (4). One eye was enucleated at 2 months after fSRT. Conclusions: Preliminary results demonstrate that fSRT is an effective and safe treatment modality for uveal melanoma with an excellent local control and mild acute side effects. The follow-up should be prolonged to study both long-term local control and late toxicity.

  1. Metastasis of Ciliary Body Melanoma to the Contralateral Eye: A Case Report and Review of Uveal Melanoma Literature

    PubMed Central

    Torossian, Nouritza M.; Wallace, Roy T.; Hwu, Wen-Jen; Bedikian, Agop Y.

    2015-01-01

    Many types of cancers metastasize to the eye. However, uveal melanoma metastasizing to the contralateral choroid is very rare. We report the case of a 68-year-old man with history of treated uveal melanoma of the right eye that developed metastasis to the liver and the choroid of the left eye. Ten years earlier, he was diagnosed to have uveal melanoma of the right eye and was initially treated with plaque radiotherapy. Two years later, upon progression of the disease in the right eye he had enucleation of the eye. We describe the patient's clinical history, the diagnosis of recurrent disease in the contralateral eye, therapy of the left eye, and systemic metastasis. In addition, we reviewed the published medical literature and described the recent advances in the management of uveal melanoma. PMID:25874144

  2. Histopathology of uveal melanomas treated with charged particle radiation

    SciTech Connect

    Crawford, J.B.; Char, D.H.

    1987-06-01

    The authors have treated 255 uveal melanomas with helium ion radiation. Twenty-three eyes have been enucleated because of complications and five eyes have been obtained at autopsy. We have evaluated 27 of these eyes. Neovascular glaucoma (10 eyes), painful keratitis (6 eyes), continued tumor growth (4 eyes), and vitreous hemorrhage (2 eyes) were the major complications of treatment that led to enucleation. The degree of tumor necrosis correlated with the size, pigmentation, and anterior extent of the tumor. It did not correlate with the interval from irradiation or with the amount of tumor shrinkage. Mitotic figures were extremely rare in treated tumors, suggesting that the tumor cells have lost their ability to cycle.

  3. Use of the Chick Embryo Model in Uveal Melanoma.

    PubMed

    Kalirai, Helen; Shahidipour, Haleh; Coupland, Sarah E; Luyten, Gregorius

    2015-04-01

    Animal models play a crucial role in basic and translational oncology research. Conventional rodent experiments, however, face ethical, practical and technical issues that limit their use. The chick embryo represents an accessible and economical in vivo model, which has long been used in developmental biology and for the study of angiogenesis. It is also a recognised xenograft model, and because of its lack of immune system in early development, the chick embryo has established itself as a key model system for cancer research, with which to study various steps in the metastatic process. In this chapter, we review the chick embryo model and the technical approaches adopted by cancer biologists, including advances in real-time imaging, and discuss how this has been or can be applied to improve our understanding of the biological events during uveal melanoma development and metastasis.

  4. Frequency, molecular pathology and potential clinical significance of partial chromosome 3 aberrations in uveal melanoma.

    PubMed

    Abdel-Rahman, Mohamed H; Christopher, Benjamin N; Faramawi, Mohammed F; Said-Ahmed, Khaled; Cole, Carol; McFaddin, Andrew; Ray-Chaudhury, Abhik; Heerema, Nyla; Davidorf, Frederick H

    2011-07-01

    The clinical significance of partial chromosome 3 alteration in uveal melanoma is still not clear. Also, the reported frequencies vary considerably in the published literature from 0 to 48%. The aims of the following study were to identify the frequency, molecular pathology and potential clinical significance of partial chromosome 3 alteration in uveal melanoma. We studied 47 uveal melanomas with an average follow-up of 36 months. Of these, 14 had confirmed metastasis. Allelic imbalance/loss of heterozygosity was studied using microsatellite markers on chromosome 3 enriched in markers located in the previously reported smallest regions of deletion overlap. Chromosomal alterations were assessed by conventional cytogenetics or comparative genomic hybridization (CGH) in a subset of patients. Utilizing genotyping, partial chromosome 3 alteration was detected in 14/47 tumors (30%). In the 23 tumors with available cytogenetic/CGH, partial chromosome 3 alteration was detected in 8/23 (38%) and was caused by both gains (4/8) and losses (4/8) of chromosome 3 with high frequency of complex chromosome 3 aberrations detected by cytogenetics. Out of the 14 tumors with confirmed metastasis, only 1 showed partial chromosome 3 alteration and the remaining showed monosomy 3. By limiting the aggressive disease marker to monosomy 3, genotyping showed 93% sensitivity and 67% specificity for detection of aggressive uveal melanoma. In conclusion, partial chromosome 3 alterations are common in uveal melanoma and mostly caused by complex cytogenetic changes leading to partial gains and/or partial losses of chromosome 3. Partial chromosome 3 alteration is not likely to be associated with highly aggressive uveal melanoma that metastasizes within the first 3 years after treatment. Microsatellite-based genotyping of chromosome 3 is highly sensitive for detection of aggressive uveal melanoma.

  5. Outcomes of Iodine-125 Plaque Brachytherapy for Uveal Melanoma With Intraoperative Ultrasonography and Supplemental Transpupillary Thermotherapy

    SciTech Connect

    Badiyan, Shahed N.; Rao, Rajesh C.; Apicelli, Anthony J.; Acharya, Sahaja; Verma, Vivek; Garsa, Adam A.; DeWees, Todd; Speirs, Christina K.; Garcia-Ramirez, Jose; Esthappan, Jacqueline; Grigsby, Perry W.; Harbour, J. William

    2014-03-15

    Purpose: To assess the impact on local tumor control of intraoperative ultrasonographic plaque visualization and selective application of transpupillary thermotherapy (TTT) in the treatment of posterior uveal melanoma with iodine-125 (I-125) episcleral plaque brachytherapy (EPB). Methods and Materials: Retrospective analysis of 526 patients treated with I-125 EPB for posterior uveal melanoma. Clinical features, dosimetric parameters, TTT treatments, and local tumor control outcomes were recorded. Statistical analysis was performed using Cox proportional hazards and Kaplan-Meier life table method. Results: The study included 270 men (51%) and 256 women (49%), with a median age of 63 years (mean, 62 years; range, 16-91 years). Median dose to the tumor apex was 94.4 Gy (mean, 97.8; range, 43.9-183.9) and to the tumor base was 257.9 Gy (mean, 275.6; range, 124.2-729.8). Plaque tilt >1 mm away from the sclera at plaque removal was detected in 142 cases (27%). Supplemental TTT was performed in 72 patients (13.7%). One or 2 TTT sessions were required in 71 TTT cases (98.6%). After a median follow-up of 45.9 months (mean, 53.4 months; range, 6-175 months), local tumor recurrence was detected in 19 patients (3.6%). Local tumor recurrence was associated with lower dose to the tumor base (P=.02). Conclusions: Ultrasound-guided plaque localization of I-125 EPB is associated with excellent local tumor control. Detection of plaque tilt by ultrasonography at plaque removal allows supplemental TTT to be used in patients at potentially higher risk for local recurrence while sparing the majority of patients who are at low risk. Most patients require only 1 or 2 TTT sessions.

  6. 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

  7. Paraneoplastic cerebellar degeneration with anti-Yo antibodies associated with metastatic uveal melanoma.

    PubMed

    Valpione, Sara; Zoccarato, Marco; Parrozzani, Raffaele; Pigozzo, Jacopo; Giometto, Bruno; Laveder, Francesco; Aliberti, Camillo; Chiarion-Sileni, Vanna

    2013-12-15

    Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute development of pancerebellar dysfunction as a remote effect of a systemic cancer and usually develops in patients affected by gynecological tumors. Uveal melanoma is a very rare disease with a severe prognosis. A 58-year-old man affected by uveal melanoma developed anti-Yo positive paraneoplastic cerebellar degeneration (PCD) 42 months after the initial diagnosis. The onset and worsening of the neurological symptoms were parallel to the course of liver metastasis. To our knowledge this is the first case of PCD in a patient with uveal melanoma. We speculate that the cerebellar degeneration-related protein 2 (CDR2), to which the anti-Yo antibodies are directed, may have been expressed in melanoma cells and conferred proliferative advantage to the disease. PMID:24035275

  8. Repression of genes involved in melanocyte differentiation in uveal melanoma

    PubMed Central

    Bergeron, Marjorie-Allison; Champagne, Sophie; Gaudreault, Manon; Deschambeault, Alexandre

    2012-01-01

    Purpose Uveal melanoma (UM) has been the subject of intense interest due to its distinctive metastatic pattern, which involves hematogenous dissemination of cancerous cells toward the liver in 50% of patients. To search for new UM prognostic markers, the Suppressive Subtractive Hybridization (SSH) technique was used to isolate genes that are differentially expressed between UM primary tumors and normal uveal melanocytes (UVM). Methods A subtracted cDNA library was prepared using cDNA from uncultured UM primary tumors and UVM. The expression level of selected genes was further validated by cDNA microarray, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence analyses. Results One hundred-fifteen genes were identified using the SSH technique. Microarray analyses comparing the gene expression profiles of UM primary tumors to UVM validated a significant differential expression for 48% of these genes. The expression pattern of selected genes was then analyzed by semi-quantitative RT–PCR and was found to be consistent with the SSH and cDNA microarray findings. A down-regulation of genes associated with melanocyte differentiation was confirmed in UM primary tumors. Presence of undifferentiated cells in the UM was demonstrated by the expression of stem cell markers ATP-binding cassette sub-family G member 2 (ABCG2) and octamer-binding protein 4 (OCT4). Conclusions We demonstrated that the SSH technique is efficient to detect differentially expressed genes between UM and UVM. The genes identified in this study represent valuable candidates for further functional analysis in UM and should be informative in studying the biology of this tumor. In addition, deregulation of the melanocyte differentiation pathway revealed the presence of UM cells exhibiting a stem cell-like phenotype. PMID:22815634

  9. Precision, high dose radiotherapy: helium ion treatment of uveal melanoma

    SciTech Connect

    Saunders, W.M.; Char, D.H.; Quivey, J.M.; Castro, J.R.; Chen, G.T.Y.; Collier, J.M.; Cartigny, A.; Blakely, E.A.; Lyman, J.T.; Zink, S.R.

    1985-02-01

    The authors report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) the authors have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons.

  10. iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors

    PubMed Central

    Crabb, John W.; Hu, Bo; Crabb, John S.; Triozzi, Pierre; Saunthararajah, Yogen; Singh, Arun D.

    2015-01-01

    Background Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. Methods Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch’s membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors. Results Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens. Conclusions The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and

  11. Substantial expression of luteinizing hormone-releasing hormone (LHRH) receptor type I in human uveal melanoma

    PubMed Central

    Schally, Andrew V.; Block, Norman L; Dezso, Balazs; Olah, Gabor; Rozsa, Bernadett; Fodor, Klara; Buglyo, Armin; Gardi, Janos; Berta, Andras; Halmos, Gabor

    2013-01-01

    Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, these analogs could be considered for the LHRH receptor-based treatment of uveal melanoma. PMID:24077773

  12. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma

    PubMed Central

    Moore, Amanda R; Ceraudo, Emilie; Sher, Jessica J; Guan, Youxin; Shoushtari, Alexander N; Chang, Matthew T; Zhang, Jenny Q; Walczak, Edward G; Kazmi, Manija A; Taylor, Barry S; Huber, Thomas; Chi, Ping; Sakmar, Thomas P; Chen, Yu

    2016-01-01

    Uveal melanomas are molecularly distinct from cutaneous melanomas and lack mutations in BRAF, NRAS, KIT, and NF1. Instead, they are characterized by activating mutations in GNAQ and GNA11, two highly homologous α subunits of Gαq/11 heterotrimeric G proteins, and in PLCB4 (phospholipase C β4), the downstream effector of Gαq signaling 1–3. We analyzed genomics data from 136 uveal melanoma samples and found a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ, GNA11, and PLCB4 but in 0 of 127 samples that harbored mutations in these genes. The Leu129Gln CysLT2R mutant protein constitutively activates endogenous Gαq and is unresponsive to stimulation by leukotriene. Expression of Leu129Gln CysLT2R in melanocytes enforces expression of a melanocyte-lineage signature, drives phorbol ester–independent growth in vitro, and promotes tumorigenesis in vivo. Our findings implicate CYSLTR2 as a uveal melanoma oncogene and highlight the critical role of Gαq signaling in uveal melanoma pathogenesis. PMID:27089179

  13. Long noncoding RNA MALAT1 promotes uveal melanoma cell growth and invasion by silencing of miR-140

    PubMed Central

    Sun, Lei; Sun, Peng; Zhou, Qi-ying; Gao, Xiangchun; Han, Qing

    2016-01-01

    Increasing evidences have demonstrated that long noncoding RNAs (LncRNAs) play a significant role in the development of tumor. However, the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in uveal melanoma remains unknown. In this study, we demonstrated that the expression of MALAT1 was upregulated in the uveal melanoma tissues compared to normal tissues. Among them, MALAT1 was upregulated in 72% (18/25) uveal melanoma tissues compared to their paired normal tissues. Knockdown of MALAT1 suppressed uveal melanoma cell proliferation, colony information, invasion and migration. Moreover, we showed that knockdown of MALAT1 promoted miR-140 expression and suppressed Slug and ADAM10 expression in the MUM-2C cell. In addition, we demonstrated that miR-140 was downregulated in the uveal melanoma tissues compared to normal tissues and cell lines. The expression level of MALAT1 was inversely correlated with the expression level of miR-140 in uveal melanoma tissues. These results suggested that MALAT1 served as an oncogenic LncRNA in the development of uveal melanoma. PMID:27725873

  14. Plaque Brachytherapy for Uveal Melanoma: A Vision Prognostication Model

    SciTech Connect

    Khan, Niloufer; Khan, Mohammad K.; Bena, James; Macklis, Roger; Singh, Arun D.

    2012-11-01

    Purpose: To generate a vision prognostication model after plaque brachytherapy for uveal melanoma. Methods and Materials: All patients with primary single ciliary body or choroidal melanoma treated with iodine-125 or ruthenium-106 plaque brachytherapy between January 1, 2005, and June 30, 2010, were included. The primary endpoint was loss of visual acuity. Only patients with initial visual acuity better than or equal to 20/50 were used to evaluate visual acuity worse than 20/50 at the end of the study, and only patients with initial visual acuity better than or equal to 20/200 were used to evaluate visual acuity worse than 20/200 at the end of the study. Factors analyzed were sex, age, cataracts, diabetes, tumor size (basal dimension and apical height), tumor location, and radiation dose to the tumor apex, fovea, and optic disc. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log rank analysis) were used to estimate freedom from vision loss. Results: Of 189 patients, 92% (174) were alive as of February 1, 2011. At presentation, visual acuity was better than or equal to 20/50 and better than or equal to 20/200 in 108 and 173 patients, respectively. Of these patients, 44.4% (48) had post-treatment visual acuity of worse than 20/50 and 25.4% (44) had post-treatment visual acuity worse than 20/200. By multivariable analysis, increased age (hazard ratio [HR] of 1.01 [1.00-1.03], P=.05), increase in tumor height (HR of 1.35 [1.22-1.48], P<.001), and a greater total dose to the fovea (HR of 1.01 [1.00-1.01], P<.001) were predictive of vision loss. This information was used to develop a nomogram predictive of vision loss. Conclusions: By providing a means to predict vision loss at 3 years after treatment, our vision prognostication model can be an important tool for patient selection and treatment counseling.

  15. Risk factors for residual and recurrent uveal melanoma after trans-scleral local resection.

    PubMed Central

    Damato, B E; Paul, J; Foulds, W S

    1996-01-01

    AIMS: The aims of this study were to report local tumour control after trans-scleral local resection of uveal melanoma and to identify risk factors for (i) clinical residual tumour recognised immediately after surgery, and (ii) delayed tumour recurrence from subclinical microscopic deposits. METHODS: The sample included 310 patients, treated by choroidectomy (188), cyclochoroidectomy (87), or iridocyclectomy (35), with follow up ranging from 42 days to 20.9 years (median 36 months), a mean basal largest tumour diameter of 13.2 mm, and a mean tumour thickness of 7.4 mm. RESULTS: There were 24 patients with residual tumour. Forward stepwise logistic regression indicated that posterior extension to within 1 disc diameter of the optic disc or fovea was the sole best indicator of the risk of residual disease (p < 0.001). After excluding these cases, 286 patients were studied for the development of delayed local recurrence, which occurred in 57 cases. Forward stepwise multivariate analysis showed the statistically significant predictors for recurrent tumour to be epithelioid cellularity (p = 0.002), posterior tumour extension to < 1 disc diameter of disc of fovea (p = 0.002), large tumour diameter > or = 16 mm (p = 0.019) and lack of adjunctive plaque radiotherapy (p = 0.018). CONCLUSIONS: The recurrence rate at 4 years varied from 6% if no risk factors were present to 57% if there were more than two risk factors. PMID:8814738

  16. Descriptive epidemiology of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe.

    PubMed

    Mallone, S; De Vries, E; Guzzo, M; Midena, E; Verne, J; Coebergh, J W; Marcos-Gragera, R; Ardanaz, E; Martinez, R; Chirlaque, M D; Navarro, C; Virgili, G

    2012-05-01

    This work provides descriptive epidemiological data of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe as defined as in the RARECARE project. We analysed 8669 incident cases registered in the period 1995-2002 by 76 population-based cancer registries (CRs), and followed up for vital status to 31st December 2003. Age-standardised incidence to the European standard population was obtained restricting the analysis to 8416 cancer cases collected by 64 not specialised CRs or with information available only for some anatomical sites. Period survival rates at 2000-2002 were estimated on 45 CRs data. Twenty-two CRs which covered the period 1988-2002 were analysed to obtain the 15-year prevalence (1st January 2003 as reference date). Complete prevalence was calculated by using the completeness index method which estimates surviving cases diagnosed prior to 1988 ('unobserved' prevalence). The expected number of new cases per year and of prevalent cases in Europe was then obtained multiplying the crude incidence and complete prevalence rates to the European population at 2008. We estimated 5204 new cases per year (10.5 per million) to occur in Europe, of which 48.7% were melanomas of uvea, 24.8% melanomas of mucosa and 26.5% adnexal carcinomas of the skin. Five-year relative survival was 40.6% and 68.9% for mucosal and uveal melanomas, respectively. Adnexal skin carcinomas showed a good prognosis with a survival of 87.7% 5 years after diagnosis. Northern Europe, United Kingdom (UK) and Ireland showed the highest 5-year survival rate for uveal melanomas (72.6% and 73.4%), while Southern Europe showed the lowest rate (63.7%). More than 50,000 persons with a past diagnosis of one of these rare cancers were estimated to be alive at 2008 in Europe, most of them (58.8%, n=29,676) being patients with uveal melanoma. Due to the good prognosis and high incidence of uveal melanomas, these malignancies are highly represented among the long-term survivors of

  17. Effects of Zeaxanthin on Growth and Invasion of Human Uveal Melanoma in Nude Mouse Model

    PubMed Central

    Xu, Xiaoliang L.; Iacob, Codrin; Jordan, Adrienne; Gandhi, Sandipkumar; Gierhart, Dennis L.; Rosen, Richard

    2015-01-01

    Uveal melanoma cells were inoculated into the choroid of nude mice and treated with or without intraocular injection of zeaxanthin. After 21 days, mice were sacrificed and the eyes enucleated. Histopathological analysis was performed in hematoxylin and eosin stained frozen sections. Melanoma developed rapidly in the control group (without treatment of zeaxanthin). Tumor-bearing eye mass and tumor mass in the control group were significantly greater than those in zeaxanthin treated group. Melanoma in the controlled eyes occupied a large part of the eye, was epithelioid in morphology, and was with numerous mitotic figures. Scleral perforation and extraocular extension were observed in half of the eyes. Melanomas in zeaxanthin treated eyes were significantly smaller with many necrosis and apoptosis areas and no extraocular extension could be found. Quantitative image analysis revealed that the tumor size was reduced by 56% in eyes treated with low dosages of zeaxanthin and 92% in eyes treatment with high dosages of zeaxanthin, as compared to the controls. This study demonstrated that zeaxanthin significantly inhibits the growth and invasion of human uveal melanoma in nude mice, suggesting that zeaxanthin may be a promising agent to be explored for the prevention and treatment of uveal melanoma. PMID:26682063

  18. Evidence for the Role of Blue Light in the Development of Uveal Melanoma

    PubMed Central

    Logan, Patrick; Bernabeu, Miguel; Ferreira, Alberto; Burnier, Miguel N.

    2015-01-01

    Uveal melanoma is the most common malignancy of the adult eye. Although it is a relatively infrequent tumor, clinical prognosis is often poor owing to a high incidence of aggressive metastatic disease, for which there are limited treatment options. Little is known about the etiology of this condition, although several risk factors have been identified. Unlike cutaneous melanoma, however, ultraviolet radiation does not figure prominently among these risk factors. In this review, we focus on an associated form of visible electromagnetic radiation, high-energy short-wave (blue) light, a causative agent in various forms of age-related retina damage, as a previously overlooked risk factor in uveal melanoma development and progression. Finally, we discuss the impact of these data on contemporary ocular therapy, particularly the debate surrounding the filtering capabilities of intraocular lenses used to replace dysfunctional crystalline lenses during cataract surgery. PMID:26075084

  19. The use of pembrolizumab for the treatment of metastatic uveal melanoma.

    PubMed

    Kottschade, Lisa A; McWilliams, Robert R; Markovic, Svetomir N; Block, Matthew S; Villasboas Bisneto, Jose; Pham, Anthony Q; Esplin, Brandt L; Dronca, Roxana S

    2016-06-01

    Uveal melanoma is a rare type of melanoma, with only five to seven cases per one million persons diagnosed each year. Patients with metastatic melanoma of uveal origin tend to have lower response rates on traditional therapies. Herein we report our experience with 10 patients with metastatic uveal melanoma (MUM) who received pembrolizumab. Eligible patients were more than or equal to 18 years old, had unresectable MUM, progressed on prior ipilimumab therapy, had good performance status (Eastern Cooperative Oncology Group of 0 or 1), and adequate organ and marrow function. Patients could have central nervous system disease, but needed to be clinically stable. Patients were treated with 2 mg/kg pembrolizumab intravenously over 30 min every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years. Between April 2014 and October 2014, we treated a total of 10 patients with MUM with pembrolizumab. Median age was 65 years, with 70% being female. As of the data cutoff date of 14 May 2015, median progression-free survival was 18 weeks (range 3.14-49.3 weeks), with four patients still currently receiving therapy. Of eight evaluable patients, there was one complete response, two partial responses, and one patient with stable disease. Four patients had rapidly progressive disease. Toxicities were as expected and were usually grade 1/2 in nature. Although this cohort of patients was small, to our knowledge this is the first such report of outcomes in uveal melanoma patients being treated with anti-PD1 therapy. In the absence of a clinical trial, treatment with pembrolizumab appears to be a viable option for patients with MUM.

  20. Five-year follow-up of helium ion therapy for uveal melanoma

    SciTech Connect

    Char, D.H.; Castro, J.R.; Kroll, S.M.; Irvine, A.R.; Quivey, J.M.; Stone, R.D. )

    1990-02-01

    One hundred sixty-four patients with uveal melanoma were treated with helium ion irradiation prior to May 1984, and the data were analyzed in June 1989. Most uveal melanomas were large, with a mean tumor thickness of 6.5 mm; approximately 60% of the patients had tumors that extended anterior to the equator. A complete follow-up was obtained for all patients. One hundred twelve patients were alive at the time of this report; 18% of the patients developed clinical and laboratory evidence of metastases and eventually died of widespread tumor. Eighty-four percent of eyes were retained. Data were analyzed with a number of parametric and nonparametric techniques. Larger tumors and those located in close proximity to the optic nerve and fovea had a higher incidence of most complications, especially visual loss.

  1. ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma.

    PubMed

    Yoo, Jae Hyuk; Shi, Dallas S; Grossmann, Allie H; Sorensen, Lise K; Tong, ZongZhong; Mleynek, Tara M; Rogers, Aaron; Zhu, Weiquan; Richards, Jackson R; Winter, Jacob M; Zhu, Jie; Dunn, Christine; Bajji, Ashok; Shenderovich, Mark; Mueller, Alan L; Woodman, Scott E; Harbour, J William; Thomas, Kirk R; Odelberg, Shannon J; Ostanin, Kirill; Li, Dean Y

    2016-06-13

    Activating mutations in Gαq proteins, which form the α subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and β-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small-molecule inhibitor reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for Gα-mediated diseases. PMID:27265506

  2. Charged Particle Radiation Therapy for Uveal Melanoma: A Systematic Review and Meta-Analysis

    SciTech Connect

    Wang, Zhen; Nabhan, Mohammed; Schild, Steven E.; Stafford, Scott L.; Petersen, Ivy A.; Foote, Robert L.; Murad, M. Hassan

    2013-05-01

    Charged particle therapy (CPT) delivered with either protons, helium ions, or carbon ions, has been used to treat uveal melanoma. The present analysis was performed to systematically evaluate the efficacy and adverse effects of CPT for uveal melanoma. We searched EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and SciVerse Scopus and cross-referenced recent systematic reviews through January 2012. Two independent reviewers identified clinical trials and observational studies of CPT (protons, helium ions, and carbon ions). These reviewers extracted data and assessed study quality. Twenty-seven studies enrolling 8809 uveal melanoma patients met inclusion criteria. The rate of local recurrence was significantly less with CPT than with brachytherapy (odds ratio [OR] = 0.22, 95% confidence interval [CI], 0.21-0.23). There were no significant differences in mortality or enucleation rates. Results were robust in multiple sensitivity analyses. CPT was also associated with lower retinopathy and cataract formation rates. Data suggest better outcomes may be possible with charged particle therapy with respect to local recurrence, retinopathy, and cataract formation rates. The overall quality of the evidence is low, and higher quality comparative effectiveness studies are needed to provide better evidence.

  3. In vivo Confocal Microscopy in Differentiating Ipilimumab-Induced Anterior Uveitis from Metastatic Uveal Melanoma

    PubMed Central

    Kiratli, Hayyam; Mocan, Mehmet C.; İrkeç, Murat

    2016-01-01

    This report aims to describe the facilitating role of in vivo confocal microscopy in differentiating inflammatory cells from a metastatic process in a patient with uveal melanoma and multiple systemic metastases who developed anterior uveitis while under ipilimumab treatment. A 43-year-old woman developed systemic metastases 11 months after treatment of amelanotic choroidal melanoma in her right eye with 30 Gy fractionated stereotactic radiotherapy. She first received temozolomide and then 4 cycles of ipilimumab 3 mg/kg/day. After the third cycle, severe anterior uveitis with coarse pigment clumps on the lens was seen in the left eye. Her left visual acuity declined from 20/20 to 20/80. Confocal microscopy revealed globular keratic precipitates with hyperreflective inclusions and endothelial blebs all suggestive of granulomatous uveitis. The uveitic reaction subsided after a 3-week course of topical corticosteroids, and her visual acuity was 20/20 again. Although uveal melanoma metastatic to the intraocular structures of the fellow eye is exceedingly rare and metastasis masquerading uveitis without any identifiable uveal lesion is even more unusual, it was still mandatory to rule out this distant possibility in our particular patient who already had widespread systemic metastases. Confocal microscopy was a useful complementary tool by identifying the inflammatory features of the keratic precipitates. PMID:27790127

  4. Optimizing LINAC-based stereotactic radiotherapy of uveal melanomas: 7 years' clinical experience

    SciTech Connect

    Dieckmann, Karin . E-mail: Karin.Dieckmann@akhwien.at; Georg, Dietmar; Bogner, Joachim; Zehetmayer, Martin; Petersch, Bernhard; Chorvat, Martin; Weitmann, Hajo; Poetter, Richard

    2006-11-15

    Purpose: To report on the clinical outcome of LINAC-based stereotactic radiotherapy (SRT) of uveal melanomas. Additionally, a new prototype (hardware and software) for automated eye monitoring and gated SRT using a noninvasive eye fixation technique is described. Patients and Methods: Between June 1997 and March 2004, 158 patients suffering from uveal melanoma were treated at a LINAC with 6 MV (5 x 14 Gy; 5 x 12 Gy prescribed to 80% isodose) photon beams. To guarantee identical patient setup during treatment planning (CT and MRI) and treatment delivery, patients were immobilized with a BrainLAB thermoplastic mask. Eye immobilization was achieved by instructing the patient to fixate on a light source integrated into the mask system. A mini-video camera was used to provide on-line information about the eye and pupil position, respectively. A new CT and magnetic resonance (MR) compatible prototype, based on head-and-neck fixation and the infrared tracking system ExacTrac, has been developed and evaluated since 2002. This system records maximum temporal and angular deviations during treatment and, based on tolerance limits, a feedback signal to the LINAC enables gated SRT. Results: After a median follow-up of 33.4 months (range, 3-85 months), local control was achieved in 98%. Fifteen patients (9.0%) developed metastases. Secondary enucleation was performed in 23 patients (13.8%). Long-term side effects were retinopathy (n = 70; 44%), cataract (n = 30; 23%), optic neuropathy (n = 65; 41%), and secondary neovascular glaucoma (n = 23; 13.8%). Typical situations when preset deviation criteria were exceeded were slow drifts (fatigue), large sudden eye movements (irritation), or eye closing (fatigue). In these cases, radiation was reliably interrupted by the gating system. In our clinical setup, the novel system for computer-controlled gated SRT of uveal melanoma was well tolerated by about 30 of the patients treated with this system so far. Conclusion: LINAC-based SRT of

  5. The pharmacological NF-κB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells.

    PubMed

    Hu, Shuiqing; Luo, Qingqiong; Cun, Biyun; Hu, Dan; Ge, Shengfang; Fan, Xianqun; Chen, Fuxiang

    2012-01-01

    Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma.

  6. The Pharmacological NF-κB Inhibitor BAY11-7082 Induces Cell Apoptosis and Inhibits the Migration of Human Uveal Melanoma Cells

    PubMed Central

    Hu, Shuiqing; Luo, Qingqiong; Cun, Biyun; Hu, Dan; Ge, Shengfang; Fan, Xianqun; Chen, Fuxiang

    2012-01-01

    Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma. PMID:23443086

  7. The pharmacological NF-κB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells.

    PubMed

    Hu, Shuiqing; Luo, Qingqiong; Cun, Biyun; Hu, Dan; Ge, Shengfang; Fan, Xianqun; Chen, Fuxiang

    2012-01-01

    Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma. PMID:23443086

  8. Management of uveal melanoma: a consensus-based provincial clinical practice guideline

    PubMed Central

    Weis, E.; Salopek, T.G.; McKinnon, J.G.; Larocque, M.P.; Temple-Oberle, C.; Cheng, T.; McWhae, J.; Sloboda, R.; Shea-Budgell, M.

    2016-01-01

    Introduction Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. Methods A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. Results Eighty-four publications, including five existing guidelines, formed the evidence base. Summary Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases. PMID:26966414

  9. Artesunate in the treatment of metastatic uveal melanoma--first experiences.

    PubMed

    Berger, Thomas G; Dieckmann, Detlef; Efferth, Thomas; Schultz, Erwin S; Funk, Jens-Oliver; Baur, Andreas; Schuler, Gerold

    2005-12-01

    Artesunate (ART) is a derivative of artemisinin, the active principle of the Chinese herb Artemisia annua L. Artesunate is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile. It has been shown that Artesunate, apart from its anti-malarial activity, has cytotoxic effects on a number of human cancer cell lines, including leukemia, colon cancer and melanoma. We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months. Despite the small number of treated patients, ART might be a promising adjuvant drug for the treatment of melanoma and possibly other tumors in combination with standard chemotherapy. Its good tolerability and lack of serious side effects will facilitate prospective randomized trials in the near future. PMID:16273263

  10. Quantification of melanin and iron content in uveal malignant melanomas and correlation with magnetic resonance image.

    PubMed Central

    Ferris, J D; Bloom, P A; Goddard, P R; Collins, C

    1993-01-01

    Eleven patients with uveal malignant melanomas (MM) were studied by magnetic resonance (MR) imaging before enucleation. The MR appearances varied, but often were different from those previously reported to be characteristic of these tumours. Using an image analyser to assess quantitatively the melanin and iron content of each tumour, a wide range of tumour melanin concentrations was found, but universally low tumour iron concentrations. These values were compared with MR appearances that were quantified and expressed as contrast to noise ratios. The correlation between T1 and T2 shortening and increasing melanin content did not reach statistical significance. There was no correlation between MR appearances and iron content. The theories postulated to explain the diverse MR appearances of uveal MMs are discussed and variations in tumour melanin content and differences in scanner strengths are suggested as the most likely explanations. Images PMID:8318467

  11. Ki-67 immunostaining in uveal melanoma. The effect of pre-enucleation radiotherapy

    SciTech Connect

    Mooy, C.M.; de Jong, P.T.; Van der Kwast, T.H.; Mulder, P.G.; Jager, M.J.; Ruiter, D.J. )

    1990-10-01

    The reactivity of 33 choroidal and ciliary body melanomas with monoclonal antibody Ki-67, which recognizes a proliferation associated nuclear antigen, has been assessed and compared with clinicopathologic parameters. In 23 cases, 8 Gy irradiation was given 2 days before enucleation. Nonirradiated melanomas had a significantly higher proliferation rate as defined by staining with monoclonal antibody Ki-67 as compared with irradiated tumors (P = 0.007). Similarly, a strong relationship was found between pre-enucleation irradiation and low mitotic activity (P = 0.001). There was no significant correlation between the presence of Ki-67-positive nuclei and histologic classification, largest tumor diameter, localization of the tumor, age, sex, scleral invasion, pigmentation, and lymphocytic infiltration. The relevance of Ki-67 immunohistochemistry for the assessment of the life prognosis of patients with uveal melanoma has to be studied prospectively.

  12. Proton Beam Radiotherapy for Uveal Melanomas at Nice Teaching Hospital: 16 Years' Experience

    SciTech Connect

    Caujolle, Jean-Pierre; Mammar, Hamid; Chamorey, Emmanuel Phar; Pinon, Fabien; Herault, Joel; Gastaud, Pierre

    2010-09-01

    Purpose: To present the results of uveal melanomas treated at Nice Teaching Hospital. Methods and Materials: This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. Results: The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. Conclusions: We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy.

  13. Predictive factors for the development of rubeosis following proton beam radiotherapy for uveal melanoma

    PubMed Central

    Foss, A.; Whelehan, I.; Hungerford, J.; Anderson, D.; Errington, R; Kacperek, A.; Restori, M.; Kongerud, J.; Sheen, M.

    1997-01-01

    AIMS/BACKGROUND—Proton beam radiotherapy can effectively treat primary uveal melanomas of any size. Some patients, however, develop adverse late effects following treatment and the purpose of this study was to determine which factors give rise to a poor local outcome.
METHODS—The hospital records from a first cohort of 127 patients treated by protons from 1989 to 1992 were reviewed retrospectively. The presence of rubeosis was selected as a measure of significant ocular damage. Split file analysis was performed with 73 cases forming a test group with the remaining 54 cases acting as a validation group.
RESULTS—Large tumour size and the presence of retinal detachment were significant, independent risk factors for developing rubeosis for both the test and validation groups. These factors also predicted subsequent enucleation for uncontrolled ocular pain. Patients with tumours too large to plaque and with an associated retinal detachment had a 90% chance of developing rubeosis within 4 years of proton beam radiotherapy.
CONCLUSIONS—Patients with a uveal melanoma too large for plaque therapy and an associated retinal detachment run a very high risk of developing rubeosis after proton beam radiotherapy and one third of individuals developing rubeosis required enucleation for pain even if local tumour control was satisfactory.

 PMID:9422926

  14. Molecular genetic testing of uveal melanoma from routinely processed and stained cytology specimens.

    PubMed

    Christopher, Benjamin N; Cebulla, Colleen M; Wakely, Paul E; Davidorf, Frederick H; Abdel-Rahman, Mohamed H

    2011-11-01

    In the following study we investigated the utility of molecular genetic testing of the DNA extracted from routinely stained and processed smears from uveal melanoma (UM). Smears from five uveal melanoma cell lines and 12 primary tumors were prepared and stained with Papanicolaou and Romanowsky stains. Genotyping was carried out utilizing 14 microsatellite markers on chromosomes 3, 6 and 8. Mutational screening for alterations in GNAQ and GNA11 genes was carried out by restriction fragment length polymorphism. The results were compared to those obtained through direct sequencing of frozen tumor tissues. High quality DNA was extracted from the stained slides with no difference in the efficiency of DNA extraction between the two staining techniques. The extracted DNA was of adequate quality for genotyping and mutational screening. DNA extracted from approximately 200 tumor cells is sufficient for reproducible testing of allelic imbalances and for studying the common somatic mutations in GNAQ and GNA11 genes. In conclusion, we presented the feasibility of utilizing routinely stained cytology smears from UM for molecular genetic testing. The DNA obtained is of sufficient quality to carry out genotyping for markers on chromosome 3, 6 and 8, as well as screening for somatic mutations in GNAQ and GNA11 genes.

  15. Conservation treatment of the eye: Conformal proton reirradiation for recurrent uveal melanoma

    SciTech Connect

    Marucci, Laura; Lane, Anne M.; Li Wenjun; Egan, Kathleen M.; Gragoudas, Evangelos S.; Adams, Judy; Collier, John M.; Munzenrider, John E. . E-mail: jmunzenrider@partners.org

    2006-03-15

    Purpose: To evaluate the outcomes of a second course of proton beam radiation therapy (PBRT) in patients with recurrent uveal melanoma. Methods and Materials: Thirty-one patients received a second course of PBRT. The mean interval between the first and the second PBRT course was 50.2 months (range, 8-165 months). Most patients (87%) received 70 cobalt Gray equivalent (CGE) for both courses. Visual acuity was 20/200 or better in 30 patients initially and in 22 patients at the second treatment. The mean follow-up time after the second treatment was 50 months (range, 6-164 months). Results: At the time of the last follow-up, 20 patients were classified as having no evidence of disease, defined as tumor regression or an absence of tumor progression. Nine eyes (29%) were enucleated because of local recurrence (n = 5) or intractable pain (n = 4). The 5-year eye retention rate was 55% (95% confidence interval: 25.2-77.4). Six of the 22 patients who retained the eye (27%) had useful vision (20/200 or better). Conclusions A second course of PBRT for recurrent uveal melanoma to total doses between 118 and 140 CGE was associated with a relatively good probability of local control and a low enucleation rate. Although most patients lost vision, the majority were able to retain the reirradiated eye. Further evaluation is needed to assess metastasis-free survival of additional proton irradiation vs. enucleation after local recurrence.

  16. 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

  17. A Rare Thyroid Metastasis from Uveal Melanoma and Response to Immunotherapy Agents

    PubMed Central

    Collins, Dearbhaile Catherine; Yela, Ruben; Horgan, Noel; Power, Derek Gerard

    2016-01-01

    Thyroid metastasis is a rare occurrence with cutaneous melanoma and even more uncommon with uveal melanoma. The management of such metastasis is uncertain due to its infrequency and, in the era of immunotherapy, the effect of these novel drugs on uncommon metastasis, such as to the thyroid, is unknown. We report the rare case of a thyroid metastasis in a patient diagnosed with ocular melanoma initially managed with enucleation. Metastatic disease developed in the lung and thyroid gland. The case patient received the immunotherapy ipilimumab with stable disease in the thyroid and progressive disease elsewhere. The patient was then further treated with a second immunotherapy agent, pembrolizumab, and remains with stable disease one year later. We discuss the current literature on thyroid metastases from all causes and the optimal known management strategies. Furthermore, we provide an original report on the response of this disease to the novel immunomodulators, ipilimumab, and pembrolizumab with stable disease four years after initial diagnosis of ocular melanoma. PMID:27110415

  18. A Subset of Nuclear Receptors are Uniquely Expressed in Uveal Melanoma Cells

    PubMed Central

    Huffman, Kenneth Edward; Carstens, Ryan; Martinez, Elisabeth D.

    2015-01-01

    Uveal melanoma (UM) is recognized as the most common intraocular malignancy and the second most common form of melanoma. Nearly 50% of UM patients develop untreatable and fatal metastases. The 48-member nuclear receptor (NR) superfamily represents a therapeutically targetable group of transcription factors known for their regulation of key cancer pathways in numerous tumor types. Here, we profiled the expression of the 48 human NRs by qRT-PCR across a melanoma cell line panel including 5 UM lines, 9 cutaneous melanoma (CM) lines, and normal primary melanocytes. NR expression patterns identified a few key features. First, in agreement with our past studies identifying RXRg as a CM-specific marker, we found that UM cells also exhibit high levels of RXRg expression, making it a universal biomarker for melanoma tumors. Second, we found that LXRb is highly expressed in both UM and CM lines, suggesting that it may be a therapeutic target in a UM metastatic setting as it has been in CM models. Third, we found that RARg, PPARd, EAR2, RXRa, and TRa expressions could subdivide UM from CM. Previous studies of UM cancers identified key mutations in three genes: GNAQ, GNA11, and BRAF. We found unique NR expression profiles associated with each of these UM mutations. We then performed NR-to-NR and NR-to-genome expression correlation analyses to find potential NR-driven transcriptional programs activated in UM and CM. Specifically, RXRg controlled gene networks were identified that may drive melanoma-specific signaling and metabolism. ERRa was identified as a UM-defining NR and genes correlated with its expression confirm the role of ERRa in metabolic control. Given the plethora of available NR agonists, antagonists, and selective receptor modulators, pharmacologic manipulation of these NRs and their transcriptional outputs may lead to a more comprehensive understanding of key UM pathways and how we can leverage them for better therapeutic alternatives. PMID:26217306

  19. Identification of differentially expressed genes in uveal melanoma using suppressive subtractive hybridization

    PubMed Central

    Landreville, Solange; Lupien, Caroline B.; Vigneault, Francois; Gaudreault, Manon; Mathieu, Mélissa; Rousseau, Alain P.; Guérin, Sylvain L.

    2011-01-01

    Purpose Uveal melanoma (UM) is the most common primary cancer of the eye, resulting not only in vision loss, but also in metastatic death. This study attempts to identify changes in the patterns of gene expression that lead to malignant transformation and proliferation of normal uveal melanocytes (UVM) using the Suppressive Subtractive Hybridization (SSH) technique. Methods The SSH technique was used to isolate genes that are differentially expressed in the TP31 cell line derived from a primary UM compared to UVM. The expression level of selected genes was further validated by microarray, semi-quantitative RT–PCR and western blot analyses. Results Analysis of the subtracted libraries revealed that 37 and 36 genes were, respectively, up- and downregulated in TP31 cells compared to UVM. Differential expression of the majority of these genes was confirmed by comparing UM cells with UVM by microarray. The expression pattern of selected genes was analyzed by semi-quantitative RT–PCR and western blot, and was found to be consistent with the SSH findings. Conclusions We demonstrated that the SSH technique is efficient to detect differentially expressed genes in UM. The genes identified in this study represent valuable candidates for further functional analysis in UM and should be informative in studying the biology of this tumor. PMID:21647268

  20. Expression patterns of cyclin D1 and related proteins regulating G1-S phase transition in uveal melanoma and retinoblastoma

    PubMed Central

    Coupland, S; Bechrakis, N; Schuler, A; Anagnostopoulos, I; Hummel, M; Bornfeld, N; Stein, H

    1998-01-01

    BACKGROUND/AIMS—A checkpoint mechanism in late G1, whose regulation via loss of retinoblastoma protein (pRB) or p16, or overexpression of cyclin D1 or cyclin dependent kinase 4 (CDK4), has been proposed to constitute a common pathway to malignancy. The aims of this study were (a) to compare markers of cell cycle G1-S phase transition in an intraocular tumour with known pRB deficiency (retinoblastoma) and compare it with one with an apparently functional pRB (uveal melanoma); (b) to determine if one of these markers may have a role in the pathogenesis of uveal melanoma; and (c) to determine if there is a difference in cell cycle marker expression following treatment of uveal melanoma and retinoblastoma.
METHODS—90 eyes were enucleated from 89 patients for retinoblastoma (n=24) or for choroidal or ciliary body melanoma (n=66). Conventional paraffin sections were assessed for cell type and degree of differentiation. Additional slides were investigated applying standard immunohistochemical methods with antibodies specific for cyclin D1 protein, pRB, p53, p21, p16, BCL-2, and MIB-1.
RESULTS—Cyclin D1 protein and pRB were negative in retinoblastoma using the applied antibodies. In contrast, cyclin D1 protein expression was observed in 65% of uveal melanomas; a positive correlation between cyclin D1 cell positivity and tumour cell type, location, growth fraction, as well as with pRB positivity was observed. p53, p21, and p16 could be demonstrated in both tumours. An inverse relation between p53 and p21 expression was demonstrated in most choroidal melanomas and in some retinoblastomas. Apart from a decrease in the growth fractions of the tumours as determined by MIB-1, a significant difference in the expression of G1-S phase transition markers in vital areas of uveal melanoma and retinoblastoma following treatment with radiotherapy and/or chemotherapy was not observed.
CONCLUSION—Retinoblastomas and uveal melanomas, two tumours of differing pRB status

  1. High-resolution MRI of uveal melanoma using a microcoil phased array at 7 T.

    PubMed

    Beenakker, J W M; van Rijn, G A; Luyten, G P M; Webb, A G

    2013-12-01

    High-field MRI is a promising technique for the characterisation of ocular tumours, both in vivo and after enucleation. For in vivo imaging at 7 T, a dedicated three-element microcoil array was constructed as a high-sensitivity receive-only device. Using a dedicated blink/fixation protocol, high-resolution in vivo images could be acquired within 3 min in volunteers and patients with no requirement for post-acquisition image registration. Quantitative measures of axial length, aqueous depth and lens thickness in a healthy volunteer were found to agree well with standard ocular biometric techniques. In a patient with uveal melanoma, in vivo MRI gave excellent tumour/aqueous body contrast. Ex vivo imaging of the enucleated eye showed significant heterogeneity within the tumour.

  2. Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences

    SciTech Connect

    Caujolle, Jean-Pierre; Paoli, Vincent; Chamorey, Emmanuel; Maschi, Celia; Baillif, Stéphanie; Herault, Joël; Gastaud, Pierre; Hannoun-Levi, Jean Michel

    2013-04-01

    Purpose: To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT). Methods and Materials: This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model. Results: Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Five factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences. Conclusion: Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies.

  3. Proton beam radiotherapy for uveal melanoma: Results of Curie Institut-Orsay Proton Therapy Center (ICPO)

    SciTech Connect

    Dendale, Remi . E-mail: remi.dendale@curie.net; Lumbroso-Le Rouic, Livia; Noel, Georges; Feuvret, Loic; Levy, Christine; Delacroix, Sabine; Meyer, Anne; Nauraye, Catherine; Mazal, Alejandro; Mammar, Hamid; Garcia, Paul; D'Hermies, Francois; Frau, Eric; Plancher, Corine; Asselain, Bernard; Schlienger, Pierre; Mazeron, Jean Jacques; Desjardins, Laurence

    2006-07-01

    Purpose: This study reports the results of proton beam radiotherapy based on a retrospective series of patients treated for uveal melanoma at the Orsay Center. Methods and Materials: Between September 1991 and September 2001, 1,406 patients with uveal melanoma were treated by proton beam radiotherapy. A total dose of 60 cobalt Gray equivalent (CGE) was delivered in 4 fractions on 4 days. Survival rates were determined using Kaplan-Meier estimates. Prognostic factors were determined by multivariate analysis using the Cox model. Results: The median follow-up was 73 months (range, 24-142 months). The 5-year overall survival and metastasis-free survival rates were 79% and 80.6%, respectively. The 5-year local control rate was 96%. The 5-year enucleation for complications rate was 7.7%. Independent prognostic factors for overall survival were age (p < 0.0001), gender (p < 0.0003), tumor site (p < 0.0001), tumor thickness (p = 0.02), tumor diameter (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.003). Independent prognostic factors for metastasis-free survival were age (p = 0.0042), retinal detachment (p = 0.01), tumor site (p < 0.0001), tumor volume (p < 0.0001), local recurrence (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.002). Independent prognostic factors for local control were tumor diameter (p = 0.003) and macular area receiving at least 30 CGE (p = 0.01). Independent prognostic factors for enucleation for complications were tumor thickness (p < 0.0001) and lens volume receiving at least 30 CGE (p = 0.0002). Conclusion: This retrospective study confirms that proton beam radiotherapy ensures an excellent local control rate. Further clinical studies are required to decrease the incidence of postirradiation ocular complications.

  4. Radioembolization as Locoregional Therapy of Hepatic Metastases in Uveal Melanoma Patients

    SciTech Connect

    Klingenstein, A.; Haug, A. R.; Zech, C. J.; Schaller, U. C.

    2013-02-15

    To retrospectively evaluate the overall survival, safety, and efficacy of metastatic uveal melanoma patients after radioembolization as salvage therapy. Thirteen patients were treated with radioembolization of branches of the hepatic artery with resin-based yttrium-90 ({sup 90}Y)-labelled microspheres. Twelve patients underwent a single application, and 1 patient underwent 4 interventions. Dosages from 644 to 2,450 MBq (mean activity 1,780) were applied. Treatment response was evaluated by way of liver magnetic resonance imaging and computed tomography (CT) as well as whole-body fluorodeoxyglucose positron emission tomography (PET)/CT with evaluation of percentage changes in SUV{sub max} before and at 2-3 months after therapy. Kaplan-Meier analysis was calculated to determine overall survival. Partial remission (PR) was observed in 8 (62 %), stable disease (SD) in 2 (15 %), and progressive disease (PD) in 3 (23 %) patients under terms of standard criteria and PR in 3 (23 %), SD in 3 (23 %), and PD in 7 (54 %) patients according to PET criteria. Neither RECIST nor PET criteria showed a significant difference in predicting overall survival (P = 0.12 and 0.11, respectively). Median survival time after radioembolization was 7 months. No acute toxicity with in-hospital morbidity was observed. One patient developed hepatomegaly, and 1 patient developed gastric ulceration. Throughout follow-up, progression of extrahepatic metastases was observed. Radioembolization may be a promising therapy in uveal melanoma patients with predominant hepatic metastases. At first follow-up, we observed PR or SD in 77 % patients under terms of standard criteria with an acceptable toxicity profile.

  5. Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma.

    PubMed

    Metz, Claudia Hd; Scheulen, Max; Bornfeld, Norbert; Lohmann, Dietmar; Zeschnigk, Michael

    2013-04-01

    Elevated levels of cell-free DNA (cfDNA) are frequently observed in tumor patients. Activating mutations in exon 4 (R183) and exon 5 (Q209) of GNAQ and GNA 11 are almost exclusively found in uveal melanoma, thus providing a highly specific marker for the presence of circulating tumor DNA (ctDNA). To establish a reliable, noninvasive assay that might allow early detection and monitoring of metastatic disease, we determined the proportion of GNAQ or GNA 11 mutant reads in cfDNA of uveal melanoma patients by ultradeep sequencing. Cell-free DNA from 28 uveal melanoma patients with metastases or extraocular growth was isolated and quantified by real-time polymerase chain reaction (PCR) (7-1550 ng DNA/mL plasma). GNAQ and GNA 11 regions of interest were amplified in 22 of 28 patients and ultradeep sequencing of amplicons was performed to detect even low proportions of mutant reads. We detected Q209 mutations (2-38% mutant reads) in either GNAQ or GNA 11 in the plasma of 9 of 22 metastasized patients. No correlation between the proportion of mutant reads and the concentration of cfDNA could be detected. Among the nine ctDNA-positive patients, four had metastases in bone, whereas no metastases were detected in the 13 ctDNA-negative patients at this location (P = 0.025). Furthermore, ctDNA-positive patients tended to be younger at initial diagnosis and show larger metastases. The results show that ultradeep amplicon sequencing can be used to detect tumor DNA in plasma of metastasized uveal melanoma patients. It remains to be shown if this approach can be used for early detection of disseminated tumor disease.

  6. Lack of GNAQ germline mutations in uveal melanoma patients with high risk for hereditary cancer predisposition.

    PubMed

    Abdel-Rahman, Mohamed H; Pilarski, Robert; Massengill, James B; Christopher, Benjamin B; Davidorf, Frederick H

    2011-06-01

    A high frequency of somatic mutation in GNAQ has been reported in uveal melanoma (UM). GNAQ is located in the chromosomal band 9q21, the same chromosomal band that harbors a putative candidate gene for hereditary UM. We investigated the frequency of germline sequence alterations in the GNAQ gene in UM patients with increased predisposition to hereditary cancer. A total of 44 high risk UM patients were studied including three patients with a family history of UM, 15 patients with a family history of cutaneous melanoma (CM), three patients with early age at onset of their UM (<30 years) and 23 patients with strong family history of cancer and/or personal history of multiple primary tumors. Mutational screening of the seven exons of GNAQ and nearby intronic sequence was carried out by direct sequencing. We identified two deep intronic variants but no potential pathogenic mutations in GNAQ. Our results exclude GNAQ as a candidate gene in UM patients with a high risk for hereditary cancer predisposition.

  7. Genetic markers of pigmentation are novel risk loci for uveal melanoma.

    PubMed

    Ferguson, Robert; Vogelsang, Matjaz; Ucisik-Akkaya, Esma; Rai, Karan; Pilarski, Robert; Martinez, Carlos N; Rendleman, Justin; Kazlow, Esther; Nagdimov, Khagay; Osman, Iman; Klein, Robert J; Davidorf, Frederick H; Cebulla, Colleen M; Abdel-Rahman, Mohamed H; Kirchhoff, Tomas

    2016-01-01

    While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r(2) > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility. PMID:27499155

  8. Genetic markers of pigmentation are novel risk loci for uveal melanoma

    PubMed Central

    Ferguson, Robert; Vogelsang, Matjaz; Ucisik-Akkaya, Esma; Rai, Karan; Pilarski, Robert; Martinez, Carlos N.; Rendleman, Justin; Kazlow, Esther; Nagdimov, Khagay; Osman, Iman; Klein, Robert J.; Davidorf , Frederick H.; Cebulla, Colleen M.; Abdel-Rahman, Mohamed H.; Kirchhoff , Tomas

    2016-01-01

    While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415–0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419–0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339–0.637; p = 3.04E-07) are correlated (r2 > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility. PMID:27499155

  9. Differential expression of TYRP1 in adult human retinal pigment epithelium and uveal melanoma cells

    PubMed Central

    QIU, CHUN; LI, PENG; BI, JIANJUN; WU, QING; LU, LINNA; QIAN, GUANXIANG; JIA, RENBING; JIA, RONG

    2016-01-01

    Uveal melanoma (UM) is the most frequently occurring primary intraocular malignancy in adults. Tyrosinase (TYR) is a copper-containing enzyme and a type I membrane protein that is involved in the generation of melanin, the main pigment in vertebrates. TYR-related protein 1 (TYRP1) is regarded to have a crucial role in the immunotherapy of melanoma. As biomarkers, the TYR-related proteins, TYRP1 and TYRP2, exhibit specific expression in melanocytes, while also contributing to melanin synthesis within melanosomes. In the present study, the differential expression of TYRP1 was investigated at the mRNA, protein and morphological levels in four human UM cell lines (SP6.5, OM431, OCM1 and OCM290) and the human retinal pigment epithelium (RPE) cell line, using polymerase chain reaction, western blotting, immunocytochemistry and immunofluorescence staining. It was found that SP6.5 cells expressed the highest level of TYRP1, in comparison to SP6.5 OCM1 and OM431 cells, which produced less TYRP1, and OCM290 cells, which produced almost no TYRP1. No TYRP1 protein expression was identified in the RPE cell line. These findings indicate the potential use of TYRP1 in the development of therapy for UM. PMID:27073483

  10. Radioembolization and Ipilimumab in Treating Patients With Uveal Melanoma With Liver Metastases

    ClinicalTrials.gov

    2016-03-09

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

  11. Anterior segment sparing to reduce charged particle radiotherapy complications in uveal melanoma

    NASA Technical Reports Server (NTRS)

    Daftari, I. K.; Char, D. H.; Verhey, L. J.; Castro, J. R.; Petti, P. L.; Meecham, W. J.; Kroll, S.; Blakely, E. A.; Chatterjee, A. (Principal Investigator)

    1997-01-01

    PURPOSE: The purpose of this investigation is to delineate the risk factors in the development of neovascular glaucoma (NVG) after helium-ion irradiation of uveal melanoma patients and to propose treatment technique that may reduce this risk. METHODS AND MATERIALS: 347 uveal melanoma patients were treated with helium-ions using a single-port treatment technique. Using univariate and multivariate statistics, the NVG complication rate was analyzed according to the percent of anterior chamber in the radiation field, tumor size, tumor location, sex, age, dose, and other risk factors. Several University of California San Francisco-Lawrence Berkeley National Laboratory (LBNL) patients in each size category (medium, large, and extralarge) were retrospectively replanned using two ports instead of a single port. By using appropriate polar and azimuthal gaze angles or by treating patients with two ports, the maximum dose to the anterior segment of the eye can often be reduced. Although a larger volume of anterior chamber may receive a lower dose by using two ports than a single port treatment. We hypothesize that this could reduce the level of complications that result from the irradiation of the anterior chamber of the eye. Dose-volume histograms were calculated for the lens, and compared for the single and two-port techniques. RESULTS: NVG developed in 121 (35%) patients. The risk of NVG peaked between 1 and 2.5 years posttreatment. By univariate and multivariate analysis, the percent of lens in the field was strongly correlated with the development of NVG. Other contributing factors were tumor height, history of diabetes, and vitreous hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques demonstrate that for some patients in the medium and large category tumor groups, a significant decrease in dose to the structures in the anterior segment of the eye could have been achieved with the use of two ports. CONCLUSION: The development of NVG after

  12. p63 is required beside p53 for PERP-mediated apoptosis in uveal melanoma

    PubMed Central

    Awais, Raheela; Spiller, David G; White, Michael R H; Paraoan, Luminita

    2016-01-01

    Background: PERP (p53 apoptosis effector related to PMP-22), a transcriptional target of p53, is downregulated and contributes to the impairment of apoptosis in uveal melanoma (UM). Intriguingly, PERP is not induced in UM despite functional p53. p63, located on chromosome 3, which is characteristically altered in high-risk UM, can transactivate PERP. Here, we determine the functional role of p63 expression in the initiation of p53/PERP-mediated apoptosis in UM. Methods: PERP expression was monitored by quantitative PCR (qPCR) and immunoblotting in UM cell lines treated with DNA-damaging agents. The functional role of p63 was assessed by transient expression of p63-turbo GFP (p63-tGFP) in the apoptosis- resistant, 3q-deficient OCM-1 cells. Expression and localisation of p63, PERP and p53, and induction of apoptosis were characterised by qPCR, immunoblotting and live cell confocal microscopy. Results: PERP expression was significantly downregulated in all UM cell lines. DNA-damaging treatments failed to induce apoptosis and activate PERP in OCM-1 cells, which displayed non-functional levels of p63. Expression of p63-tGFP induced apoptosis with marked increase in PERP expression and associated p53 accumulation. Conclusions: Lack of p63 contributes to reduced PERP levels and impaired p53-mediated apoptosis in UM. p63 expression is required for PERP-mediated apoptosis in UM. PMID:27584665

  13. Uveal melanomas near the optic disc or fovea. Visual results after proton beam irradiation

    SciTech Connect

    Seddon, J.M.; Gragoudas, E.S.; Egan, K.M.; Glynn, R.J.; Munzenrider, J.E.; Austin-Seymour, M.; Goitein, M.; Verhey, L.; Urie, M.; Koehler, A.

    1987-04-01

    Proximity to the disc and fovea is a risk factor for visual loss after proton beam irradiation of uveal melanomas. Of 562 eyes treated over a 10-year period with pretreatment visual acuity of 20/200 or better, 363 (64.6%) contained tumors within 2 disc diameters (DD) of the disc or fovea. Rates of visual loss after treatment to worse than 20/200 and causes of visual decline were evaluated using Kaplan-Meier analysis. Cumulative rates of visual loss among subjects with tumors near the disc or fovea were 33 and 47% 1 and 2 years after treatment compared to 17 and 28%, respectively, for subjects with tumors located farther from both structures. The leading cause of visual loss in the first year among eyes with tumors near the disc or fovea was retinal detachment. Controlling for other predictors of visual loss to worse than 20/200, location near the disc or fovea was independently related to visual loss primarily due to retinal detachment, cataract, and radiation retinopathy. Despite the unfavorable location of these tumors, over half of patients with 20/200 or better pretreatment visual acuity had useful vision 2 years after treatment.

  14. The risk of enucleation after proton beam irradiation of uveal melanoma

    SciTech Connect

    Egan, K.M.; Gragoudas, E.S.; Seddon, J.M.; Glynn, R.J.; Munzenreider, J.E.; Goitein, M.; Verhey, L.; Urie, M.; Koehler, A. )

    1989-09-01

    Enucleation after proton beam irradiation of uveal melanomas occurred in 64 (6.4%) of 994 eyes with a median follow-up time of 2.7 years. The median time between irradiation and enucleation in the 64 enucleated eyes was 13 months. The probability of retaining the eye was 95 and 90%, 2 and 5 years postirradiation, respectively. Three percent of eyes were enucleated during posttreatment year 1, and the yearly rate was 1% by the fourth year. No patient had enucleation later than 5 1/2 years posttreatment. The complication most likely to result in enucleation was neovascular glaucoma although this was frequently managed without enucleation. Other common reasons for enucleation were documented or suspected tumor growth and complete retinal detachment with associated loss of vision. The leading risk factors for enucleation were anterior tumor margin involving the ciliary body, tumor height greater than 8 mm, and proximity of the tumor to the fovea. Based on the presence or absence of these factors, 5-year eye retention rates were 99, 92, and 76% for low-, moderate-, and high-risk groups, respectively. Thus, the probability of eye retention after proton beam irradiation is high even among those at greatest risk of enucleation.

  15. Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival.

    PubMed

    Abdel-Rahman, Mohamed H; Cebulla, Colleen M; Verma, Vishal; Christopher, Benjamin N; Carson, William E; Olencki, Thomas; Davidorf, Frederick H

    2012-07-01

    The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression. Twelve pathologically confirmed UM metastases from 11 patients were included. Molecular genetic alterations in chromosomes 3 (including the BAP1 region), 8q, 6p, and 1p were investigated by microsatellite genotyping. Mutations in codon 209 of GNAQ and GNA11 genes were studied by restriction-fragment length polymorphism (RFLP). We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease. In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003). Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression. Prominent mononuclear inflammatory infiltrate was observed in tumors from patients with slowly progressive disease. In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis. These findings should be considered when designing clinical trials testing effectiveness of various therapies of metastatic UM.

  16. BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells.

    PubMed

    Ambrosini, Grazia; Sawle, Ashley D; Musi, Elgilda; Schwartz, Gary K

    2015-10-20

    Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations. PMID:26397223

  17. Ion therapy for uveal melanoma in new human eye phantom based on GEANT4 toolkit.

    PubMed

    Mahdipour, Seyed Ali; Mowlavi, Ali Asghar

    2016-01-01

    Radiotherapy with ion beams like proton and carbon has been used for treatment of eye uveal melanoma for many years. In this research, we have developed a new phantom of human eye for Monte Carlo simulation of tumors treatment to use in GEANT4 toolkit. Total depth-dose profiles for the proton, alpha, and carbon incident beams with the same ranges have been calculated in the phantom. Moreover, the deposited energy of the secondary particles for each of the primary beams is calculated. The dose curves are compared for 47.8MeV proton, 190.1MeV alpha, and 1060MeV carbon ions that have the same range in the target region reaching to the center of tumor. The passively scattered spread-out Bragg peak (SOBP) for each incident beam as well as the flux curves of the secondary particles including neutron, gamma, and positron has been calculated and compared for the primary beams. The high sharpness of carbon beam׳s Bragg peak with low lateral broadening is the benefit of this beam in hadrontherapy but it has disadvantages of dose leakage in the tail after its Bragg peak and high intensity of neutron production. However, proton beam, which has a good conformation with tumor shape owing to the beam broadening caused by scattering, can be a good choice for the large-size tumors. PMID:26831752

  18. Heterogeneity revealed by integrated genomic analysis uncovers a molecular switch in malignant uveal melanoma.

    PubMed

    de Lange, Mark J; van Pelt, Sake I; Versluis, Mieke; Jordanova, Ekaterina S; Kroes, Wilma G M; Ruivenkamp, Claudia; van der Burg, Sjoerd H; Luyten, Grégorius P M; van Hall, Thorbald; Jager, Martine J; van der Velden, Pieter A

    2015-11-10

    Gene expression profiles as well as genomic imbalances are correlated with disease progression in uveal melanoma (UM). We integrated expression and genomic profiles to obtain insight into the oncogenic mechanisms in development and progression of UM. We used tumor tissue from 64 enucleated eyes of UM patients for profiling. Mutations and genomic imbalances were quantified with digital PCR to study tumor heterogeneity and molecular pathogenesis. Gene expression analysis divided the UM panel into three classes. Class I presented tumors with a good prognosis and a distinct genomic make up that is characterized by 6p gain. The UM with a bad prognosis were subdivided into class IIa and class IIb. These classes presented similar survival risks but could be distinguished by tumor heterogeneity. Class IIa presented homogeneous tumors while class IIb tumors, on average, contained 30% of non-mutant cells. Tumor heterogeneity coincided with expression of a set of immune genes revealing an extensive immune infiltrate in class IIb tumors. Molecularly, class IIa and IIb presented the same genomic configuration and could only be distinguished by 8q copy number. Moreover, UM establish in the void of the immune privileged eye indicating that in IIb tumors the infiltrate is attracted by the UM. Combined our data show that chromosome 8q contains the locus that causes the immune phentotype of UM. UM thereby provides an unique opportunity to study immune attraction by tumors. PMID:26462151

  19. Patient-derived xenografts recapitulate molecular features of human uveal melanomas.

    PubMed

    Laurent, Cécile; Gentien, David; Piperno-Neumann, Sophie; Némati, Fariba; Nicolas, André; Tesson, Bruno; Desjardins, Laurence; Mariani, Pascale; Rapinat, Audrey; Sastre-Garau, Xavier; Couturier, Jérôme; Hupé, Philippe; de Koning, Leanne; Dubois, Thierry; Roman-Roman, Sergio; Stern, Marc-Henri; Barillot, Emmanuel; Harbour, J William; Saule, Simon; Decaudin, Didier

    2013-06-01

    We have previously developed a new method for the development and maintenance of uveal melanoma (UM) xenografts in immunodeficient mice. Here, we compare the genetic profiles of the primary tumors to their corresponding xenografts that have been passaged over time. The study included sixteen primary UMs and corresponding xenografts at very early (P1), early (P4), and late (P9) in vivo passages. The tumors were analyzed for mutation status of GNAQ, GNA11, GNAS, GNA15, BAP1, and BRAF, chromosomal copy number alterations using Affymetrix GeneChip(®) Genome-Wide Human SNP6.0 arrays, gene expression profiles using GeneChip(®) Human Exon 1.0 ST arrays, BAP1 mRNA and protein expression, and MAPK pathway status using Reverse Phase Protein Arrays (RPPA). The UM xenografts accurately recapitulated the genetic features of primary human UMs and they exhibited genetic stability over the course of their in vivo maintenance. Our technique for establishing and maintaining primary UMs as xenograft tumors in immunodeficient mice exhibit a high degree of genetic conservation between the primary tumors and the xenograft tumors over multiple passages in vivo. These models therefore constitute valuable preclinical tool for drug screening in UM.

  20. The effects of a cyclooxygenase-2 (COX-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production

    PubMed Central

    Marshall, Jean-Claude; Caissie, Amanda L; Cruess, Stephanie R; Cools-Lartigue, Jonathan; Burnier, Miguel N

    2007-01-01

    Background Cyclooxygenase-2 (COX-2) expression has previously been identified in uveal melanoma although the biological role of COX-2 in this intraocular malignancy has not been elucidated. This study aimed to investigate the effect of a COX-2 inhibitor on the proliferation rate of human uveal melanoma cells, as well as its effect on the cytotoxic response of macrophages. Methods Human uveal melanoma cell lines were transfected to constitutively express COX-2 and the proliferative rate of these cells using two different methods, with and without the addition of Amfenac, was measured. Nitric oxide production by macrophages was measured after exposure to melanoma-conditioned medium from both groups of cells as well as with and without Amfenac, the active metabolite of Nepafenac. Results Cells transfected to express COX-2 had a higher proliferation rate than those that did not. The addition of Amfenac significantly decreased the proliferation rate of all cell lines. Nitric oxide production by macrophages was inhibited by the addition of melanoma conditioned medium, the addition of Amfenac partially overcame this inhibition. Conclusion Amfenac affected both COX-2 transfected and non-transfected uveal melanoma cells in terms of their proliferation rates as well as their suppressive effects on macrophage cytotoxic activity. PMID:18042295

  1. Adjuvant Sunitinib or Valproic Acid in High-Risk Patients With Uveal Melanoma

    ClinicalTrials.gov

    2016-07-25

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Iris Melanoma; Stage I Intraocular Melanoma; Stage IIA Intraocular Melanoma; Stage IIB Intraocular Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIC Intraocular Melanoma

  2. Uveal Melanoma Recurrence After Fractionated Proton Beam Therapy: Comparison of Survival in Patients Treated With Reirradiation or With Enucleation

    SciTech Connect

    Marucci, Laura; Ancukiewicz, Marek; Lane, Anne Marie; Collier, John M.; Gragoudas, Evangelos S.; Munzenrider, John E.

    2011-03-01

    Purpose: To retrospectively compare survival in recurrent uveal melanoma, between patients treated by enucleation or by a second course of fractionated proton beam therapy (PBT). Methods and Materials: Tumor recurrence was documented in 73 patients treated with PBT for uveal melanoma. Of the patients, 31 received a second course of PBT and 42 underwent enucleation. The mean patient age was 56 and 61 years for those undergoing enucleation and those undergoing reirradiation, respectively. Both primary and recurrent tumors were larger in patients undergoing enucleation. Tumor location and the presence or absence of ciliary body involvement did not differ significantly between the groups. The median follow-up after enucleation and after re-treatment was 79 and 59 months, respectively. Cumulative rates of outcomes and differences in rates between the reirradiated and enucleation groups were calculated by the Cox proportional hazards model and the log-rank test, respectively. Results: The median survival duration in the enucleated and reirradiated groups was 42 and 90 months, respectively. The median time free of metastases was 38 months in enucleated patients and 97 months in reirradiated patients. At 5 years after enucleation and after reirradiation, the probability of overall survival was 36% and 63%, respectively (p = 0.040, log-rank test); the probability of freedom from metastases was 31% and 66%, respectively (p = 0.028, log-rank test). These differences persisted after adjustment for recurrent tumor largest diameter and volume at the time of reirradiation or enucleation. Conclusions: This retrospective analysis suggests that survival in reirradiated patients is not compromised by administration of a second course of PBT for recurrent uveal melanoma.

  3. Quality of life in the follow-up of uveal melanoma patients after CyberKnife treatment.

    PubMed

    Klingenstein, Annemarie; Fürweger, Christoph; Nentwich, Martin M; Schaller, Ulrich C; Foerster, Paul I; Wowra, Berndt; Muacevic, Alexander; Eibl, Kirsten H

    2013-12-01

    To assess quality of life in uveal melanoma patients within the first and second year after CyberKnife radiosurgery. Overall, 91 uveal melanoma patients were evaluated for quality of life through the Short-form (SF-12) Health Survey at baseline and at every follow-up visit over 2 years after CyberKnife radiosurgery. Statistical analysis was carried out using SF Health Outcomes Scoring Software and included subgroup analysis of patients developing secondary glaucoma and of patients maintaining a best corrected visual acuity (BCVA) of the treated eye of 0.5 log(MAR) or better. Analysis of variance, Greenhouse-Geisser correction, Student's t-test, and Fisher's exact test were used to determine statistical significance. Physical Functioning (PF) and Role Physical (RP) showed a significant decrease after CyberKnife radiosurgery, whereas Mental Health (MH) improved (P=0.007, P<0.0001 and P=0.023). MH and Social Functioning (SF) increased significantly (P=0.0003 and 0.026) in the no glaucoma group, MH being higher compared with glaucoma patients (P=0.02). PF and RP were significantly higher in patients with higher BCVA at the second follow-up (P=0.02). RP decreased in patients with BCVA<0.5 log(MAR) (P=0.013). Vitality (VT) increased significantly in patients whose BCVA could be preserved (P=0.031). Neither tumor localization nor size influenced the development of secondary glaucoma or change in BCVA. Although PF and RP decreased over time, MH improved continuously. Prevention of secondary glaucoma has a significant influence on both SF and MH, whereas preservation of BCVA affects VT. Emotional stability throughout follow-up contributes positively toward overall quality of life. CyberKnife radiosurgery may contribute to attenuation of emotional distress in uveal melanoma patients.

  4. Oncogenic role of microRNA-20a in human uveal melanoma

    PubMed Central

    Zhou, Jinzi; Jiang, Jian; Wang, Shuhong; Xia, Xiaobo

    2016-01-01

    As a member of the microRNA (miR)-17-92 cluster, miR-20a has been indicated to be involved in the regulation of the proliferation and invasion of various cancer cells. Previous studies have observed elevated plasma levels of miR-20a in patients with uveal melanoma (UM), compared with normal controls. In the present study, the potential function of miR-20a in UM was investigated. Reverse transcription-quantitative polymerase chain reaction analysis was performed to detect the expression levels of miR-20a in UM cells and tissues. The functions of miR-20a on cell proliferation, migration and invasion were determined in vitro using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays, respectively. The expression levels of miR-20a were significantly increased in the UM cells and tissues (P<0.05). Subsequently, miR-20a mimics were transfected into UM cells, which led to increases in cell growth, migration and invasion activities. By contrast, miR-20a inhibition markedly suppressed the viability and motility of UM cells in vitro. These data provided convincing evidence that miR-20a may function as an oncogenic miRNA, and may be involved in promoting cell growth and motility in the molecular etiology of UM, suggesting its potential as a candidate therapeutic target for the treatment of patients with UM. PMID:27356499

  5. Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes

    PubMed Central

    van Essen, T. Huibertus; van Pelt, Sake I.; Bronkhorst, Inge H. G.; Versluis, Mieke; Némati, Fariba; Laurent, Cécile; Luyten, Gregorius P. M.; van Hall, Thorbald; van den Elsen, Peter J.; van der Velden, Pieter A.; Decaudin, Didier; Jager, Martine J.

    2016-01-01

    Introduction Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors should be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors. Methods 28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array. Results Increased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes, and their regulators. Conclusion Our data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies. PMID:27764126

  6. Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.

    PubMed

    Mergler, Stefan; Derckx, Raissa; Reinach, Peter S; Garreis, Fabian; Böhm, Arina; Schmelzer, Lisa; Skosyrski, Sergej; Ramesh, Niraja; Abdelmessih, Suzette; Polat, Onur Kerem; Khajavi, Noushafarin; Riechardt, Aline Isabel

    2014-01-01

    Uveal melanoma (UM) is both the most common and fatal intraocular cancer among adults worldwide. As with all types of neoplasia, changes in Ca(2+) channel regulation can contribute to the onset and progression of this pathological condition. Transient receptor potential channels (TRPs) and cannabinoid receptor type 1 (CB1) are two different types of Ca(2+) permeation pathways that can be dysregulated during neoplasia. We determined in malignant human UM and healthy uvea and four different UM cell lines whether there is gene and functional expression of TRP subtypes and CB1 since they could serve as drug targets to either prevent or inhibit initiation and progression of UM. RT-PCR, Ca(2+) transients, immunohistochemistry and planar patch-clamp analysis probed for their gene expression and functional activity, respectively. In UM cells, TRPV1 and TRPM8 gene expression was identified. Capsaicin (CAP), menthol or icilin induced Ca(2+) transients as well as changes in ion current behavior characteristic of TRPV1 and TRPM8 expression. Such effects were blocked with either La(3+), capsazepine (CPZ) or BCTC. TRPA1 and CB1 are highly expressed in human uvea, but TRPA1 is not expressed in all UM cell lines. In UM cells, the CB1 agonist, WIN 55,212-2, induced Ca(2+) transients, which were suppressed by La(3+) and CPZ whereas CAP-induced Ca(2+) transients could also be suppressed by CB1 activation. Identification of functional TRPV1, TRPM8, TRPA1 and CB1 expression in these tissues may provide novel drug targets for treatment of this aggressive neoplastic disease.

  7. Development and External Validation of a Prognostic Nomogram for Metastatic Uveal Melanoma

    PubMed Central

    Valpione, Sara; Moser, Justin C.; Parrozzani, Raffaele; Bazzi, Marco; Mansfield, Aaron S.; Mocellin, Simone; Pigozzo, Jacopo; Midena, Edoardo; Markovic, Svetomir N.; Aliberti, Camillo; Campana, Luca G.; Chiarion-Sileni, Vanna

    2015-01-01

    Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials. PMID:25780931

  8. Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma

    PubMed Central

    Diallo, Alhassane; Etienne-Grimaldi, Marie-Christine; Bidard, François-Clément; Rodrigues, Manuel; Plancher, Corine; Mariani, Pascale; Cassoux, Nathalie; Decaudin, Didier; Asselain, Bernard; Servois, Vincent

    2016-01-01

    Lessons Learned Trials dedicated to metastatic uveal melanoma are needed because of the poor prognosis of this rare cancer and because its biology is distinct from that of cutaneous melanoma. Agents targeting the MEK/ERK/MAP kinase pathways are being tested. Background. In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells. Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine. Methods. This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m2 on days 1–7 and 15–21) in 36 patients with metastatic uveal melanoma (MUM). The primary endpoint was the progression-free rate (PFR) at 6 months. Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%. Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Results. First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively. Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10–39), with long-lasting stable disease in 5 patients (14%). Median PFS and OS were 12 weeks and 10 months, respectively. No unexpected toxicity occurred. Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival. Conclusion. In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%. PMID:26911405

  9. Uveal tumour resection

    PubMed Central

    Char, D.; Miller, T.; Crawford, J

    2001-01-01

    AIM—To review the ocular retention rates, visual results, and metastases in uveal tumours managed with eye wall resection techniques.
METHODS—This was a retrospective analysis of consecutive local uveal tumour resections performed by a single surgeon. All enucleation specimens were reviewed by one author. Both parametric and non-parametric analysis of data were performed.
RESULTS—138 eyes were scheduled for eye wall resection surgery. The mean age was 52 years (range 11-86 years). Tumours involved predominantly the iris in 14 cases, iris-ciliary body in 57, ciliary body alone in 18 patients, and in 49 cases the choroid was involved (ciliochoroidal, iris-ciliary body-choroid, or choroid). 125 eyes harboured melanomas; posterior tumours were more likely to have epithelioid cells (p<0.05). The mean follow up was 6 years. The mean clock hours in iris and iris-ciliary body tumours was 3.5. In tumours that involved the choroid the mean largest diameter was 12.9 mm and the mean thickness 8.5 mm. 105 of 138 (76%) eyes were retained. Histological assessment of surgical margins did not correlate evidence of tumour in enucleated eyes or metastatic disease. Surgical margins of more anterior tumours were more likely to be clear on histological evaluation (p<0.05). Approximately 53% of retained eyes had a final visual acuity of ⩾20/40; visual results were significantly better in more anteriorly located tumours (p<0.05). All retained iris tumour cases had ⩾20/40 final visual acuity. In tumours that involved the choroid nine of 31 retained eyes kept that level of visual acuity. Eight patients developed metastases; all metastatic events developed in patients with tumours that involved the choroid, and seven of eight were mixed cell melanomas.
CONCLUSIONS—76% of eyes were retained and 53% of these had a final visual acuity of ⩾20/40. Only 7% of uveal melanoma patients developed metastatic disease with a mean follow up of 6 years. Survival did not

  10. Risk Factors for Neovascular Glaucoma After Proton Beam Therapy of Uveal Melanoma: A Detailed Analysis of Tumor and Dose–Volume Parameters

    SciTech Connect

    Mishra, Kavita K.; Daftari, Inder K.; Weinberg, Vivian; Cole, Tia; Quivey, Jeanne M.; Castro, Joseph R.; Phillips, Theodore L.; Char, Devron H.

    2013-10-01

    Purpose: To determine neovascular glaucoma (NVG) incidence and identify contributing tumor and dosing factors in uveal melanoma patients treated with proton beam radiation therapy (PBRT). Methods and Materials: A total of 704 PBRT patients treated by a single surgeon (DHC) for uveal melanoma (1996-2010) were reviewed for NVG in our prospectively maintained database. All patients received 56 GyE in 4 fractions. Median follow-up was 58.3 months. Analyses included the Kaplan-Meier method to estimate NVG distributions, univariate log–rank tests, and Cox's proportional hazards multivariate analysis using likelihood ratio tests to identify independent risk factors of NVG among patient, tumor, and dose–volume histogram parameters. Results: The 5-year PBRT NVG rate was 12.7% (95% confidence interval [CI] 10.2%-15.9%). The 5-year rate of enucleation due to NVG was 4.9% (95% CI 3.4%-7.2%). Univariately, the NVG rate increased significantly with larger tumor diameter (P<.0001), greater height (P<.0001), higher T stage (P<.0001), and closer proximity to the disc (P=.002). Dose–volume histogram analysis revealed that if >30% of the lens or ciliary body received ≥50% dose (≥28 GyE), there was a higher probability of NVG (P<.0001 for both). Furthermore, if 100% of the disc or macula received ≥28 GyE, the NVG rate was higher (P<.0001 and P=.03, respectively). If both anterior and posterior doses were above specified cut points, NVG risk was highest (P<.0001). Multivariate analysis confirmed significant independent risk factors to include tumor height (P<.0001), age (P<.0001), %disc treated to ≥50% Dose (<100% vs 100%) (P=.0007), larger tumor diameter (P=.01), %lens treated to ≥90% Dose (0 vs >0%-30% vs >30%) (P=.01), and optic nerve length treated to ≥90% Dose (≤1 mm vs >1 mm) (P=.02). Conclusions: Our current PBRT patients experience a low rate of NVG and resultant enucleation compared with historical data. The present analysis shows that tumor height

  11. Ruthenium-106 brachytherapy for thick uveal melanoma: reappraisal of apex and base dose radiation and dose rate

    PubMed Central

    Jaberi, Ramin; Sedaghat, Ahad; Azma, Zohreh; Nojomi, Marzieh; Falavarjani, Khalil Ghasemi; Nazari, Hossein

    2016-01-01

    Purpose To evaluate the outcomes of ruthenium-106 (106Ru) brachytherapy in terms of radiation parameters in patients with thick uveal melanomas. Material and methods Medical records of 51 patients with thick (thickness ≥ 7 mm and < 11 mm) uveal melanoma treated with 106Ru brachytherapy during a ten-year period were reviewed. Radiation parameters, tumor regression, best corrected visual acuity (BCVA), and treatment-related complications were assessed. Results Fifty one eyes of 51 consecutive patients including 25 men and 26 women with a mean age of 50.5 ± 15.2 years were enrolled. Patients were followed for 36.1 ± 26.5 months (mean ± SD). Mean radiation dose to tumor apex and to sclera were 71 (± 19.2) Gy and 1269 (± 168.2) Gy. Radiation dose rates to tumor apex and to sclera were 0.37 (± 0.14) Gy/h and 6.44 (± 1.50) Gy/h. Globe preservation was achieved in 82.4%. Preoperative mean tumor thickness of 8.1 (± 0.9) mm decreased to 4.5 (± 1.6) mm, 3.4 (± 1.4) mm, and 3.0 (± 1.46) mm at 12, 24, and 48 months after brachytherapy (p = 0.03). Four eyes that did not show regression after 6 months of brachytherapy were enucleated. Secondary enucleation was performed in 5 eyes because of tumor recurrence or neovascular glaucoma. Tumor recurrence was evident in 6 (11.8%) patients. Mean Log MAR (magnification requirement) visual acuity declined from 0.75 (± 0.63) to 0.94 (± 0.5) (p = 0.04). Best corrected visual acuity of 20/200 or worse was recorded in 37% of the patients at the time of diagnosis and 61.7% of the patients at last exam (p = 0.04). Non-proliferative and proliferative radiation-induced retinopathy was observed in 20 and 7 eyes. Conclusions Thick uveal melanomas are amenable to 106Ru brachytherapy with less than recommended apex radiation dose and dose rates. PMID:26985199

  12. Complications after proton beam therapy for uveal malignant melanoma. A clinical and histopathologic study of five cases

    SciTech Connect

    Kincaid, M.C.; Folberg, R.; Torczynski, E.; Zakov, Z.N.; Shore, J.W.; Liu, S.J.; Planchard, T.A.; Weingeist, T.A.

    1988-07-01

    Proton beam therapy for uveal malignant melanoma has been advocated as effective therapy because of documented reduction in tumor size and few clinical complications. However, some eyes have been removed because of adverse effects. The authors report the clinical courses and pathologic findings of five eyes enucleated after proton beam irradiation. Neovascular glaucoma had developed in three eyes, two eyes had vitreous hemorrhage, and two had extraocular extension. The tumors in the radiation treatment field showed continued postirradiation growth clinically in four of the five eyes, and mitotic activity histologically in all five cases. Two and one half years after irradiation, and nearly 2 years after subsequent enucleation, one of those two patients had biopsy-proven liver metastases, and later died. Despite the considerable success rate of proton beam irradiation, the potential for clinical complications and subsequent tumor growth remains.

  13. Discrepancy between fluorescence in situ hybridization and multiplex ligation-dependent probe amplification in orbital recurrence of uveal melanoma 26 years after enucleation.

    PubMed

    Russo, Andrea; Rene, Cornelius; Coupland, Sarah E; Sagili, Suresh; Damato, Bertil

    2012-01-01

    Cytogenetic analysis has transformed the management of uveal melanoma in recent years and allows categorization of such tumors into low-grade tumors with a favorable prognosis and high-grade tumors that metastasize with a fatal outcome. The authors report the case of a 73-year-old man who presented with recurrent melanoma in his left socket, 26 years after enucleation for uveal melanoma. Chromosomal analysis by multiplex ligation-dependent probe amplification revealed partial loss of chromosome 3 and gains in chromosomes 6 and 8, which were missed with fluorescence in situ hybridization. The patient developed multiple liver metastases 14 months after orbital exenteration and died 8 months later. To the best of authors' knowledge, this is the first report of late recurrence of uveal melanoma after enucleation, in which multiplex ligation-dependent probe amplification chromosomal analysis has been used. The case also highlights the limitations of fluorescence in situ hybridization and the benefits of multiplex ligation-dependent probe amplification, which is more reliable at predicting survival.

  14. M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles.

    PubMed

    Herwig, Martina C; Bergstrom, Chris; Wells, Jill R; Höller, Tobias; Grossniklaus, Hans E

    2013-02-01

    Macrophages have been found to be negative predictors of outcome in patients with uveal melanoma. In particular, recent studies point toward a disease-progressing role of proangiogenic M2 macrophages in melanomas with monosomy 3. Although most studies implicate a protective effect of PPAR-gamma activation in tumors, PPAR-gamma has also been shown to promote the polarization of M1 macrophages toward the M2 phenotype. The purpose of this investigation was first, to characterize the phenotype of tumor infiltrating macrophages and second, to study PPAR-gamma expression in uveal melanomas with molecular gene expression profile as prognostic predictors for patients' outcome. Twenty specimens from patients with uveal melanoma were analyzed for clinical and histologic tumor characteristics. The molecular RNA profile (class 1 or class 2) was commercially determined. Using immunohistochemical techniques, the specimens were dual labeled for CD68 and CD163. CD68 + CD163- M1 macrophages and CD68 + CD163+ M2 macrophages were analyzed in ten high power fields sparing macrophage-poor areas and a mean value was calculated for each tumor. The tumors were immunostained for von Willebrand factor and the micro vascular density (MVD) was analyzed according to Foss. To assess the proliferative rate of each tumor, Ki67 expression was evaluated in ten high power fields followed by calculation of a mean value. Expression of PPAR-gamma was evaluated using a score from 0 (no staining) to 3 (tumor entirely stained). Statistical analysis and a respective correlation were made between histologic characteristics, molecular profile, type of tumor infiltrating macrophages (M1 vs. M2), MVD, proliferative rate, and PPAR-gamma expression. Our results showed a correlation between the ratio of M2/M1 macrophages and the molecular profile with a ratio of approximately 1 corresponding to molecular class 1 and a ratio of approximately 2 corresponding to molecular class 2 (p = 0.01). The ratio of M2/M1

  15. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma.

    PubMed

    Bidard, François-Clément; Madic, Jordan; Mariani, Pascale; Piperno-Neumann, Sophie; Rampanou, Aurore; Servois, Vincent; Cassoux, Nathalie; Desjardins, Laurence; Milder, Maud; Vaucher, Isabelle; Pierga, Jean-Yves; Lebofsky, Ronald; Stern, Marc-Henri; Lantz, Olivier

    2014-03-01

    Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.

  16. Monte Carlo calculations and measurements of absorbed dose per monitor unit for the treatment of uveal melanoma with proton therapy

    PubMed Central

    Koch, Nicholas; Newhauser, Wayne D; Titt, Uwe; Gombos, Dan; Coombes, Kevin; Starkschall, George

    2014-01-01

    The treatment of uveal melanoma with proton radiotherapy has provided excellent clinical outcomes. However, contemporary treatment planning systems use simplistic dose algorithms that limit the accuracy of relative dose distributions. Further, absolute predictions of absorbed dose per monitor unit are not yet available in these systems. The purpose of this study was to determine if Monte Carlo methods could predict dose per monitor unit (D/MU) value at the center of a proton spread-out Bragg peak (SOBP) to within 1% on measured values for a variety of treatment fields relevant to ocular proton therapy. The MCNPX Monte Carlo transport code, in combination with realistic models for the ocular beam delivery apparatus and a water phantom, was used to calculate dose distributions and D/MU values, which were verified by the measurements. Measured proton beam data included central-axis depth dose profiles, relative cross-field profiles and absolute D/MU measurements under several combinations of beam penetration ranges and range-modulation widths. The Monte Carlo method predicted D/MU values that agreed with measurement to within 1% and dose profiles that agreed with measurement to within 3% of peak dose or within 0.5 mm distance-to-agreement. Lastly, a demonstration of the clinical utility of this technique included calculations of dose distributions and D/MU values in a realistic model of the human eye. It is possible to predict D/MU values accurately for clinical relevant range-modulated proton beams for ocular therapy using the Monte Carlo method. It is thus feasible to use the Monte Carlo method as a routine absolute dose algorithm for ocular proton therapy. PMID:18367789

  17. Immunohistochemical characteristics of uveal melanoma assording to the age at diagnosis, histological type and extension of the tumor.

    PubMed

    Danilova, N V; Davydova, S Yu

    2014-01-01

    The purpose of this study was to investigate the relationship between MMP9 expression and tumour invasion in different structures of the eye. We also examined whether there was any correlation between the growth factors (TGFb and EGF), onco-suppressor proteins (p16 and p53) and Ki-67, and the tumour histological subtypes, atypia level and age at diagnosis. Tumour specimens were obtained from 42 primary uveal melanomas immediately after enucleation at The Helmholtz Moscow Research Institute of Eye Diseases. The patients were not treated with radio- or thermotherapy. During our systematic study, we exclusively employed 10%-formalin fixed, paraffin-wax-embedded tissue sections of UM for histological diagnosis and immunohistochemistry. According to our data the hyperexpression of MMP9 and EGFR correlates with a high proportion of spindle cells in a tumour (Kruskal-Wallis test p=0,1 for each). Moreover, we have demonstrated the association between the level of EGFR, TGFb and MMP9 expression and the initial invasion stage (Spearman's test p=0,1). In addition, we have revealed the significant correlation between TGFb hyperexpression and atypia level (Spearman's test p=0,059). Our data reflect that the diagnoses at an advanced age correlate with hyperexpression of p16 (Kruskal-Wallis test p=0,068). An interesting result is that p16 level reduced in inverse proportion to that of TGFb. On the basis of our data and previous studies, we reached the conclusion that after the lapse of time the level of p16 rises significantly in order to inhibit proliferating activity of melanocytes in the normally functioning pigmented layer. However, although the probability of UM diagnoses in elderly is increasing, we have no reliable data for the relationship with high atypia levels. PMID:25543409

  18. Clinico-Pathological Association of Delineated miRNAs in Uveal Melanoma with Monosomy 3/Disomy 3 Chromosomal Aberrations

    PubMed Central

    Venkatesan, Nalini; Kanwar, Jagat; Deepa, Perinkulam Ravi; Khetan, Vikas; Crowley, Tamsyn M.; Raguraman, Rajeswari; Sugneswari, Ganesan; Rishi, Pukhraj; Natarajan, Viswanathan; Biswas, Jyotirmay; Krishnakumar, Subramanian

    2016-01-01

    Purpose To correlate the differentially expressed miRNAs with clinico-pathological features in uveal melanoma (UM) tumors harbouring chromosomal 3 aberrations among South Asian Indian cohort. Methods Based on chromosomal 3 aberration, UM (n = 86) were grouped into monosomy 3 (M3; n = 51) and disomy 3 (D3; n = 35) by chromogenic in-situ hybridisation (CISH). The clinico-pathological features were recorded. miRNA profiling was performed in formalin fixed paraffin embedded (FFPE) UM samples (n = 6) using Agilent, Human miRNA microarray, 8x15KV3 arrays. The association between miRNAs and clinico-pathological features were studied using univariate and multivariate analysis. miRNA-gene targets were predicted using Target-scan and MiRanda database. Significantly dys-regulated miRNAs were validated in FFPE UM (n = 86) and mRNAs were validated in frozen UM (n = 10) by qRT-PCR. Metastasis free-survival and miRNA expressions were analysed by Kaplen-Meier analysis in UM tissues (n = 52). Results Unsupervised analysis revealed 585 differentially expressed miRNAs while supervised analysis demonstrated 82 miRNAs (FDR; Q = 0.0). Differential expression of 8 miRNAs: miR-214, miR-149*, miR-143, miR-146b, miR-199a, let7b, miR-1238 and miR-134 were studied. Gene target prediction revealed SMAD4, WISP1, HIPK1, HDAC8 and C-KIT as the post-transcriptional regulators of miR-146b, miR-199a, miR-1238 and miR-134. Five miRNAs (miR-214, miR146b, miR-143, miR-199a and miR-134) were found to be differentially expressed in M3/ D3 UM tumors. In UM patients with liver metastasis, miR-149* and miR-134 expressions were strongly correlated. Conclusion UM can be stratified using miRNAs from FFPE sections. miRNAs predicting liver metastasis and survival have been identified. Mechanistic linkage of de-regulated miRNA/mRNA expressions provide new insights on their role in UM progression and aggressiveness. PMID:26812476

  19. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

    PubMed Central

    Dahmani, Ahmed; Raymondie, Chloé; Cassoux, Nathalie; Piperno-Neumann, Sophie; Némati, Fariba; Laurent, Cécile; De Koning, Leanne; Halilovic, Ensar; Jeay, Sebastien; Wylie, Andrew; Emery, Caroline; Roman-Roman, Sergio

    2016-01-01

    Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients. PMID:27507190

  20. Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma

    PubMed Central

    Zimmer, Lisa; Vaubel, Julia; Mohr, Peter; Hauschild, Axel; Utikal, Jochen; Simon, Jan; Garbe, Claus; Herbst, Rudolf; Enk, Alexander; Kämpgen, Eckhart; Livingstone, Elisabeth; Bluhm, Leonie; Rompel, Rainer; Griewank, Klaus G.; Fluck, Michael; Schilling, Bastian; Schadendorf, Dirk

    2015-01-01

    Purpose Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. Patients and Methods We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed. Conclusions Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. Trial Registration ClinicalTrials.gov NCT01355120 PMID:25761109

  1. Iodine 125 Brachytherapy With Vitrectomy and Silicone Oil in the Treatment of Uveal Melanoma: 1-to-1 Matched Case-Control Series

    SciTech Connect

    McCannel, Tara A. McCannel, Colin A.

    2014-06-01

    Purpose: We initially reported the radiation-attenuating effect of silicone oil 1000 centistokes for iodine 125. The purpose of this report was to compare the clinical outcomes in case patients who had iodine 125 brachytherapy with vitrectomy and silicone oil 1000 centistokes with the outcomes in matched control patients who underwent brachytherapy alone. Methods and Materials: Consecutive patients with uveal melanoma who were treated with iodine 125 plaque brachytherapy and vitrectomy with silicone oil with minimum 1-year follow-up were included. Control patients who underwent brachytherapy alone were matched for tumor size, location, and sex. Baseline patient and tumor characteristics and tumor response to radiation, final visual acuity, macular status, central macular thickness by ocular coherence tomography (OCT), cataract progression, and metastasis at last follow-up visit were compared. Surgical complications were also determined. Results: Twenty case patients met the inclusion criteria. The average follow-up time was 22.1 months in case patients and 19.4 months in control patients. The final logMAR vision was 0.81 in case patients and 1.1 in control patients (P=.071); 8 case patients and 16 control patients had abnormal macular findings (P=.011); and the average central macular thickness by OCT was 293.2 μm in case patients and 408.5 μm in control patients (P=.016). Eleven case patients (55%) and 1 control patient (5%) had required cataract surgery at last follow-up (P=.002). Four patients in the case group and 1 patient in the control group experienced metastasis (P=.18). Among the cases, intraoperative retinal tear occurred in 3 patients; total serous retinal detachment and macular hole developed in 1 case patient each. There was no case of rhegmatogenous retinal detachment, treatment failure, or local tumor dissemination in case patients or control patients. Conclusions: With up to 3 years of clinical follow-up, silicone oil during brachytherapy

  2. Color flow mapping: a non-invasive tool for characterizing and differentiating between uveal melanomas and choroidal metastases.

    PubMed

    Neudorfer, Meira; Waisbourd, Michael; Anteby, Irene; Liran, Alon; Goldenberg, Dafna; Barak, Adiel; Kessler, Ada

    2011-01-01

    The objective of this study was to characterize and differentiate vascular patterns of choroidal melanomas and choroidal metastases by color flow mapping (CFM). We conducted a retrospective chart study on CFM findings in 18 patients with choroidal melanomas and 10 patients with choroidal metastases. We evaluated the possibilities of applying CFM to identify hypo- versus hyper-vascularity within the tumor, a central 'dominant vessel', and Doppler signals in the tumor's center and/or periphery. CFM demonstrated hypervascular patterns in 33% melanomas and 100% metastases (p<0.0001). CFM identified a central dominant vessel in 94% melanomas and 0/10 metastases (p<0.0001). Vascularity occupied the center of 11/18 melanomas and 0/10 metastases (p<0.0001), the periphery of 2/18 melanomas and 9/10 metastases (p<0.0001), and equally occupied the tumor's center and periphery of 5/18 melanomas and 1/10 metastases (p<0.0001). Based on our findings, we conclude that CFM was capable of non-invasively demonstrating different and distinct vascular patterns in malignant choroidal melanomas and choroidal metastases. PMID:21109962

  3. Melanoma candidate genes CDKN2A/p16/INK4A, p14ARF, and CDK4 sequencing in patients with uveal melanoma with relative high-risk for hereditary cancer predisposition.

    PubMed

    Abdel-Rahman, Mohamed H; Pilarski, Robert; Massengill, James B; Christopher, Benjamin N; Noss, Ryan; Davidorf, Frederick H

    2011-06-01

    The reported frequencies of germline mutations in the melanoma candidate genes are low in patients with uveal melanoma (UM). However, the number of families studied is limited and the majority of the published reports used low-sensitivity techniques for mutational screening. Identifying the frequency of alterations in any of the melanoma genes in patients with UM with increased hereditary cancer risk is important for proper counseling of these patients. We studied a total of 47 patients with UM including three with a family history of UM, 18 with a family and/or personal history of cutaneous melanoma (CM), three with early age at diagnosis (<30), 11 with increased risk for a known familial cancer syndrome, and 12 with a second primary tumor. Germline screening for mutations in CDKN2A, p14ARF, and exon 2 of CDK4 was carried out by direct sequencing. We identified a variant (IVS1-69 C>T) of uncertain significance in exon 1b of p14ARF in one of the patients with UM and his mother who also had UM. The variant was neither detected in any of the other patients with UM nor in 146 controls. We did not identify pathogenic mutations in CDKN2A nor exon 2 of CDK4 gene. Our study supports the low frequency of germline mutation of the CM candidate genes in patients with UM with family histories suggestive of a high risk for hereditary cancer. Germline testing for CDKN2A might be reserved for patients with UM with a family history of two or more CM.

  4. The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma

    PubMed Central

    Amirouchene-Angelozzi, Nabil; Frisch-Dit-Leitz, Estelle; Carita, Guillaume; Dahmani, Ahmed; Raymondie, Chloé; Liot, Géraldine; Gentien, David; Némati, Fariba; Decaudin, Didier

    2016-01-01

    Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effective therapeutic strategies for UM patients, we performed a combination screen using seven targeted agents inhibiting PKC, MEK, AKT, PI3K and mTOR in a panel of ten UM cell lines, representative of the UM disease. We identified a strong synergy between the mTOR inhibitor Everolimus and the PI3K inhibitor GDC0941. This combination resulted in an increase in apoptosis in several UM cell lines compared to monotherapies and enhanced the anti-tumor effect of each single agent in two patient-derived xenografts. Furthermore, we showed that the synergism between the two drugs was associated with the relief by GDC0491 of a reactivation of AKT induced by Everolimus. Altogether, our results highlight a novel and effective combination strategy, which could be beneficial for UM patients. PMID:26988753

  5. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

    PubMed Central

    Leyvraz, S.; Piperno-Neumann, S.; Suciu, S.; Baurain, J. F.; Zdzienicki, M.; Testori, A.; Marshall, E.; Scheulen, M.; Jouary, T.; Negrier, S.; Vermorken, J. B.; Kaempgen, E.; Durando, X.; Schadendorf, D.; Gurunath, R. Karra; Keilholz, U.

    2014-01-01

    Background In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. Patients and methods Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m2 on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. Results Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25–6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79–1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45–0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. Conclusion HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EudraCT number and ClinicalTrials.gov identifier 2004-002245-12 and NCT00110123. PMID:24510314

  6. Stages of Intraocular (Uveal) Melanoma

    MedlinePlus

    ... eye : A procedure in which high-energy sound waves (ultrasound) are bounced off the internal tissues of ... a small probe that sends and receives sound waves is placed gently on the surface of the ...

  7. Current trends in the treatment of ocular melanoma by radiotherapy.

    PubMed

    Hungerford, John L

    2003-02-01

    The Collaborative Ocular Melanoma Study (COMS) has recently confirmed once and for all that it is safe to attempt to preserve an eye with a posterior uveal melanoma by demonstrating no survival advantage of enucleation over plaque radiotherapy. While COMS has been under way, we have set out in London to define the selection criteria for conservative therapy versus enucleation for the various categories of melanoma in terms of size, location within the eye, and presence or absence of retinal detachment. The evolution of this approach has culminated in an overall ocular survival rate of 94% in 597 patients following radiation therapy combined with a mean loss of visual acuity of only 2.4 Snellen lines in the eyes preserved.

  8. 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 ...

  9. Lacrimal Gland Radiosensitivity in Uveal Melanoma Patients

    SciTech Connect

    Muller, Karin Nowak, Peter J.C.M.; Naus, Nicole; Pan, Connie de; Santen, Cornelis A. van; Levendag, Peter; Luyten, Gre P.M.

    2009-06-01

    Purpose: To find a dose-volume effect for inhomogeneous irradiated lacrimal glands. Methods and Materials: Between 1999 and 2006, 72 patients (42 men and 30 women) were treated with fractionated stereotactic radiotherapy in a prospective, nonrandomized clinical trial (median follow-up, 32 months). A total dose of 50 Gy was given on 5 consecutive days. The mean of all Schirmer test results obtained {>=}6 months after treatment was correlated with the radiation dose delivered to the lacrimal gland. Also, the appearance of dry eye syndrome (DES) was related to the lacrimal gland dose distribution. Results: Of the 72 patients, 17 developed a late Schirmer value <10 mm; 9 patients developed DES. A statistically significant relationship was found between the received median dose in the lacrimal gland vs. reduced tear production (p = 0.000) and vs. the appearance of DES (p = 0.003), respectively. A median dose of 7 Gy/fraction to the lacrimal gland caused a 50% risk of low Schirmer results. A median dose of 10 Gy resulted in a 50% probability of DES. Conclusion: We found a clear dose-volume relationship for irradiated lacrimal glands with regard to reduced tear production and the appearance of DES.

  10. Treatment Options for Intraocular (Uveal) Melanoma

    MedlinePlus

    ... eye : A procedure in which high-energy sound waves (ultrasound) are bounced off the internal tissues of ... a small probe that sends and receives sound waves is placed gently on the surface of the ...

  11. Treatment Option Overview (Intraocular [Uveal] Melanoma)

    MedlinePlus

    ... eye : A procedure in which high-energy sound waves (ultrasound) are bounced off the internal tissues of ... a small probe that sends and receives sound waves is placed gently on the surface of the ...

  12. Latitude and incidence of ocular melanoma.

    PubMed

    Yu, Guo-Pei; Hu, Dan-Ning; McCormick, Steven A

    2006-01-01

    We investigated the associations between latitude and the incidence of two different types of ocular melanoma, external ocular melanoma (exposed to sunlight) and internal melanoma (not exposed to sunlight), separately. Using 1992-2002 data from the Surveillance, Epidemiology, and End Results (SEER) Program of National Cancer Institute, we identified 2142 ocular melanoma cases in non-Hispanic whites, and then regressed the incidences of various types of ocular melanomas with latitude. Our analysis indicated that the higher the latitude (away from the equator, the less sun exposure), the lower the risk of external ocular melanoma (eyelid and conjunctival melanomas) among non-Hispanic whites (P for trend = 0.018). The incidence increased 2.48 fold from 47-48 degrees to 20-22 degrees. This trend is very similar to that of skin melanoma. The incidence of internal ocular melanoma (uveal melanoma) increased significantly with increasing latitudes (the less sun exposure, P for trend < 0.0001), it increased 4.91 fold from 20-22 degrees to 47-48 degrees. The latitudinal patterns of ocular melanomas may reflect the dual effects of sunlight exposure, i.e. a mutagenic effect of direct solar radiation on external ocular melanomas and a protective effect for internal uveal melanoma, which is similar to the sun radiation protective effects for various internal malignant tumors that are not exposed to the sunlight.

  13. Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for choroidal melanoma

    PubMed Central

    Sikuade, M J; Salvi, S; Rundle, P A; Errington, D G; Kacperek, A; Rennie, I G

    2015-01-01

    Aim To present our experience of the use of stereotactic radiosurgery and proton beam therapy to treat posterior uveal melanoma over a 10 year period. Methods and materials Case notes of patients treated with stereotactic radiosurgery (SRS), or Proton beam therapy (PBT) for posterior uveal melanoma were reviewed. Data collected included visual acuity at presentation and final review, local control rates, globe retention and complications. We analysed post-operative visual outcomes and if visual outcomes varied with proximity to the optic nerve or fovea. Results 191 patients were included in the study; 85 and 106 patients received Stereotactic radiosurgery and Proton beam therapy, respectively. Mean follow up period was 39 months in the SRS group and 34 months in the PBT group. Both treatments achieved excellent local control rates with eye retention in 98% of the SRS group and 95% in the PBT group. The stereotactic radiosurgery group showed a poorer visual prognosis with 65% losing more than 3 lines of Snellen acuity compared to 45% in the PBT group. 33% of the SRS group and 54% of proton beam patients had a visual acuity of 6/60 or better. Conclusions Stereotactic radiosurgery and proton beam therapy are effective treatments for larger choroidal melanomas or tumours unsuitable for plaque radiotherapy. Our results suggest that patients treated with proton beam therapy retain better vision post-operatively; however, possible confounding factors include age, tumour location and systemic co-morbidities. These factors as well as the patient's preference should be considered when deciding between these two therapies. PMID:26160531

  14. [Treatment of choroid melanoma by Gamma-Knife radiosurgery].

    PubMed

    Devin, F; Regis, J; Berros, P; Manera, L; Porcheron, D; Sedan, R; Peragut, J C; Saracco, J B

    1996-01-01

    Conservative treatment of uveal melanomas by Gamma Knife Radiosurgery is based on the use of cross fire technique with 201 Cobalt60 sources. A following of 13 months is available for the first case operated by Gamma-Knife Surgery in France. Technical baselines and one year preliminary results are reported. The diagnosis of uveal melanoma T3NOMO was established by converging results of clinical examination, angiography and echography. The definition of the target was based on stereotactic MRT examination. We delivered a dose of 50 Gys to the marginal isodose (50%). Today, one year after treatment the tumor decreased, the visual function was preserved. There were no side effect or complication.

  15. Choroid Melanoma Metastasis to Spine: A Rare Case Report

    PubMed Central

    Mandaliya, Hiren; Singh, Nandini; George, Sanila; George, Mathew

    2016-01-01

    Metastatic choroid melanoma is a highly malignant disease with a limited life expectancy. The liver is the most common site for metastasis of uveal melanoma followed by lung, bone, skin, and subcutaneous tissue. Metastasis from choroidal melanoma usually occurs within the first five years of treatment for primary tumours. Metastatic choroid melanoma to the spine/vertebrae is extremely rare. We report the first case of spinal metastasis from choroid melanoma in a 61-year-old man who had been treated for primary ocular melanoma three years earlier with radioactive plaque brachytherapy. Synchronously, at the time of metastasis, he was also diagnosed as having a new primary lung adenocarcinoma as well. The only other case reported on vertebral metastasis from malignant melanoma of choroid in literature in which primary choroid melanoma was enucleated. PMID:26989537

  16. Ocular surface foreign bodies: novel findings mimicking ocular malignant melanoma

    PubMed Central

    Maudgil, A; Wagner, B E; Rundle, P; Rennie, I G; Mudhar, H S

    2014-01-01

    Purpose Malignant melanoma of the eye is an uncommon condition that is important to recognise. We describe three cases in which ocular foreign bodies have masqueraded as ocular malignant melanoma. Methods Interventional case reports. Results Case 1 describes diathermy-induced carbon particle implantation, during plaque therapy for the treatment of uveal melanoma, mimicking recurrence with extra-scleral invasion. Case 2 shows a foreign body called ‘mullite' mimicking conjunctival melanoma. Case 3 demonstrates a conjunctival foreign body called ‘illite' that mimicked a limbal melanocytic lesion, clinically thought to be either melanocytoma or melanoma. Conclusion This report highlights the importance of careful history taking, examination, and appropriate biopsy in cases of suspected malignant melanoma, to prevent unnecessary and potentially radical treatment. PMID:25104745

  17. EPIDEMIOLOGICAL ANALYSIS OF OCULAR MELANOMA IN UNIVERSITY CLINIC CENTER IN TUZLA, BOSNIA AND HERZEGOVINA

    PubMed Central

    Vodencarevic, Amra Nadarevic; Jusufovic, Vahid; Terzic, Svjetlana; Burgic, Musfaha; Halibasic, Meliha; Sinanovic, Mersiha

    2016-01-01

    Aim: Melanoma represents a malignant tumour arising from melanocytes. Uveal melanoma is the most common primary ocular malignancy among the adult population. The aim of the study was to examine epidemiological characteristics of ocular melanoma in University Clinic Centre in Tuzla, Bosnia and Herzegovina from January 2001 till November 2015. Methods and Materials: In this retrospective study we used all available medical documentation to investigate the clinical findings which included age, gender, tumour size, histopathological features and the precise anatomic origin of the ocular melanoma. Results: Over the 14 year period of this study, there were 32 patients with microscopically confirmed ocular melanoma at the Department of Pathology. All malignant melanoma were uveal origin. Discussion and conclusion: For early detection of the disease, regular checkups are necessary, especially in older population. As there is a limited number of reports on the epidemiology of malignant tumors of eye and ocular adnex in our region, this is very important study. We conclude that this is a first study in Bosnia and Herzegovina that document the number of uveal melanomas. PMID:27698609

  18. EPIDEMIOLOGICAL ANALYSIS OF OCULAR MELANOMA IN UNIVERSITY CLINIC CENTER IN TUZLA, BOSNIA AND HERZEGOVINA

    PubMed Central

    Vodencarevic, Amra Nadarevic; Jusufovic, Vahid; Terzic, Svjetlana; Burgic, Musfaha; Halibasic, Meliha; Sinanovic, Mersiha

    2016-01-01

    Aim: Melanoma represents a malignant tumour arising from melanocytes. Uveal melanoma is the most common primary ocular malignancy among the adult population. The aim of the study was to examine epidemiological characteristics of ocular melanoma in University Clinic Centre in Tuzla, Bosnia and Herzegovina from January 2001 till November 2015. Methods and Materials: In this retrospective study we used all available medical documentation to investigate the clinical findings which included age, gender, tumour size, histopathological features and the precise anatomic origin of the ocular melanoma. Results: Over the 14 year period of this study, there were 32 patients with microscopically confirmed ocular melanoma at the Department of Pathology. All malignant melanoma were uveal origin. Discussion and conclusion: For early detection of the disease, regular checkups are necessary, especially in older population. As there is a limited number of reports on the epidemiology of malignant tumors of eye and ocular adnex in our region, this is very important study. We conclude that this is a first study in Bosnia and Herzegovina that document the number of uveal melanomas.

  19. Long-term follow-up of proton irradiated malignant melanoma by glucose-fructose enhanced magnetic resonance imaging.

    PubMed

    Thuomas, K A; Naeser, P

    1997-02-01

    MR imaging is frequently used to diagnose uveal melanomas due to the characteristic short T2 relaxation time. T2 may be significantly prolonged within 2 h after ingestion of glucose and fructose due to changed water distribution in the melanoma. This method is used to follow melanomas for up to 6 years after proton beam irradiation. In the tumours, T2 was shortened in parallel in all the lesions during the first 9 months. After this, T2 increased only in tumours which showed recurrence. T2 determination and histopathological examination revealed no signs of recurrence in eyes which were enucleated due to neovascular glaucoma. It is concluded that MR imaging performed with carbohydrate loading, registers metabolic changes induced in the tumour, giving this method great validity in the follow-up of choroidal malignant melanoma after irradiation. Eighteen patients treated with proton beam for uveal melanoma at the cyclotron in Uppsala, Sweden, were followed.

  20. Sympathetic ophthalmia complicating helium ion irradiation of a choroidal melanoma

    SciTech Connect

    Fries, P.D.; Char, D.H.; Crawford, J.B.; Waterhouse, W.

    1987-11-01

    Sympathetic ophthalmia was diagnosed 49 months after helium ion irradiation of a left choroidal melanoma. The patient maintained good vision until 18 months after therapy, when she developed neovascular glaucoma. This complication required multiple therapeutic procedures, including topical anti-inflammatory and antiglaucomatous drops, 360 degrees peripheral panretinal cryoblation, and a single 180 degrees application of inferior cyclocryotherapy over a 2 1/2-year period. Four weeks after the cyclocryotherapy, inflammation was noted in both eyes, and, one month later, enucleation of the left sympathogenic eye was performed. Serial histopathologic sections showed a full-thickness, fibrovascular, scleral scar and tantalum marker ring suture without uveal incarceration. Penetrating surgical trauma, a uveal melanoma, and multiple nonpenetrating treatments resulted in the development of sympathetic ophthalmia.

  1. Outcomes of Proton Therapy for the Treatment of Uveal Metastases

    SciTech Connect

    Kamran, Sophia C.; Collier, John M.; Lane, Anne Marie; Kim, Ivana; Niemierko, Andrzej; Chen, Yen-Lin E.; MacDonald, Shannon M.; Munzenrider, John E.; Gragoudas, Evangelos; Shih, Helen A.

    2014-12-01

    Purpose/Objective(s): Radiation therapy can be used to treat uveal metastases with the goal of local control and improvement of quality of life. Proton therapy can be used to treat uveal tumors efficiently and with expectant minimization of normal tissue injury. Here, we report the use of proton beam therapy for the management of uveal metastases. Methods and Materials: A retrospective chart review was made of all patients with uveal metastases treated at our institution with proton therapy between June 2002 and June 2012. Patient and tumor characteristics, fractionation and dose schemes, local control, and toxicities are reported. Results: Ninety patients were identified. Of those, 13 were excluded because of missing information. We report on 77 patients with 99 affected eyes with available data. Patients were 68% female, and the most common primary tumor was breast carcinoma (49%). The median age at diagnosis of uveal metastasis was 57.9 years. Serous retinal detachment was seen in 38% of treated eyes. The median follow-up time was 7.7 months. The median dose delivered to either eye was 20 Gy(relative biological effectiveness [RBE]) in 2 fractions. Local control was 94%. The median survival after diagnosis of uveal metastases was 12.3 months (95% confidence interval, 7.7-16.8). Death in all cases was secondary to systemic disease. Radiation vasculopathy, measured decreased visual acuity, or both was observed in 50% of evaluable treated eyes. The actuarial rate of radiation vasculopathy, measured decreased visual acuity, or both was 46% at 6 months and 73% at 1 year. The 6 eyes with documented local failure were successfully salvaged with retreatment. Conclusions: Proton therapy is an effective and efficient means of treating uveal metastases. Acutely, the majority of patients experience minor adverse effects. For longer-term survivors, the risk of retinal injury with vision loss increases significantly over the first year.

  2. 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%).

  3. 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

  4. Risk Factors and Relationship of Cutaneous and Uveal Melanocytic Lesions in Monozygotic and Dizygotic Twin Pairs

    PubMed Central

    Varga, Anita; Szabó, Hajnalka; Orvos, Hajnalka; Kemény, Lajos; Oláh, Judit

    2016-01-01

    Background The similar genetic background of a pair of twins, and the similar environmental impacts to which they are exposed allow an exact and objective investigation of various constitutional and environmental factors in naevus development. As far as we are aware, this is the first published survey that simultaneously examines cutaneous and ocular pigmented lesions in an appreciable sample of identical and non-identical twins. Methods 172 pairs of twins of Caucasian origin were included in this study. A whole-body skin examination and a detailed ophthalmological examination were performed to determine the density of melanocytic lesions. A standardized questionnaire was used to assess the data relating to constitutional, sun exposure and other variables. Results A notably high proportion of the subjects (36.78%) manifested one or more clinically atypical melanocytic naevi (CAMNs), and approximately one-third (31.4%) of them at least one benign uveal pigmented lesion (BUPL). The incidence of iris freckles (IFs), iris naevi (INs) and choroidal naevi (CHNs) proved to be 25.35%, 5.98% and 3.52%, respectively. The interclass correlation coefficients for common melanocytic naevi (CMNs), CAMNs, and INs were 0.77, 0.76 and 0.86 in monozygotic twins, as compared with 0.5, 0.27 and 0.25 in dizygotic twin pairs, respectively. A statistically significant correlation was found between the prevalence of CAMNs and that of INs. Conclusions This significant correlation suggests the existence of a subgroup of Caucasian people with an increased susceptibility to both cutaneous and ocular naevus formation. There is accumulating evidence that, besides the presence of cutaneous atypical naevi, INs can serve as a marker of a predisposed phenotype at risk of uveal melanoma. The correlation between cutaneous and ocular pigmented lesions underlines the need for the adequate ophthalmological screening of subjects with CAMNs and INs. PMID:27486750

  5. 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

  6. 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

  7. Radio-guided occult lesion localisation using iodine 125 Seeds “ROLLIS” to guide surgical removal of an impalpable posterior chest wall melanoma metastasis

    SciTech Connect

    Dissanayake, Shashini; Dissanayake, Deepthi; Taylor, Donna B

    2015-09-15

    Cancer screening and surveillance programmes and the use of sophisticated imaging tools such as positron emission tomography-computed tomography (PET-CT) have increased the detection of impalpable lesions requiring imaging guidance for excision. A new technique involves intra-lesional insertion of a low-activity iodine-125 ({sup 125}I) seed and detection of the radioactive signal in theatre using a hand-held gamma probe to guide surgery. Whilst several studies describe using this method to guide the removal of impalpable breast lesions, only a handful of publications report its use to guide excision of lesions outside the breast. We describe a case in which radio-guided occult lesion localisation using an iodine 125 seed was used to guide excision of an impalpable posterior chest wall metastasis detected on PET-CT.

  8. 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

  9. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

    SciTech Connect

    Krauthammer, Michael; Kong, Yong; Ha, Byung Hak; Evans, Perry; Bacchiocchi, Antonella; McCusker, James P.; Cheng, Elaine; Davis, Matthew J.; Goh, Gerald; Choi, Murim; Ariyan, Stephan; Narayan, Deepak; Dutton-Regester, Ken; Capatana, Ana; Holman, Edna C.; Bosenberg, Marcus; Sznol, Mario; Kluger, Harriet M.; Brash, Douglas E.; Stern, David F.; Materin, Miguel A.; Lo, Roger S.; Mane, Shrikant; Ma, Shuangge; Kidd, Kenneth K.; Hayward, Nicholas K.; Lifton, Richard P.; Schlessinger, Joseph; Boggon, Titus J.; Halaban, Ruth

    2012-10-11

    We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1{sup P29S}) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1{sup P29S} showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

  10. [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

  11. 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.

  12. Bilateral Diffuse Uveal Melanocytic Proliferation Presenting as a Giant Unilateral Choroidal Nevus: A Case Report

    PubMed Central

    Menezes, Carlos; Carvalho, Rui; Neves-Martins, Joana; Teixeira, Carla

    2015-01-01

    Background/Aims The aim of our study was to report a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) with a markedly asymmetric presentation and fundoscopic response to palliative chemotherapy. Case Report We report a 67-year-old Caucasian man who presented with vision loss in his right eye. The best-corrected visual acuities were 2/10 in the right eye and 10/10 in the left eye, and biomicroscopy revealed bilateral mild cataracts. Fundoscopy of the right eye showed a macular flat and pigmented lesion extending beyond the posterior pole with areas of giraffe-type pigmentation and an overlying exudative retinal detachment. Nothing remarkable was detected in the left eye apart from a small round hypopigmented area of retinal pigment epithelium atrophy in the papillomacular bundle. BDUMP was diagnosed, and the workup for systemic malignancy revealed a pulmonary adenocarcinoma. After chemotherapy, not only did the right eye's visual acuity improve and the serous detachment resolve, but also the pigmentation decreased. Conclusion BDUMP presentation can be markedly asymmetric and resemble a giant unilateral choroidal nevus. Response to chemotherapy was unique not only for the usual retinal detachment resolution, but also because of an evident regression of pigmentation. PMID:27171585

  13. 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.

  14. 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

  15. 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.

  16. Amelanotic uveal cyst in a Yorkshire terrier dog.

    PubMed

    Delgado, Esmeralda; Pissarra, Hugo; Sales-Luís, José; Peleteiro, Maria C

    2010-09-01

    The diagnostic challenge presented by an amelanotic uveal cyst with an atypical appearance in a 9-year-old Yorkshire terrier dog is reported. The dog was presented with a peculiar cystic neoformation adherent to the edge of the pupil of the right eye. The cyst wall was attached to the pupillary margin and it was bean-shaped, measuring approximately 4.5 × 2.5 mm. It was white in colour with several red striations and a small brown spot in the middle, which conferred on it a peculiar appearance. The cyst could not be transilluminated and partially impaired vision. Apart from that, the ophthalmic exam revealed no other abnormalities and the eye showed no signs of inflammation. Ocular ultrasound revealed the cystic nature of the neoformation. During paracentesis of the anterior chamber, the cyst was deflated and both the cyst wall and fluid were aspirated. The tissue obtained was sent for a histological examination and was considered as corresponding to a uveal cyst. The dog improved from the post-operative uveitis without any complication and after 24 months of follow-up showed no recurrences.

  17. CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.

    PubMed

    Betti, M; Aspesi, A; Biasi, A; Casalone, E; Ferrante, D; Ogliara, P; Gironi, L C; Giorgione, R; Farinelli, P; Grosso, F; Libener, R; Rosato, S; Turchetti, D; Maffè, A; Casadio, C; Ascoli, V; Dianzani, C; Colombo, E; Piccolini, E; Pavesi, M; Miccoli, S; Mirabelli, D; Bracco, C; Righi, L; Boldorini, R; Papotti, M; Matullo, G; Magnani, C; Pasini, B; Dianzani, I

    2016-08-10

    BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

  18. 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.

  19. 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 ...

  20. [Pathological and molecular genetic characteristics in patients with extrabulbar growth of uveal melanoma].

    PubMed

    Saakyan, S V; Khoroshilova-Maslova, I P; Tsygankov, A Yu; Amiryan, A G; Isaeva, R T

    2016-01-01

    Цель - анализ ассоциации экстрабульбарного роста (ЭР) опухоли с патоморфологическими и молекулярно-генетическими изменениями у больных с увеальной меланомой (УМ). Материал и методы. Обследованы и пролечены 134 пациента с УМ в возрасте от 22 до 84 лет. Средняя высота опухоли составила 9,2±2,9 мм, диаметр основания - 15,3±3,5 мм. В 97,8% случаев проведена энуклеация пораженного глаза. По гистологическому строению выделяли веретеноклеточные (n=61; 45,6%), смешанно-клеточные (n=46; 34,3%) и эпителиоидно-клеточные (n=27; 20,1%) опухоли. Методом ПЦР-ПДРФ проведено определение полной и частичной моносомии хромосомы 3, делеции короткого плеча хромосомы 1 и метилирования гена RASSF1A (n=134). Пациенты разделены на 2 группы: с наличием (n=12) и отсутствием (n=122) ЭР. Результаты. Определена топографическая связь зоны прорастания опухоли с наибольшим присутствием эмиссариев в склере, по которым происходит прорастание опухоли: передний и задний отрезок глазного яблока. Показаны особенности характера прорастания УМ: более широкое в заднем отрезке и более тонкие прослойки в переднем отрезке. Установлено два типа завершающих процесс прорастания УМ через склеральную фиброзную оболочку глаза: с формированием узла и диссеминацией опухолевых клеток по эписклере. Обнаружено различие в клеточном составе прорастающей опухолевой ткани в эписклере от основного очага в УМ в хориоидее в сторону ее большей атипизации. Показана значимо меньшая частота (20% против 47,9%) относительно благоприятного веретеноклеточного типа УМ в группе с ЭР. Частота полной или частичной моносомии хромосомы 3 в группе с ЭР опухоли значимо выше (80% против 50,4%). Заключение. Определены морфологические особенности ЭР увеальной меланомы. На статистически значимой выборке пациентов с УМ подтверждены благоприятный характер течения опухоли при ее веретеноклеточном типе и отрицательная роль моносомии хромосомы 3, показана взаимосвязь с ЭР опухоли.

  1. Solitary (primary) uveal T-cell lymphoma in a horse.

    PubMed

    Trope, Gareth D; McCowan, Christina I; Tyrrell, Dayle; Lording, Peter M; Maggs, David J

    2014-03-01

    A 22-year-old Australian stockhorse gelding was presented with anterior uveitis in the right eye which was nonresponsive to anti-inflammatory therapy. Clinical examination revealed corneal edema and vascularization, marked hypopyon, and thickening of the dorsal iris, which was confirmed by ultrasonography. Hematologic and biochemical analyses, abdominal and thoracic ultrasonography, and abdominocentesis with cytologic and biochemical analysis revealed no significant abnormalities. Cytological examination of an aqueous humor sample revealed a population of predominantly large lymphoblasts with high nuclear-to-cytoplasmic ratio, round or irregular nuclei, clumped nuclear chromatin, multiple large prominent nucleoli, and a small volume of basophilic cytoplasm. The cytologic diagnosis was intraocular lymphoma. Biopsy of the right submandibular lymph node revealed no evidence of neoplastic invasion. Euthanasia and a complete necropsy were performed and revealed no evidence of neoplasia in any tissue other than the right eye, which had an extensive, well-defined infiltrate of neoplastic lymphocytes expanding the ciliary body and iris, infiltrating the ciliary epithelium, and extending into the pars plana and peripheral choroid. Immunohistochemistry confirmed that neoplastic cells expressed the T-cell marker CD3. To the authors' knowledge, this is the first description of primary, solitary uveal T-cell lymphoma in a horse. Although apparently rare, lymphoma should be considered in horses with uveitis, even when inflammation is unilateral and in the absence of extraocular signs of neoplasia. Aqueocentesis and cytological examination provided an antemortem diagnosis in this case and should be considered as a diagnostic tool for investigation of uveal thickening and hypopyon. PMID:23802547

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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 ...

  13. 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

  14. 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.

  15. Fundus image fusion in EYEPLAN software: An evaluation of a novel technique for ocular melanoma radiation treatment planning

    SciTech Connect

    Daftari, Inder K.; Mishra, Kavita K.; O'Brien, Joan M.; and others

    2010-10-15

    patients developed distant metastasis and all three patients have since died. The replanning of six patients with their original fundus photograph superimposed showed that in four cases, the treatment field adequately covered the tumor volume. In the other two patients, the overlaid fundus photographs indicated the area of marginal miss. The replanning with the fundus photograph showed improved tumor coverage in these two macular lesions. For the remaining patients without local failure, replanning with fundus photograph superimposition confirmed the tumor volume as drawn in the original treatment plan. Conclusions: Local control was excellent in patients receiving 56 GyE of PBRT for uveal melanomas in the macular region, which traditionally can be more difficult to control. Posterior lesions are better defined with the additional use of fundus image since they can be difficult to mark surgically. In one-third of treatment failing patients, the superposition of the fundus photograph would have clearly allowed improved localization of tumor. The current practice standard is to use the superimposition of the fundus photograph in addition to the surgeon's clinical and clip mapping of the tumor and ultrasound measurement to draw the tumor volume.

  16. 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

  17. 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.

  18. Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.

    PubMed

    Wadt, Karin A W; Aoude, Lauren G; Krogh, Lotte; Sunde, Lone; Bojesen, Anders; Grønskov, Karen; Wartacz, Nine; Ek, Jakob; Tolstrup-Andersen, Morten; Klarskov-Andersen, Mette; Borg, Åke; Heegaard, Steffen; Kiilgaard, Jens F; Hansen, Thomas V O; Klein, Kerenaftali; Jönsson, Göran; Drzewiecki, Krzysztof T; Dunø, Morten; Hayward, Nicholas K; Gerdes, Anne-Marie

    2015-01-01

    Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

  19. Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.

    PubMed

    Wadt, Karin A W; Aoude, Lauren G; Krogh, Lotte; Sunde, Lone; Bojesen, Anders; Grønskov, Karen; Wartacz, Nine; Ek, Jakob; Tolstrup-Andersen, Morten; Klarskov-Andersen, Mette; Borg, Åke; Heegaard, Steffen; Kiilgaard, Jens F; Hansen, Thomas V O; Klein, Kerenaftali; Jönsson, Göran; Drzewiecki, Krzysztof T; Dunø, Morten; Hayward, Nicholas K; Gerdes, Anne-Marie

    2015-01-01

    Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma. PMID:25803691

  20. 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

  1. Concurrent versus sequential application of ferromagnetic hyperthermia and 125I brachytherapy of melanoma in an animal model.

    PubMed Central

    Mieler, W F

    1997-01-01

    OBJECTIVE: To determine the efficacy of concurrent versus sequential ferromagnetic hyperthermia (FMH), combined with Iodine-125 (125I) brachytherapy, in the treatment of uveal melanoma in a rabbit model. MATERIALS AND METHODS: A Greene melanoma cell line was implanted in rabbit eyes to establish a tumor model comparable to a uveal melanoma. Seventy-one tumor-containing rabbit eyes were treated with 125I brachytherapy at 20, 25, 35, 45, or 55 Gray (Gy)(38 eyes), and with either concurrent (15 eyes) or sequential (18 eyes) FMH, delivered at 48.2 degrees C for 1 hour. An additional 13 eyes were treated with FMH alone at 48.2 degrees C, either in a single heat application (5 eyes), or in a repetitive mode (8 eyes). The radiation and heat were delivered via an episcleral plaque. All tumors were followed with indirect ophthalmoscopy and echography. RESULTS: Tumors treated with 125I brachytherapy alone exhibited complete tumor regression in 50% of eyes at 42 Gy with none of the tumors responding to less than 35 Gy. FMH alone at 48.2 degrees C applied in one cycle limited tumor growth in 20% of eyes, while all eyes treated with repetitive heating exhibited complete tumor control. With concurrent application of FMH and 125I, the 50% tumor control rate occurred at 9.5 Gy, thus resulting in a thermal enhancement ratio (TER) of 4.4. With sequential treatment, the 50% tumor control rate was at 30 Gy, with a resultant TER of 1.4. No complications related to 125I brachytherapy were noted in any eyes, while transient retinal whitening was seen with the FMH. CONCLUSION: This study documents the enhanced synergistic interaction of concurrent FMH and 125I brachytherapy, compared to sequential treatment, in this rabbit melanoma model. PMID:9440189

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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

  7. Ciliary body and choroidal melanomas treated by proton beam irradiation. Histopathologic study of eyes

    SciTech Connect

    Seddon, J.M.; Gragoudas, E.S.; Albert, D.M.

    1983-09-01

    Proton beam irradiation resulted in clinical and/or histopathological regression of large ciliary body and choroidal melanomas in three eyes. Enucleations were performed 6 1/2 weeks, five months, and 11 months after irradiation for angle-closure glaucoma from total retinal detachment, increase in retinal detachment, and neovascular glaucoma, respectively. A direct relationship was found between the length of the interval from irradiation to enucleation and the degree of histologic changes. Vascular changes in the tumors included endothelial cell swelling and decreased lumen size, basement membrane thickening, collapse of sinusoidal vessels, and thrombosis of vessels. Although apparently unaltered tumor cells remained, degenerative changes occurred in some melanoma cells, including lipid vacuoles in cytoplasm, pyknotic nuclei, and balloon cell formation. Patchy areas of necrosis and proteinaceous exudate were present. Pigment-laden macrophages were found near tumor vessels and all had a substantial chronic inflammatory infiltrate. The effect of proton beam irradiation on tumor vessels probably plays an important role in uveal melanoma regression.

  8. Gnaq and Gna11 in the Endothelin Signaling Pathway and Melanoma

    PubMed Central

    Urtatiz, Oscar; Van Raamsdonk, Catherine D.

    2016-01-01

    In this article, we first briefly outline the function of G protein coupled receptors in cancer, and then specifically examine the roles of the seven transmembrane G protein coupled Endothelin B receptor (Ednrb) and the G proteins, GNAQ and GNA11, in both melanocyte development and melanoma. Ednrb plays an essential role in melanocyte development. GNAQ and GNA11 are oncogenes when mutated in certain types of melanocytic lesions, being extremely frequent in uveal melanoma, which forms from melanocytes located in the eye. Previously, we reported that in mice, Schwann cell precursor derived melanocytes colonize the dermis and hair follicles, while the inter-follicular epidermis is populated by other melanocytes. A pattern has emerged whereby melanocytes whose activities are affected by gain-of-function mutations of the Endothelin 3 ligand and Gαq/11 are the same subset that arise from Schwann cell precursors. Furthermore, the forced expression of the constitutively active human GNAQQ209L oncogene in mouse melanocytes only causes hyper-proliferation in the subset that arise from Schwann cell precursors. This has led us to hypothesize that in Schwann cell precursor derived melanocytes, Ednrb signals through Gαq/11. Ednrb is promiscuous and may signal through other G protein alpha subunits in melanomas located in the inter-follicular epidermis. PMID:27148356

  9. 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

  10. [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.

  11. [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.

  12. 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

  13. 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 ...

  14. 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

  15. 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.

  16. 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

  17. Role for rapid surgical intervention in uveal effusion syndrome with associated optic neuropathy.

    PubMed

    Bhullar, Shaminder S; Gray, Matthew J; Kay, Christine N

    2014-01-01

    Uveal effusion syndrome (UES) can be associated with nanophthalmos and rarely can present with concomitant optic neuropathy. This case report describes nanophthalmic UES and optic neuropathy treated with early sclerectomies. One month postoperatively, the patient experienced significant improvement in choroidal effusions and optic neuropathy, with increases in visual acuity and visual fields. Early scleral windows surgery for UES with associated optic neuropathy can provide prompt improvement of choroidal swelling, optic nerve edema, and vision, although the relapsing course of this disease presents a challenge to long-term visual prognosis. PMID:24695046

  18. 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

  19. 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

  20. 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

  1. Posterior malleolus fracture.

    PubMed

    Irwin, Todd A; Lien, John; Kadakia, Anish R

    2013-01-01

    Posterior malleolus fractures are a common component of ankle fractures. The morphology is variable; these fractures range from small posterolateral avulsion injuries to large displaced fracture fragments. The integrity of the posterior malleolus and its ligamentous attachment is important for tibiotalar load transfer, posterior talar stability, and rotatory ankle stability. Fixation of posterior malleolus fractures in the setting of rotational ankle injuries has certain benefits, such as restoring articular congruity and rotatory ankle stability, as well as preventing posterior talar translation, but current indications are unclear. Fragment size as a percentage of the anteroposterior dimension of the articular surface is often cited as an indication for fixation, although several factors may contribute to the decision, such as articular impaction, comminution, and syndesmotic stability. Outcome studies show that, in patients with ankle fractures, the presence of a posterior malleolus fracture negatively affects prognosis. Notable variability is evident in surgeon practice. PMID:23281469

  2. What Is Melanoma Skin Cancer?

    MedlinePlus

    ... that can become melanoma. They make a brown pigment called melanin , which gives the skin its tan ... to the sun, melanocytes make more of the pigment, causing the skin to tan or darken. Melanoma ...

  3. 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

  4. Lymphoscintigraphy in malignant melanoma

    SciTech Connect

    Berman, C.G.; Norman, J.; Cruse, C.W.; Reintgen, D.S.; Clark, R.A. )

    1992-01-01

    The development and rationale for the use of lymphoscintigraphy in the preoperative evaluation of patients with malignant melanoma being considered for elective lymph node dissection is reviewed. This overview is updated by an analysis of 135 patients with early stage malignant melanoma involving the head, neck, shoulders, and trunk at Moffitt Cancer Center and Research Institute at the University of South Florida (Tampa, FL). High discordancy rates (overall, 41%) were seen between drainage patterns predicted from historical anatomical guidelines and those revealed by the lymphoscintigraphic examination. The high discordancy rate was most pronounced in the head (64%) and the neck (73%). Surgical management was changed in 33% of the patients, overall. A preoperative lymphoscintigram is recommended for all patients with melanoma with head, neck, and truncal lesions evaluated for elective lymph node dissection as the lymphatic drainage patterns are often unpredictable and variable.

  5. Vitamins and Melanoma

    PubMed Central

    Russo, Irene; Caroppo, Francesca; Alaibac, Mauro

    2015-01-01

    A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus on the role played by vitamins in melanoma with particular regard to vitamin A, D, K, E and C. Given that vitamin supplementation is easy, convenient, and readily accepted by patients, in the future the use of vitamins in chemoprevention and therapy of melanoma could be encouraged if supported by pre-clinical and clinical evidence. PMID:26213971

  6. 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.

  7. The impact of body area in melanoma self-detection: a retrospective study.

    PubMed

    De Giorgi, Vincenzo; Grazzini, Marta; Savarese, Imma; Gori, Alessia; Papi, Federica; D'Errico, Antonietta; Scarfì, Federica; Gandini, Sara

    2015-07-01

    To assess the patient's capability of performing a correct skin-check examination we investigated the association of melanoma detection pattern with Breslow thickness, by melanoma body area. In this prospective observational study, patients with primary cutaneous melanoma who presented at the Department of Dermatology at the University of Florence between January 2000 and November 2011 were interviewed as part of their clinical data recording procedure at the time of their final histopathological diagnoses of melanoma. With the aim of evaluating a self skin-check, we included patients with melanoma in the anterior part of the trunk (abdomen and chest area), which is generally considered visible in the mirror, and the posterior part of the trunk, which is a more complex area to be self-checked. The treating physician specifically questioned all patients about who had first detected or suspected the lesion that resulted in the histological diagnosis of melanoma in order to compare those who had self-detected (SD) their melanoma with those who had discovered their melanoma during a regular skin-check (RSC) with a dermatologist. A total of 186 melanoma patients were analyzed, with 67% (n=125) of melanomas located on the back and 33% (n=61) in the chest and abdominal area; the majority (55%, n=103) were in the SD group. The median Breslow thickness of the SD group was significantly greater than that of the RSC group: 0.60 versus 0.50 mm (P<0.0001). In the posterior trunk, the frequency of thick melanomas (Breslow≥1.00 mm) was significantly greater in the SD group than in the RSC group (34 vs. 11%; P=0.003), whereas there was no difference in the frequency of thick melanoma by detection patterns in the anterior trunk. Given the influence of the body area in detecting threatening melanoma, we should encourage people to obtain dermatological skin-checks more often. Skin self-examinations cannot be sufficiently accurate. PMID:25325306

  8. Posterior Tibial Tendon Dysfunction

    MedlinePlus

    ... when the posterior tibial tendon becomes inflamed or torn. As a result, the tendon may not be ... repetitive use. Once the tendon becomes inflamed or torn, the arch will slowly fall (collapse) over time. ...

  9. Raman spectroscopy detects melanoma and the tissue surrounding melanoma using tissue-engineered melanoma models

    PubMed Central

    Yorucu, Ceyla; Lau, Katherine; Mittar, Shweta; Green, Nicola H.; Raza, Ahtasham; Rehman, Ihtesham Ur; MacNeil, Sheila

    2016-01-01

    ABSTRACT Invasion of melanoma cells from the primary tumor involves interaction with adjacent tissues and extracellular matrix. The extent of this interaction is not fully understood. In this study Raman spectroscopy was applied to cryo-sections of established 3D models of melanoma in human skin. Principal component analysis was used to investigate differences between the tumor and normal tissue and between the peri-tumor area and the normal skin. Two human melanoma cells lines A375SM and C8161 were investigated and compared in 3D melanoma models. Changes were found in protein conformations and tryptophan configurations across the entire melanoma samples, in tyrosine orientation and in more fluid lipid packing only in tumor dense areas, and in increased glycogen content in the peri-tumor areas of melanoma. Raman spectroscopy revealed changes around the perimeter of a melanoma tumor as well as detecting differences between the tumor and the normal tissue. PMID:27158185

  10. Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile.

    PubMed

    Larsen, Ann-Cathrine

    2016-05-01

    Conjunctival malignant melanoma is a rare disease associated with considerable mortality. Most published data have been based on case reports or series of referred patients. In addition, very little is known about the genetic and epigenetic profile of conjunctival melanoma and the resemblance to uveal, cutaneous and mucosal melanoma. The aim was to determine the incidence rate of conjunctival melanoma, and to relate clinicopathological features and treatment to prognosis. A further aim was to determine the prevalence of BRAF mutations in conjunctival melanoma, to determine whether BRAF mutations are early events in pathogenesis, and relate clinicopathological features and prognosis to BRAF-mutation status. Finally, we wanted to identify tumour-specific and prognostic microRNAs in conjunctival melanoma, and to compare these with the microRNA expression of other melanoma subtypes. In order to investigate these rare tumours, we studied all the conjunctival melanomas that had been surgically removed in Denmark over a period of 52 years (1960-2012). Tissue samples, clinical files, pathology reports and follow-up data were collected and re-evaluated. Using droplet digital polymerase chain reaction and immunohistochemistry, we investigated BRAF mutations; and using microRNA expression profiling, we investigated differentially expressed microRNAs. The overall incidence of conjunctival melanoma was 0.5/1 000 000/year, and it increased in Denmark over 52 years. The increase was mainly caused by an increase in older patients (>65 years) and bulbar lesions. Clinicopathological features significantly associated with a poor prognosis were extrabulbar location, involvement of adjacent tissue structures, tumour thickness exceeding 2 mm and local tumour recurrence. Patients undergoing incisional biopsy and/or treatment involving excision without adjuvant therapy fared worse than patients treated with excision and any type of adjuvant treatment. We found that 35% (39/110) of

  11. Melanoma of the Skin

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 76,380 % of All New Cancer Cases 4.5% Estimated Deaths in 2016 10,130 % of All Cancer ... of This Cancer : In 2013, there were an estimated 1,034,460 people living with melanoma of ...

  12. Spice Blocks Melanoma Growth

    ERIC Educational Resources Information Center

    Science Teacher, 2005

    2005-01-01

    Curcumin, the pungent yellow spice found in both turmeric and curry powders, blocks a key biological pathway needed for development of melanoma and other cancers, according to a study that appears in the journal Cancer. Researchers from The University of Texas M. D. Anderson Cancer Center demonstrate how curcumin stops laboratory strains of…

  13. Melanoma Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing melanoma cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  14. 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.

  15. Indirect posterior composite resins.

    PubMed

    Leinfelder, Karl F

    2005-07-01

    The use of indirect posterior composite restorations has facilitated the generation of ideal anatomic form, marginal adaptation, and appropriate proximal contact and contour. Unfortunately, however, the use of post-cure heat treatments has done little to enhance the overall clinical performance of the restoration. The development of new curing techniques in conjunction with modifications of the formulae have contributed to a substantial improvement in both the mechanical characteristics and long-term clinical performance of indirect posterior composite resins.

  16. Presymptomatic diagnosis of bronchogenic carcinoma associated with bilateral diffuse uveal melanocytic proliferation.

    PubMed

    Sen, Julia; Clewes, Adrian R; Quah, Say-Aun; Hiscott, Paul S; Bucknall, Roger C; Damato, Bertil E

    2006-03-01

    A 62-year-old man presented with bilateral diffuse uveal melanocytic proliferations (BDUMP) and painful flexor contractures of the fingers of both hands. All these features were considered paraneoplastic but extensive and repeated investigations revealed no underlying malignancy. Oral steroids and orbital radiotherapy were ineffective. The diagnosis was confirmed by trans-scleral biopsy of the right choroid. Rapidly progressive cataracts were treated by phacoemulsification. Severe exudative retinal detachment with rubeosis and neovascular glaucoma in the left eye were treated successfully by partial choroidectomy. Fifteen months after presentation, investigations detected a 22 mm, poorly differentiated adenocarcinoma, which was resected without complication. The ocular tumours in both eyes regressed, without improvement in vision of Light Perception, and the palmar fasciitis also improved. The patient remained free of tumour recurrence until sudden death from myocardial infarction five years after he first presented.

  17. 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)

  18. Oncogenes in melanoma: an update.

    PubMed

    Kunz, Manfred

    2014-01-01

    Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage. BRAF, NRAS, and KIT are three well-known oncogenes involved in melanoma pathogenesis. Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology. However, recurrences regularly occur within several months, which supposedly involve further oncogenes. Moreover, oncogenic driver mutations have not been described for up to 30% of all melanomas. In order to obtain a more complete picture of the mutational landscape of melanoma, more recent studies used high-throughput DNA sequencing technologies. A number of new oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, GRM3, RAC1, and PREX2 were identified. Their particular role in melanoma biology is currently under investigation. Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments. However, these findings await further validation in clinical studies. This review provides an overview on well-known melanoma oncogenes and new oncogene candidates, based on recent high-throughput sequencing studies. The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area. The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future. PMID:24468268

  19. 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.

  20. AZD2171 in Treating Patients With Recurrent or Stage IV Melanoma

    ClinicalTrials.gov

    2015-06-01

    Acral Lentiginous Malignant Melanoma; Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Intraocular Melanoma; Iris Melanoma; Lentigo Maligna Malignant Melanoma; Recurrent Melanoma; Stage, Intraocular Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma

  1. The tibialis posterior tendon.

    PubMed

    Lhoste-Trouilloud, A

    2012-02-01

    The tibialis posterior tendon is the largest and anteriormost tendon in the medial ankle. It produces plantar flexion and supination of the ankle and stabilizes the plantar vault. Sonographic assessment of this tendon is done with high-frequency, linear-array transducers; an optimal examination requires transverse retromalleolar, longitudinal retromalleolar, and distal longitudinal scans, as well as dynamic studies. Disorders of the posterior tibial tendon include chronic tendinopathy with progressive rupture, tenosynovitis, acute rupture, dislocation and instability, enthesopathies. The most common lesion is a progressive "chewing gum" lesion that develops in a setting of chronic tendinopathy; it is usually seen in overweight women over 50 years of age with valgus flat feet. Medial ankle pain must also be carefully investigated, and the presence of instability assessed with dynamic maneuvers (forced inversion, or dorsiflexion) of the foot. Sonography plays an important role in the investigation of disorders involving the posterior tibial tendon.

  2. Primary pineal malignant melanoma

    PubMed Central

    Cedeño Diaz, Oderay Mabel; Leal, Roberto García; La Cruz Pelea, Cesar

    2011-01-01

    Primary pineal malignant melanoma is a rare entity, with only thirteen cases reported in the world literature to date. We report a case of a 70-year-old man, who consulted with gait disturbance of six months duration, associated in the last month with dizziness, visual abnormalities and diplopia. No other additional melanocytic lesions were found elsewhere. The magnetic resonance showed a 25 mm expansive mass in the pineal gland that was associated with hydrocephaly, ventricular and transependimary oedema. The lesion was partially excised by a supracerebellar infratentorial approach. The histological examination revealed a melanoma. The patient received radiation therapy, but died of disease 16 weeks later. We herein review the literature on this rare tumour and comment on its clinical, radiological and histopathological features and differential diagnosis. PMID:24765293

  3. Tibialis Posterior Tendon Entrapment Within Posterior Malleolar Fracture Fragment.

    PubMed

    Fantry, Amanda; Lareau, Craig; Vopat, Bryan; Blankenhorn, Brad

    2016-01-01

    Management of posterior malleolus fractures continues to be controversial, with respect to both need for fixation and fixation methods. Fixation methods include an open posterior approach to the ankle as well as percutaneous reduction and fixation with or without arthroscopy for visualization of the articular surface. Plain radiographs are unreliable in identifying fracture pattern and intraoperative reduction, making arthroscopy a valuable adjunct to posterior malleolus fracture management. In this article, we report a case of tibialis posterior tendon entrapment within a posterior malleolus fracture, as identified by arthroscopy and managed with open reduction. Tibialis posterior tendon entrapment within a posterior malleolus has not been previously reported. Ankle arthroscopy for posterior malleolus fractures provides an opportunity to identify soft-tissue or tendinous entrapment, articular surface reduction, and articular cartilage injuries unlikely to be identified with fluoroscopy alone and should be considered in reduction and fixation of posterior malleolus fractures.

  4. Tibialis Posterior Tendon Entrapment Within Posterior Malleolar Fracture Fragment.

    PubMed

    Fantry, Amanda; Lareau, Craig; Vopat, Bryan; Blankenhorn, Brad

    2016-01-01

    Management of posterior malleolus fractures continues to be controversial, with respect to both need for fixation and fixation methods. Fixation methods include an open posterior approach to the ankle as well as percutaneous reduction and fixation with or without arthroscopy for visualization of the articular surface. Plain radiographs are unreliable in identifying fracture pattern and intraoperative reduction, making arthroscopy a valuable adjunct to posterior malleolus fracture management. In this article, we report a case of tibialis posterior tendon entrapment within a posterior malleolus fracture, as identified by arthroscopy and managed with open reduction. Tibialis posterior tendon entrapment within a posterior malleolus has not been previously reported. Ankle arthroscopy for posterior malleolus fractures provides an opportunity to identify soft-tissue or tendinous entrapment, articular surface reduction, and articular cartilage injuries unlikely to be identified with fluoroscopy alone and should be considered in reduction and fixation of posterior malleolus fractures. PMID:26991573

  5. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma.

    PubMed

    Läubli, Heinz; Balmelli, Cathrin; Bossard, Matthias; Pfister, Otmar; Glatz, Kathrin; Zippelius, Alfred

    2015-01-01

    Antibodies that stimulate the immune system by targeting inhibitory T cell receptors were successfully introduced into oncological practice and are capable to overcome tumor-induced immune evasion. In particular, targeting of the inhibitory receptors CTLA-4 and PD-1 or its ligand PD-L1 have been shown to be beneficial for patients with melanoma, renal cell cancer, non-small cell lung cancer and a growing list of other cancers with impressive response rates. Here, we report a severe, potentially life-threatening side effect of anti-PD-1 immunotherapy with pembrolizumab, which has not been previously described in the literature. A 73-year-old woman with metastatic uveal melanoma treated with pembrolizumab in third line developed severe heart failure due to pembrolizumab-mediated autoimmune myocarditis. Echocardiographic studies revealed a severely impaired left ventricular function with dyssynchrony. All tests for cardiotropic viruses were negative and histological analysis of a myocardial biopsy showed lymphocytic infiltration with a predominance of CD8 positive cells and a reduction of FOXP3 positive regulatory T cells. After initiation of corticosteroids and guideline-conform heart failure therapy, the symptoms rapidly improved and the left ventricular function recovered. While autoimmune myocarditis is a documented side effect of other checkpoint inhibitors, as for example ipilimumab and in one case with anti-PD-L1 antibody, it is not described for anti-PD-1-antibodies like pembrolizumab or nivolumab. As the FDA recently approved both pembrolizumab and nivolumab for melanoma progressing after anti-CTLA-4 treatment with ipilimumab, more patients will soon receive anti-PD-1 therapy. Thus, it is important to be aware of such rare, but severe immune-related adverse events.

  6. 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

  7. The gene expression signatures of melanoma progression

    PubMed Central

    Haqq, Christopher; Nosrati, Mehdi; Sudilovsky, Daniel; Crothers, Julia; Khodabakhsh, Daniel; Pulliam, Brian L.; Federman, Scot; Miller, James R.; Allen, Robert E.; Singer, Mark I.; Leong, Stanley P. L.; Ljung, Britt-Marie; Sagebiel, Richard W.; Kashani-Sabet, Mohammed

    2005-01-01

    Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma. PMID:15833814

  8. Tumor vascularity and hematogenous metastasis in experimental murine intraocular melanoma.

    PubMed Central

    Grossniklaus, H E

    1998-01-01

    PURPOSE: The purpose of this study is to test the hypothesis that primary tumor vascularity in a murine model of intraocular melanoma positively correlates with the development and hematogenous spread of metastasis. METHODS: Forty 12-week-old C57BL6 mice were inoculated in either the anterior chamber (AC) or posterior compartment (PC) of 1 eye with 5 x 10(5) cells/microL of Queens tissue culture melanoma cells. The inoculated eye was enucleated at 2 weeks; the mice were sacrificed at 4 weeks postinoculation, and necropsies were performed. The enucleated eyes were examined for histologic and ultrastructural features, including relationship of tumor cells to tumor vascular channels, vascular pattern, and mean vascular density. RESULTS: Melanoma grew and was confined to the eye in 12 of 20 AC eyes and 10 of 20 PC eyes. Histologic and electron microscopic examination showed tumor invasion into vascular channels. Five of 12 AC tumors (42%) and 8 of 10 PC tumors (80%) metastasized. All of the AC tumors, but none of the PC tumors, that distantly metastasized also metastasized to ipsilateral cervical lymph nodes (P = .00535). There was no statistically significant difference of vascular pattern between the melanomas that did and did not metastasize to lungs in the PC group (P = .24), although there was a significant difference in the AC group (P = .02). Tumors with high-grade vascular patterns were more likely to metastasize than tumors with low-grade vascular patterns in the AC group. The mean vascular density positively correlated with the presence and number of metastases in both groups (P = .0000 and P < .001, respectively). There was no statistically significant difference of vascular pattern and mean vascular density for AC versus PC melanoma (P = .97). CONCLUSIONS: The rate of metastasis in this murine intraocular melanoma model positively correlates with primary tumor vascularity. The melanoma metastasizes via invasion of tumor vascular channels. AC melanoma also

  9. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

    SciTech Connect

    Ungerer, Christopher; Doberstein, Kai; Boehm, Beate; Pfeilschifter, Josef; Mihic-Probst, Daniela; Gutwein, Paul

    2010-10-22

    Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.

  10. 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

  11. Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQQ209L-driven melanoma

    PubMed Central

    Patel, B R; Tall, G G

    2016-01-01

    The heterotrimeric G protein α subunit oncogenes GNAQ or GNA11 carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas. Forced expression of GNAQ/11Q209L in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice. No known drugs directly target these oncogenic G proteins. Ric-8A is the molecular chaperone that selectively folds Gαq/i/13 subunits. Targeting Ric-8A serves as a rational, yet unexplored approach to reduce the functional abundance of oncogenic Gαq/11 in order to blunt cancer signaling. Here, using mouse melanocyte cell graft tumorigenesis models, we determined that Ric-8A genetic ablation attenuated the abundance and melanoma-driving potential of Gαq-Q209L. A new conditional Ric-8AFlox/Flox; Rosa-CreER+/− mouse strain was derived and used as a tissue source to culture an immortalized, tamoxifen-inducible Ric-8A knockout melanocyte cell line that required 12-O-tetradecanoylphorbol-13-acetate (TPA, phorbol ester) for growth. The cell line failed to grow tumors when grafted into immune-compromised mice regardless of Ric-8A expression. Stable expression of human GNAQQ209L, but not GNAQWT in the cell line promoted TPA-independent cell proliferation, and upon cell grafting in mice, the initiation and robust growth of darkly-pigmented melanoma tumors. Deletion of Ric-8A in GNAQQ209L cells restored TPA-dependent growth, reduced Gαq-Q209L below detectable levels and completely mitigated tumorigenesis from primary or secondary cell line grafts. Interestingly, TPA treatment of cultured GNAQQ209L cells or host animals grafted with GNAQQ209L cells also sharply reduced Gαq-Q209L abundance and tumorigenic capacity. Finally, tumorigenesis initiated from GNAQQ209L cell grafts, followed by host mouse systemic tamoxifen treatment to delete Ric-8A in the grafted cells completely abrogated GNAQQ209L-driven tumor progression unless a stable human RIC-8A transgene was used to rescue the floxed

  12. Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQ(Q209L)-driven melanoma.

    PubMed

    Patel, B R; Tall, G G

    2016-01-01

    The heterotrimeric G protein α subunit oncogenes GNAQ or GNA11 carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas. Forced expression of GNAQ/11(Q209L) in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice. No known drugs directly target these oncogenic G proteins. Ric-8A is the molecular chaperone that selectively folds Gαq/i/13 subunits. Targeting Ric-8A serves as a rational, yet unexplored approach to reduce the functional abundance of oncogenic Gαq/11 in order to blunt cancer signaling. Here, using mouse melanocyte cell graft tumorigenesis models, we determined that Ric-8A genetic ablation attenuated the abundance and melanoma-driving potential of Gαq-Q209L. A new conditional Ric-8A(Flox/Flox); Rosa-CreER(+/)(-) mouse strain was derived and used as a tissue source to culture an immortalized, tamoxifen-inducible Ric-8A knockout melanocyte cell line that required 12-O-tetradecanoylphorbol-13-acetate (TPA, phorbol ester) for growth. The cell line failed to grow tumors when grafted into immune-compromised mice regardless of Ric-8A expression. Stable expression of human GNAQ(Q209L), but not GNAQ(WT) in the cell line promoted TPA-independent cell proliferation, and upon cell grafting in mice, the initiation and robust growth of darkly-pigmented melanoma tumors. Deletion of Ric-8A in GNAQ(Q209L) cells restored TPA-dependent growth, reduced Gαq-Q209L below detectable levels and completely mitigated tumorigenesis from primary or secondary cell line grafts. Interestingly, TPA treatment of cultured GNAQ(Q209L) cells or host animals grafted with GNAQ(Q209L) cells also sharply reduced Gαq-Q209L abundance and tumorigenic capacity. Finally, tumorigenesis initiated from GNAQ(Q209L) cell grafts, followed by host mouse systemic tamoxifen treatment to delete Ric-8A in the grafted cells completely abrogated GNAQ(Q209L)-driven tumor progression unless a stable human RIC-8A transgene was used to

  13. Posterior microphthalmos pigmentary retinopathy syndrome.

    PubMed

    Pehere, Niranjan; Jalali, Subhadra; Deshmukh, Himanshu; Kannabiran, Chitra

    2011-04-01

    Posterior Microphthalmos Pigmentary Retinopathy Syndrome (PMPRS). Posterior microphthalmos (PM) is a relatively infrequent type of microphthalmos where posterior segment is predominantly affected with normal anterior segment measurements. Herein, we report two siblings with posterior microphthalmos retinopathy syndrome with postulated autosomal recessive mode of inheritance. A 13-year-old child had PM and retinitis pigmentosa (RP) and his 7-year-old sister had PM, RP, and foveoschisis. The genetics of this syndrome and variable phenotype is discussed. Importance of being aware of posterior microphthalmos and its posterior segment associations is highlighted.

  14. Melanoma and naevi: Incidence, interrelationships and implications

    SciTech Connect

    Elwood, J.M.

    1988-01-01

    This book contains 11 chapters. Some of the chapter titles are: Trend with Time of the Incidence of Malignant Melanoma of Skin in White Populations; Classical and Molecular Genetics of Malignant Melanoma and Dysplastic Naevi; Individuals at High Risk of Melanoma (with 1 color plate); Control of Melanoma in High-Risk Populations; and Frequency of Benign Pigmented Naevi in the General Population.

  15. 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

  16. Proteomic Findings in Melanoma

    PubMed Central

    Sengupta, Deepanwita; Tackett, Alan J

    2016-01-01

    Although the emergence of proteomics as an independent branch of science is fairly recent, within a short period of time it has contributed substantially in various disciplines. The tool of mass spectrometry has become indispensable in the analysis of complex biological samples. Clinical applications of proteomics include detection of predictive and diagnostic markers, understanding mechanism of action of drugs as well as resistance mechanisms against them and assessment of therapeutic efficacy and toxicity of drugs in patients. Here, we have summarized the major contributions of proteomics towards the study of melanoma, which is a deadly variety of skin cancer with a high mortality rate. PMID:27274624

  17. Recurrent inactivating RASA2 mutations in melanoma

    PubMed Central

    Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel; Wilmott, James S.; Gartner, Jared J.; Di Pizio, Antonella; Winograd-Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton-Regester, Ken; Johansson, Peter; Pritchard, Antonia; Waddell, Nicola; Hill, Victoria K.; Lin, Jimmy C.; Hevroni, Yael; Rosenberg, Steven A.; Khan, Javed; Ben-Dor, Shifra; Niv, Masha Y.; Ulitsky, Igor; Mann, Graham J; Scolyer, Richard A.; Hayward, Nicholas K.; Samuels, Yardena

    2016-01-01

    Analysis of 501 melanoma exomes revealed RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings reveal RASA2 inactivation as a melanoma driver and highlight the importance of Ras GAPs in cancer. PMID:26502337

  18. A Case of Uveal Colobomas Showing Marked Left-Right Difference in Diabetic Retinopathy

    PubMed Central

    Moriya, Takeshi; Ochi, Ryosuke; Imagawa, Yukihiro; Sato, Bumpei; Morishita, Seita; Tonari, Masahiro; Fukumoto, Masanori; Suzuki, Hiroyuki; Kobayashi, Takatoshi; Kida, Teruyo; Ikeda, Tsunehiko

    2016-01-01

    Purpose Congenital uveal colobomas, including inferior iris and choroidal colobomas, are associated with microcornea and microphthalmia and often show left-right differences (laterality). The purpose of this study was to report a case of choroidal coloboma associated with left-right differences in diabetic retinopathy (DR). Case This study reports a 59-year-old male with bilateral iris and choroidal colobomas. The colobomatous area in the patient's right eye extended to the macula, and his right eye had been amblyopic since birth. The colobomatous area in his left eye was less extensive and did not involve the macula. Examination of the patient's left eye revealed multiple hemorrhages and hard exudates in the macula due to DR, but examination of his right eye showed almost no changes in DR, thus revealing a marked left-right difference. Optical coherence tomography showed more extensive retinal thinning in the patient's right eye than in his left eye. Fluorescein fundus angiography revealed a retinal nonperfusion area only in the left eye, and panretinal photocoagulation was subsequently performed. Conclusion Our findings show that the reason for the left-right difference in DR was attributed to the more severe choroidal coloboma and retinal thinning in the patient's right eye compared to his left eye, thus reducing oxygen demand, as is also seen in eyes with severe myopia. PMID:27099608

  19. 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

  20. 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

  1. Adjuvant therapy of melanoma.

    PubMed

    Agarwala, S S; Kirkwood, J M

    1998-06-01

    Patients with AJCC Stage IIB and III melanoma have a poor 5-year survival rate which has been the driving force behind attempts to find an effective adjuvant therapy for this stage of disease that would effectively reduce relapse and improve survival. Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum, and levamisole have not been successful in achieving this goal, nor have trials with chemotherapy in the adjuvant setting, including high-dose chemotherapy with autologous bone marrow transplantation. The recent Eastern Cooperative Oncology Group (ECOG) 1684 study showed significant improvement in relapse-free and overall survival with high doses of alpha interferon (IFNalpha) given for 1 year. Lower dosages of IFNalpha have to date been unsuccessful in impacting upon long-term survival. Recent data with vaccines have been encouraging, and the GM2-KLH vaccine is the focus of ongoing intergroup study comparing this treatment with IFNalpha in resected Stage IIB and III melanoma. The various regimens are reviewed in this article. PMID:9588723

  2. Targeted Radionuclide Therapy of Melanoma.

    PubMed

    Norain, Abdullah; Dadachova, Ekaterina

    2016-05-01

    An estimated 60,000 individuals in the United States and 132,000 worldwide are yearly diagnosed with melanoma. Until recently, treatment options for patients with stages III-IV metastatic disease were limited and offered marginal, if any, improvement in overall survival. The situation changed with the introduction of B-RAF inhibitors and anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1 immunotherapies into the clinical practice. With only some patients responding well to the immune therapies and with very serious side effects and high costs of immunotherapy, there is still room for other approaches for the treatment of metastatic melanoma. Targeted radionuclide therapy of melanoma could be divided into the domains of radioimmunotherapy (RIT), radiolabeled peptides, and radiolabeled small molecules. RIT of melanoma is currently experiencing a renaissance with the clinical trials of alpha-emitter (213)Bi-labeled and beta-emitter (188)Rhenium-labeled monoclonal antibodies in patients with metastatic melanoma producing encouraging results. The investigation of the mechanism of efficacy of melanoma RIT points at killing of melanoma stem cells by RIT and involvement of immune system such as complement-dependent cytotoxicity. The domain of radiolabeled peptides for targeted melanoma therapy has been preclinical so far, with work concentrated on radiolabeled peptide analogues of melanocyte-stimulating hormone receptor and on melanin-binding peptides. The field of radiolabeled small molecule produced radioiodinated benzamides that cross the cellular membrane and bind to the intracellular melanin. The recent clinical trial demonstrated measurable antitumor effects and no acute or midterm toxicities. We are hopeful that the targeted radionuclide therapy of metastatic melanoma would become a clinical reality as a stand-alone therapy or in combination with the immunotherapies such as anti-PD1 programmed cell death protein 1 monoclonal antibodies

  3. Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients.

    PubMed

    Boudewijns, Steve; Westdorp, Harm; Koornstra, Rutger H T; Aarntzen, Erik H J G; Schreibelt, Gerty; Creemers, Jeroen H A; Punt, Cornelis J A; Figdor, Carl G; de Vries, I Jolanda M; Gerritsen, Winald R; Bol, Kalijn F

    2016-01-01

    The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8 T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome. PMID:27227325

  4. Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients

    PubMed Central

    Boudewijns, Steve; Westdorp, Harm; Koornstra, Rutger H.T.; Aarntzen, Erik H.J.G.; Schreibelt, Gerty; Creemers, Jeroen H.A.; Punt, Cornelis J.A.; Figdor, Carl G.; Gerritsen, Winald R.; Bol, Kalijn F.

    2016-01-01

    The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8+ T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome. PMID:27227325

  5. Morphogenesis of early stage melanoma

    NASA Astrophysics Data System (ADS)

    Chatelain, Clément; Amar, Martine Ben

    2015-08-01

    Melanoma early detection is possible by simple skin examination and can insure a high survival probability when successful. However it requires efficient methods for identifying malignant lesions from common moles. This paper provides an overview first of the biological and physical mechanisms controlling melanoma early evolution, and then of the clinical tools available today for detecting melanoma in vivo at an early stage. It highlights the lack of diagnosis methods rationally linking macroscopic observables to the microscopic properties of the tissue, which define the malignancy of the tumor. The possible inputs of multiscale models for improving these methods are shortly discussed.

  6. What's New in Research and Treatment of Melanoma Skin Cancer?

    MedlinePlus

    ... Topic Additional resources for melanoma skin cancer What’s new in melanoma skin cancer research? Research into the ... Melanoma Talking With Your Doctor After Treatment What`s New in Skin Cancer - Melanoma Research? Other Resources and ...

  7. Posterior Urethral Strictures.

    PubMed

    Gelman, Joel; Wisenbaugh, Eric S

    2015-01-01

    Pelvic fracture urethral injuries are typically partial and more often complete disruptions of the most proximal bulbar and distal membranous urethra. Emergency management includes suprapubic tube placement. Subsequent primary realignment to place a urethral catheter remains a controversial topic, but what is not controversial is that when there is the development of a stricture (which is usually obliterative with a distraction defect) after suprapubic tube placement or urethral catheter removal, the standard of care is delayed urethral reconstruction with excision and primary anastomosis. This paper reviews the management of patients who suffer pelvic fracture urethral injuries and the techniques of preoperative urethral imaging and subsequent posterior urethroplasty. PMID:26691883

  8. Posterior Urethral Strictures

    PubMed Central

    Gelman, Joel; Wisenbaugh, Eric S.

    2015-01-01

    Pelvic fracture urethral injuries are typically partial and more often complete disruptions of the most proximal bulbar and distal membranous urethra. Emergency management includes suprapubic tube placement. Subsequent primary realignment to place a urethral catheter remains a controversial topic, but what is not controversial is that when there is the development of a stricture (which is usually obliterative with a distraction defect) after suprapubic tube placement or urethral catheter removal, the standard of care is delayed urethral reconstruction with excision and primary anastomosis. This paper reviews the management of patients who suffer pelvic fracture urethral injuries and the techniques of preoperative urethral imaging and subsequent posterior urethroplasty. PMID:26691883

  9. Posterior Tibial Tendon Transfer.

    PubMed

    Shane, Amber M; Reeves, Christopher L; Cameron, Jordan D; Vazales, Ryan

    2016-01-01

    When performed correctly with the right patient population, a tibialis posterior muscle/tendon transfer is an effective procedure. Many different methods have been established for fixating the tendon, each of which has its' own indications. Passing through the interosseous membrane is the preferred and recommended method and should be used unless this is not possible. Good surgical planning based on patient needs and expectations, along with excellent postoperative care including early range of motion and physical therapy minimizes risk of complications and allows for the optimal outcome to be achieved. PMID:26590722

  10. Circulating epigenetic biomarkers in melanoma.

    PubMed

    Xin, Yu; Li, Zheng; Chan, Matthew T V; Wu, William Ka Kei

    2016-02-01

    Recent researches have shed new light on the importance of epigenetic alterations, including promoter hypermethylation and microRNA dysregulation, in the initiation and progression of melanoma. The clinical utilization of circulating epigenetic markers in melanoma has also been investigated. In this review, we explored the literature and summarized the latest progress in the discovery of circulating epigenetic markers, namely methylated DNA and microRNAs, for non-invasive diagnosis of melanoma, as well as their measurability and predictability. We also discussed the utility of these epigenetic markers as novel prognostic and predictive markers and their association with melanoma clinical phenotypes, including recurrence and patients' survival. Large-cohort validations are warranted to maximize the clinical utilization of these markers. PMID:26662802

  11. What Does Melanoma Look Like?

    MedlinePlus

    ... that begins in melanocytes ( cells that make the pigment melanin ). Below are photos of melanoma that formed ... often ragged, notched, or blurred in outline. The pigment may spread into the surrounding skin. Color that ...

  12. 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

  13. [Choroidal melanoma - evolution and prognosis].

    PubMed

    Chiruţa, Daria; Stan, Cristina

    2014-01-01

    Choroidal melanoma is the most common primary intraocular malignant tumor. We present the case of a 62 year old patient who was diagnosed with intraocular tumor in his right eye, for about three years. Regarding the fact that the patient refused any kind of treatment during this period, we just had the opportunity to monitor this case. Finally, the diagnosis was choroidal melanoma, confirmed by the histopathological exam.

  14. Diagnostic Challenge of Desmoplastic Melanoma

    PubMed Central

    Andreevscaia, Olga; Theate, Ivan; Goossens, Cathy; Vanhooteghem, Olivier

    2016-01-01

    Desmoplastic melanoma (DM) is a rare variant of spindle-cell malignant melanoma. DM is easily misdiagnosed at an early stage because it can be confused with benign entities. Histological analysis, including careful attention to the presence of atypical spindle cells, as well as to lymphocytic aggregates in an abundant fibrotic stroma in the dermis, provides clues for diagnosis. The adjunction of an immunohistochemical panel, and particularly testing for S-100 protein, is needed for the final diagnosis. PMID:27134705

  15. Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J; Lehmann, Manja; Schott, Jonathan M; Rabinovici, Gil D; Rossor, Martin N; Fox, Nick C

    2013-01-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management. PMID:22265212

  16. Melanoma therapy: Check the checkpoints.

    PubMed

    Furue, Masutaka; Kadono, Takafumi

    2016-02-01

    Recent mutational and translational studies have revealed that the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway plays a key role in melanomagenesis. Mutations in NRAS and BRAF are found in the majority of melanomas resulting in the formation of constitutively active NRAS and BRAF molecules, which leads to the proliferation and survival of melanoma cells through the activation of MEK/ERK signals. Inhibitors of BRAF or MEK significantly extend the progression-free survival and overall survival of melanoma patients compared with conventional chemotherapies. Combining BRAF and MEK inhibitors further enhances the clinical effectiveness. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an immune checkpoint molecule that downregulates T-cell activation by binding to B7 (CD80/CD86) molecules on antigen-presenting cells. Programmed death receptor ligand 1 on melanoma cells negatively regulates T-cell function by binding to the programmed death-1 (PD-1) receptor on T cells. Antibodies against CTLA-4 and PD-1 also enhance the survival of melanoma patients. In this review, we summarize the clinical effectiveness and adverse events of the BRAF inhibitors, MEK inhibitors and anti-immune checkpoint antibodies in melanoma treatment.

  17. Racial differences in melanoma incidence.

    PubMed Central

    Crombie, I. K.

    1979-01-01

    The incidences of malignant melanoma recorded by 59 population-based cancer registries were investigated to determine the effects of racial and skin-colour differences. White populations exhibited a wide range of melanoma incidences and females commonly, though not invariably, had a higher incidence than males. Non-white populations experienced in general a much lower incidence of melanoma although there was some overlap of white and non-white rates. No predominant sex difference emerged among non-whites. Populations of African descent were found to have a higher incidence than those of Asiatic origin, but it was concluded that this was due largely to the high frequency of tumours among Africans on the sole of the foot. A clear negative correlation between degree of skin pigmentation and melanoma incidence emerged for the exposed body sites. These data provide strong support for the hypotheses that UV radiation is a major cause of malignant melanoma and that melanin pigmentation protects against it. Further research is required to elucidate the aetiology of melanoma of the sole of the foot. PMID:475965

  18. Uveal spindle cell tumor of blue-eyed dogs: an immunohistochemical study.

    PubMed

    Zarfoss, M K; Klauss, G; Newkirk, K; Kiupel, M; Jones, Y; Colitz, C M H; Dubielzig, R R

    2007-05-01

    Immunohistochemical techniques were used to investigate the origin of a spindle cell tumor in the anterior uveal tract of dogs and the influence of ultraviolet radiation on the development of this tumor. Thirteen tumors were identified from the 4,007 canine ocular samples examined at the Comparative Ocular Pathology Laboratory of Wisconsin between 1978 and 2005. Siberian Husky and Siberian Husky mix dogs were overrepresented (10/13 dogs, overall median age 10 years). Light microscopic evaluation (all dogs) and electron microscopy (2 dogs) were performed. Immunohistochemical staining included alpha-smooth muscle actin (SMA), vimentin, S-100, desmin, glial fibrillary acidic protein (GFAP), Melan A, microphthalmic transcription factor (MITF-1), protein gene product 9.5 (PGP 9.5), laminin, gadd45, p53, proliferating cell nuclear antigen (PCNA), anti-UVssDNA (antibody for detection of (6-4)-dipyrimidine photoproducts), and telomerase reverse transcriptase (TERT). All tumors occurred in the iris with or without ciliary body involvement and were composed of spindle cells arranged in fascicles and whorls (variable Antoni A and B behavior). All tumors were positive when immunostained for vimentin and S-100. Nine of 13 tumors exhibited GFAP immunopositivity. All tumors were negative for SMA, desmin, Melan A, and MITF-1. Tumors were variably positive for PGP 9.5, laminin, gadd45, p53, PCNA, anti-UVssDNA, and TERT. Electron microscopy revealed intermittent basal laminae between cells. These tumors are morphologically and immunohistochemically most consistent with schwannoma. The relationship between spindle cell tumors of the anterior uvea of dogs, altered neural crest, blue iris color, and ultraviolet radiation has not yet been fully elucidated.

  19. Patterns of tumor initiation in choroidal melanoma.

    PubMed

    Li, W; Judge, H; Gragoudas, E S; Seddon, J M; Egan, K M

    2000-07-15

    This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the macula and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma. Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis for analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates. The retinal sphere was divided into 61 mutually exclusive sectors defined according to clock hour and anteroposterior distance from the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors. Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63). However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4, 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated with light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest

  20. Aldesleukin and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

    ClinicalTrials.gov

    2016-10-26

    Metastatic 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

  1. Novel posterior fixation keratoprosthesis

    NASA Astrophysics Data System (ADS)

    Lacombe, Emmanuel

    1992-08-01

    The keratoprosthesis is the last solution for corneally blind patients that cannot benefit from corneal transplants. Keratoprostheses that have been designed to be affixed anteriorly usually necessitate multi-step surgical procedures and are continuously subjected to the extrusion forces generated by the positive intraocular pressure; therefore, clinical results in patients prove inconsistent. We proposed a novel keratoprosthesis concept that utilizes posterior corneal fixation which `a priori' minimizes the risk of aqueous leakage and expulsion. This prosthesis is implanted in a single procedure thereby reducing the number of surgical complications normally associated with anterior fixation devices. In addition, its novel design makes this keratoprosthesis implantable in phakic eyes. With an average follow-up of 13 months (range 3 to 25 months), our results on 21 cases are encouraging. Half of the keratoprostheses were implanted in severe burn cases, with the remainder in cases of pseudo- pemphigus. Good visual results and cosmetic appearance were obtained in 14 of 21 eyes.

  2. Modeling Melanoma In Vitro and In Vivo

    PubMed Central

    Beaumont, Kimberley A.; Mohana-Kumaran, Nethia; Haass, Nikolas K.

    2013-01-01

    The behavior of melanoma cells has traditionally been studied in vitro in two-dimensional cell culture with cells adhering to plastic dishes. However, in order to mimic the three-dimensional architecture of a melanoma, as well as its interactions with the tumor microenvironment, there has been the need for more physiologically relevant models. This has been achieved by designing 3D in vitro models of melanoma, such as melanoma spheroids embedded in extracellular matrix or organotypic skin reconstructs. In vivo melanoma models have typically relied on the growth of tumor xenografts in immunocompromised mice. Several genetically engineered mouse models have now been developed which allow the generation of spontaneous melanoma. Melanoma models have also been established in other species such as zebrafish, which are more conducive to imaging and high throughput studies. We will discuss these models as well as novel techniques that are relevant to the study of the molecular mechanisms underlying melanoma progression. PMID:27429258

  3. Isolated Malignant Melanoma Metastasis to the Pancreas

    PubMed Central

    Krag, Christen; Geertsen, Poul; Jakobsen, Linda P.

    2013-01-01

    Summary: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field. PMID:25289269

  4. Tool to Distinguish Moles from Melanoma

    Cancer.gov

    “Moles to Melanoma: Recognizing the ABCDE Features” presents photos that show changes in individual pigmented lesions over time, and describes the different appearances of moles, dysplastic nevi, and melanomas.

  5. Donor transmission of melanoma following renal transplant.

    PubMed

    Chen, Kathryn T; Olszanski, Anthony; Farma, Jeffrey M

    2012-01-01

    Donor transmission of melanoma is one of the more common and lethal of recipient malignancies, often presenting with systemic disease. Although some patients may receive durable remission of melanoma following explantation of the allograft and withdrawal of immunosuppression, donor transmission of melanoma is fatal in most patients. Here we present a case of a 44-year-old male who developed metastatic melanoma following renal transplant.

  6. Surgical management of primary and recurrent melanoma.

    PubMed

    Farma, Jeffrey M; Kulkarni, Nandini; Hsu, Cary

    2015-04-01

    Melanoma accounts for less than 2% of skin cancer cases but causes most skin cancer-related deaths. Surgery continues to be the cornerstone of treatment of melanoma and surgical principles are guided by data derived from clinical research. This article examines the evolution of surgical techniques for the diagnosis and treatment of primary and locally recurrent melanoma.

  7. When narrative medicine helps in the diagnosis of conjunctival melanoma – an exceptional case report

    PubMed Central

    Nunes, Ana Teresa; Almeida, Leonor; Crujo, Conceição; Monteiro-Grillo, Manuel

    2012-01-01

    Introduction: Conjunctival melanoma is a relatively rare ocular malignancy with substantial associated morbidity and mortality. It can arise in previously unblemished and unpigmented regions (approximately 10% of cases), from a preexisting nevus (approximately 20% of cases), or from the flat, spreading pigmentation of primary acquired melanosis with atypia (60–70% of cases), actually called conjunctival melanocytic intraepithelial neoplasia (C-MIN) with atypia (histopathologically more accurately term). Purpose: The authors describe an extremely rare case of malignant conjunctival melanoma, with a long evolution, in a young black woman. Results: Until now the patient has not shown any sign of relapse of this melanoma, after local excision. Conclusion: Conjunctival melanoma is a condition of concern because of its rarity and lethal potential. Advances in the understanding and management of this neoplasm have markedly reduced the mortality and possibly the morbidity associated with this malignancy. We observe that there are some cases of conjunctival melanoma that might be cured with only a local excision with posterior cryotherapy without more aggressive methods. The practice of narrative medicine brings new possibilities in the diagnosis and collection of classical history.

  8. 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

  9. 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

  10. 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

  11. Gossypiboma mimicking posterior urethral stricture

    PubMed Central

    Kumar, Bindey; Kumar, Prem; Sinha, Sanjay Kumar; Sinha, Neelam; Hasan, Zaheer; Thakur, Vinit Kumar; Anand, Utpal; Priyadarshi, Rajiv Nayan; Mandal, Manish

    2013-01-01

    INTRODUCTION Foreign bodies in the urogenital tract are not uncommon. Hairpins, glass rods, umbilical tapes, ball point pen are described in lower urogenital tract. Retained gauze piece (gossypiboma) in posterior urethra may cause diagnostic dilemma. Symptoms and investigations may mimic stricture of posterior urethra. PRESENTATION OF CASE Two cases of retained gauze pieces in the urethra are described here. The micturating cystourethrogram was suggestive of posterior urethral stricture. DISCUSSION Two cases described here had retained gauze piece as a cause of filling defect and abnormal appearance in the micturating cystourethrogram. Gossypiboma may be a possibility where posterior urethral stricture are seen after previous surgery in paediatric age group. CONCLUSION In the setting of previous urogenital surgery gossypiboma should be kept in the differential diagnosis where posterior urethral stricture are seen in the paediatric age group. PMID:23500749

  12. High accuracy of family history of melanoma in Danish melanoma cases.

    PubMed

    Wadt, Karin A W; Drzewiecki, Krzysztof T; Gerdes, Anne-Marie

    2015-12-01

    The incidence of melanoma in Denmark has immensely increased over the last 10 years making Denmark a high risk country for melanoma. In the last two decades multiple public campaigns have sought to increase the awareness of melanoma. Family history of melanoma is a known major risk factor but previous studies have shown that self-reported family history of melanoma is highly inaccurate. These studies are 15 years old and we wanted to examine if a higher awareness of melanoma has increased the accuracy of self-reported family history of melanoma. We examined the family history of 181 melanoma probands who reported 199 cases of melanoma in relatives, of which 135 cases where in first degree relatives. We confirmed the diagnosis of melanoma in 77% of all relatives, and in 83% of first degree relatives. In 181 probands we validated the negative family history of melanoma in 748 first degree relatives and found only 1 case of melanoma which was not reported in a 3 case melanoma family. Melanoma patients in Denmark report family history of melanoma in first and second degree relatives with a high level of accuracy with a true positive predictive value between 77 and 87%. In 99% of probands reporting a negative family history of melanoma in first degree relatives this information is correct. In clinical practice we recommend that melanoma diagnosis in relatives should be verified if possible, but even unverified reported melanoma cases in relatives should be included in the indication of genetic testing and assessment of melanoma risk in the family. PMID:26094006

  13. Medical management of malignant melanoma.

    PubMed

    Atkinson, Victoria

    2015-06-01

    The treatment and outcomes for people with metastatic melanoma have changed considerably in the past few years with the introduction of targeted anticancer drugs. About half of the patients with metastatic melanoma will have activating mutations in the BRAF gene. These people may benefit from a BRAF inhibitor (vemurafenib or dabrafenib) or a MEK inhibitor (trametinib). Addition of a MEK inhibitor to a BRAF inhibitor improves progression-free survival and alters the adverse effect profile. Ipilimumab is another drug indicated for metastatic melanoma. It works by altering the patient's own immune response to the tumour. Toxicities are common with these drugs and include arthralgias, fatigue, photosensitivity, squamous cell carcinomas, fever, diarrhoea, pruritus and immune-related adverse effects. PMID:26648623

  14. Hyperspectral imaging for melanoma screening

    NASA Astrophysics Data System (ADS)

    Martin, Justin; Krueger, James; Gareau, Daniel

    2014-03-01

    The 5-year survival rate for patients diagnosed with Melanoma, a deadly form of skin cancer, in its latest stages is about 15%, compared to over 90% for early detection and treatment. We present an imaging system and algorithm that can be used to automatically generate a melanoma risk score to aid clinicians in the early identification of this form of skin cancer. Our system images the patient's skin at a series of different wavelengths and then analyzes several key dermoscopic features to generate this risk score. We have found that shorter wavelengths of light are sensitive to information in the superficial areas of the skin while longer wavelengths can be used to gather information at greater depths. This accompanying diagnostic computer algorithm has demonstrated much higher sensitivity and specificity than the currently commercialized system in preliminary trials and has the potential to improve the early detection of melanoma.

  15. Cell Cycle Regulation and Melanoma.

    PubMed

    Xu, Wen; McArthur, Grant

    2016-06-01

    Dysregulation of cell cycle control is a hallmark of melanomagenesis. Agents targeting the G1-S and G2-M checkpoints, as well as direct anti-mitotic agents, have all shown promising preclinical activity in melanoma. However, in vivo, standalone single agents targeting cell cycle regulation have only demonstrated modest efficacy in unselected patients. The advent of specific CDK 4/6 inhibitors targeting the G1-S transition, with an improved therapeutic index, is a significant step forward. Potential synergy exists with the combination of CDK4/6 inhibitors with existing therapies targeting the MAPK pathway, particularly in subsets of metastatic melanomas such as NRAS and BRAF mutants. This reviews summaries of the latest developments in both preclinical and clinical data with cell cycle-targeted therapies in melanoma. PMID:27106898

  16. 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

  17. [Laboratory markers of melanoma progression].

    PubMed

    Bánfalvi, Teodóra; Edesné, Mariann B; Gergye, Mária; Udvarhelyi, Nóra; Orosz, Zsolt; Gilde, Katalin; Kremmer, Tibor; Ottó, Szabolcs; Tímár, József

    2003-01-01

    Extracellular tumour markers may have potential role in the follow-up of patients with malignant melanoma, in therapy monitoring and in prediction of prognosis. In our article circulating tumour markers in melanoma (melanoma inhibitory activity, lipid bound sialic acid, neuron specific enolase, TA90 immune complex, S-100B protein, 5-S-cysteinyldopa, tyrosinase, cytokines, metalloproteinases, LDH) were reviewed. Among laboratory melanoma markers the S-100B protein is the most investigated. S-100B protein has high specificity, appropriate sensitivity and proved to be significant prognostic factor independent from stages. High serum values are associated with shorter survival. However, before S-100B monitoring immunohistochemistry for the detection of S-100B is required. In the case of malignant melanomas with low expression serum S-100B monitoring may not be sensitive enough to follow disease progression. Although the serum concentration of 5-S-cysteinyldopa did not prove to be independent prognostic factor in our previous studies comprising the highest patient number in the literature, the marker was suggested for therapy monitoring. The survival analysis indicated that the elevated 5-S-cysteinyldopa level predicts shorter survival. In spite of the calculated low correlation between the two markers, parallel elevation of S-100B protein and 5-S-cysteinyldopa indicated shorter survival. On the basis of the literature LDH is the most appropriate tumour marker in stage IV to predict prognosis, but its sensitivity and specificity could not achieve that of S-100B protein. S-100B and LDH proved to be similarly reliable in respect to the clinical outcome. Determination of serum concentration of MIA and tyrosinase are also reliable markers in malignant melanoma. The other investigated markers are not well known yet or do not provide useful information to the clinicians. PMID:12704461

  18. Recurrent inactivating RASA2 mutations in melanoma.

    PubMed

    Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel; Wilmott, James S; Gartner, Jared J; Di Pizio, Antonella; Winograd-Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton-Regester, Ken; Johansson, Peter; Pritchard, Antonia L; Waddell, Nicola; Hill, Victoria K; Lin, Jimmy C; Hevroni, Yael; Rosenberg, Steven A; Khan, Javed; Ben-Dor, Shifra; Niv, Masha Y; Ulitsky, Igor; Mann, Graham J; Scolyer, Richard A; Hayward, Nicholas K; Samuels, Yardena

    2015-12-01

    Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer. PMID:26502337

  19. 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

  20. The effect of sunscreen on melanoma risk.

    PubMed

    Mulliken, Jennifer S; Russak, Julie E; Rigel, Darrell S

    2012-07-01

    Total cumulative sun exposure is associated with the development of squamous cell and basal cell cancers, whereas intense intermittent sun exposure is associated with the development of melanoma. Exposure to UV radiation is the only known modifiable cause of melanoma, but the role of sunscreen in melanoma prevention remains somewhat controversial. This article discusses how UV radiation contributes to the pathogenesis of melanoma, how sunscreen modulates the action of UV radiation on the skin, and the effect of sunscreen on the risk of developing melanoma. A review of available sunscreen agents and their sun-protective properties is also included.

  1. Familial skin cancer syndromes: Increased melanoma risk.

    PubMed

    Ransohoff, Katherine J; Jaju, Prajakta D; Jaju, Prajaka D; Tang, Jean Y; Carbone, Michele; Leachman, Sancy; Sarin, Kavita Y

    2016-03-01

    Phenotypic traits, such as red hair and freckling, increase melanoma risk by 2- to 3-fold. In addition, approximately 10% of melanomas are caused by inherited germline mutations that increase melanoma risk from 4- to >1000-fold. This review highlights the key genes responsible for inherited melanoma, with an emphasis on when a patient should undergo genetic testing. Many genetic syndromes associated with increased melanoma risk are also associated with an increased risk of other cancers. Identification of these high-risk patients is essential for preventive behavior reinforcement, genetic counseling, and ensuring other required cancer screenings.

  2. 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

  3. 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

  4. Melanoma incidence and frequency modulation (FM) broadcasting.

    PubMed

    Hallberg, Orjan; Johansson, Olle

    2002-01-01

    The incidence of melanoma has been increasing steadily in many countries since 1960, but the underlying mechanism causing this increase remains elusive. The incidence of melanoma has been linked to the distance to frequency modulation (FM) broadcasting towers. In the current study, the authors sought to determine if there was also a related link on a larger scale for entire countries. Exposure-time-specific incidence was extracted from exposure and incidence data from 4 different countries, and this was compared with reported age-specific incidence of melanoma. Geographic differences in melanoma incidence were compared with the magnitude of this environmental stress. The exposure-time-specific incidence from all 4 countries became almost identical, and they were approximately equal to the reported age-specific incidence of melanoma. A correlation between melanoma incidence and the number of locally receivable FM transmitters was found. The authors concluded that melanoma is associated with exposure to FM broadcasting.

  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. Injuries of the posterior cruciate ligament.

    PubMed

    Moyer, R A; Marchetto, P A

    1993-04-01

    A review of the anatomy and biomechanics of the posterior cruciate ligament, and the systematic approach for the diagnosis and treatment of isolated posterior cruciate ligament injuries and posterior cruciate ligament insufficiency in combination with other ligamentous instabilities is discussed.

  8. Effect of Uveal Melanocytes on Choroidal Morphology in Rhesus Macaques and Humans on Enhanced-Depth Imaging Optical Coherence Tomography

    PubMed Central

    Yiu, Glenn; Vuong, Vivian S.; Oltjen, Sharon; Cunefare, David; Farsiu, Sina; Garzel, Laura; Roberts, Jeffrey; Thomasy, Sara M.

    2016-01-01

    Purpose To compare cross-sectional choroidal morphology in rhesus macaque and human eyes using enhanced-depth imaging optical coherence tomography (EDI-OCT) and histologic analysis. Methods Enhanced-depth imaging–OCT images from 25 rhesus macaque and 30 human eyes were evaluated for choriocapillaris and choroidal–scleral junction (CSJ) visibility in the central macula based on OCT reflectivity profiles, and compared with age-matched histologic sections. Semiautomated segmentation of the choriocapillaris and CSJ was used to measure choriocapillary and choroidal thickness, respectively. Multivariate regression was performed to determine the association of age, refractive error, and race with choriocapillaris and CSJ visibility. Results Rhesus macaques exhibit a distinct hyporeflective choriocapillaris layer on EDI-OCT, while the CSJ cannot be visualized. In contrast, humans show variable reflectivities of the choriocapillaris, with a distinct CSJ seen in many subjects. Histologic sections demonstrate large, darkly pigmented melanocytes that are densely distributed in the macaque choroid, while melanocytes in humans are smaller, less pigmented, and variably distributed. Optical coherence tomography reflectivity patterns of the choroid appear to correspond to the density, size, and pigmentation of choroidal melanocytes. Mean choriocapillary thickness was similar between the two species (19.3 ± 3.4 vs. 19.8 ± 3.4 μm, P = 0.615), but choroidal thickness may be lower in macaques than in humans (191.2 ± 43.0 vs. 266.8 ± 78.0 μm, P < 0.001). Racial differences in uveal pigmentation also appear to affect the visibility of the choriocapillaris and CSJ on EDI-OCT. Conclusions Pigmented uveal melanocytes affect choroidal morphology on EDI-OCT in rhesus macaque and human eyes. Racial differences in pigmentation may affect choriocapillaris and CSJ visibility, and may influence the accuracy of choroidal thickness measurements. PMID:27792810

  9. [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

  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. Adjuvant therapy of malignant melanoma.

    PubMed

    Molife, R; Hancock, B W

    2002-10-01

    High risk surgically resected melanoma is associated with a less than 50% 5-year survival. Adjuvant therapy is an appropriate treatment modality in this setting, and is more likely to be effective as the tumour burden here is small. Clinical observations of spontaneous tumour regressions and a highly variable rate of disease progression suggest a role of the immune system in the natural history of melanoma. Biological agents have therefore been the subjects of numerous adjuvant studies. Early, randomised controlled trials (RCTs) of Bacillus Calmette-Guerin (BCG), levamisole, Corynebacterium parvum, chemotherapy, isolated limb perfusion (ILP), radiotherapy, transfer factor (TF), megestrol acetate and vitamin A yielded largely negative results. Current trials focus on vaccines and the interferons. To date the latter is the only therapy to have shown a significant benefit in the prospective randomised controlled phase III setting. This report represents a systematic review of studies in adjuvant therapy in melanoma. Data from ongoing studies is awaited before a role for adjuvant agents in high risk melanoma is confirmed. PMID:12399001

  12. [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?

  13. Comparison of aesthetic posterior restorations.

    PubMed

    Trushkowsky, R D

    1991-09-01

    In the past decade there has been an increased desire by the profession and the public for an aesthetic restoration that will restore a posterior tooth to its original form and function. The currently available aesthetic posterior restoration materials and techniques are porcelain, cast ceramic, direct composite, direct-indirect composite, indirect composite, and CAD-CAM fabrications. The indications and contraindications of these restorative materials and proper diagnosis and case selection are described.

  14. 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

  15. Genetic alterations of PTEN in human melanoma.

    PubMed

    Aguissa-Touré, Almass-Houd; Li, Gang

    2012-05-01

    The PTEN gene is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Inactivating mutations and deletions of the PTEN gene are found in many types of cancers, including melanoma. However, the exact frequency of PTEN alteration in melanoma is unknown. In this study, we comprehensively reviewed 16 studies on PTEN genetic changes in melanoma cell lines and tumor biopsies. To date, 76 PTEN alterations have been reported in melanoma cell lines and 38 PTEN alterations in melanoma biopsies. The rate of PTEN alterations in melanoma cell lines, primary melanoma, and metastatic melanoma is 27.6, 7.3, and 15.2%, respectively. Three mutations were found in both melanoma cell lines and biopsies. These mutations are scattered throughout the gene, with the exception of exon 9. A mutational hot spot is found in exon 5, which encodes the phosphatase activity domain. Evidence is also presented to suggest that numerous homozygous deletions and missense variants exist in the PTEN transcript. Studying PTEN functions and implications of its mutations and other genes could provide insights into the precise nature of PTEN function in melanoma and additional targets for new therapeutic approaches. PMID:22076652

  16. Caring for patients with melanoma in the primary care setting.

    PubMed

    Rea, Mary; Perrino, Laura; Sheets, Victoria; McDaniel, M Jane

    2014-07-01

    The incidence of melanoma is steadily rising and mortality continues to increase. This article describes types of melanoma and the role of primary care providers in the long-term management and follow-up of patients diagnosed with melanoma.

  17. Use of imiquimod for residual acral melanoma.

    PubMed

    Sue, Gloria R; Hanlon, Allison; Lazova, Rossitza; Narayan, Deepak

    2014-01-01

    Recent reports suggest that topical imiquimod cream is an effective treatment option for certain types of melanomas. No reports exist on the efficacy of using imiquimod cream to treat melanoma located on the plantar surface of the foot. We present two patients with a melanoma of the foot who had residual melanoma following surgical excision with acceptable margins. The patients were then treated with topical imiquimod for 8 weeks after which a repeat biopsy of the affected region showed no evidence of residual melanoma in situ. The use of topical imiquimod cream should be considered in the management of residual melanoma in situ of the plantar surface of the foot. PMID:25188932

  18. 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

  19. 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.

  20. Pediatric melanoma, moles, and sun safety.

    PubMed

    Hawryluk, Elena B; Liang, Marilyn G

    2014-04-01

    Although pediatric melanoma is a rare disease, diagnosis and management of pigmented lesions in the pediatric population, particularly dysplastic nevi and Spitz nevi, can be challenging. In this article, we provide an overview of pigmented lesions in children, including melanoma and management of melanoma risk factors and melanocytic nevi in the pediatric population. Congenital melanocytic nevi, Spitz nevi, dysplastic and acquired nevi, and changes over time are reviewed. We discuss considerations for excision and management of pigmented lesions in children.

  1. 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.

  2. Immunohistochemical diagnostic and prognostic markers for melanoma.

    PubMed

    Nosrati, Mehdi; Kashani-Sabet, Mohammed

    2014-01-01

    Recent studies in our laboratory have identified novel molecular diagnostic and prognostic markers based on analyses in large cohorts of melanoma patients. These markers were initially derived from gene expression profiling analyses of distinct stages of melanoma progression. Immunohistochemical analyses confirmed the differential expression of these markers, and immunohistochemistry-based multimarker assays were developed to assess melanoma diagnosis and prognosis at the molecular level. In this chapter we review the development of these assays and the methodologies used to assess marker expression in both nevi and primary melanomas. PMID:24258983

  3. 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

  4. Photoablation of ocular melanoma with a high-powered argon endolaser.

    PubMed

    Jaffe, G J; Mieler, W F; Burke, J M; Williams, G A

    1989-01-01

    We studied the use of a 15-W argon blue-green laser in the treatment of choroidal melanoma in a rabbit model. Greene melanoma cells were used to produce 2- to 4-mm thick tumors posteriorly in the suprachoroidal space in pigmented rabbits. Endophotocoagulation delivered through a 600-micron fiberoptic probe was performed to ablate the tumor tissue and a surrounding margin of normal tissue. A vitreous cutter was used simultaneously to remove liberated necrotic debris. The effect of the laser on tumor and normal ocular tissue was evaluated by light microscopy and the extent of the proliferative response by tritiated thymidine radioautography. Application of 100 to 400 pulses of laser energy using treatment parameters of 12 to 14 W of power and 0.1-s pulses resulted in complete ablation of melanoma tissue, overlying retina, and choroid. There was no substantial intraoperative or postoperative hemorrhage. Material liberated during the laser treatment was found to be nonviable. The effect of the laser on tissue appeared localized to within approximately 1.25 mm of the margin of the central lesion. The high-energy argon laser seems to offer a means of effectively ablating melanoma tissue via an internal resection approach. PMID:2910269

  5. Neutron capture therapy for melanoma

    SciTech Connect

    Coderre, J.A.; Glass, J.D.; Micca, P.; Fairchild, R.G.

    1988-01-01

    The development of boron-containing compounds which localize selectively in tumor may require a tumor-by-tumor type of approach that exploits any metabolic pathways unique to the particular type of tumor. Melanin-producing melanomas actively transport and metabolize aromatic amino acids for use as precursors in the synthesis of the pigment melanin. It has been shown that the boron-containing amino acid analog p-borono-phenylalanine (BPA) is selectively accumulated in melanoma tissue, producing boron concentrations in tumor that are within the range estimated to be necessary for successful boron neutron capture therapy (BNCT). We report here the results of therapy experiments carried out at the Brookhaven Medical Research Reactor (BMRR). 21 refs., 5 figs., 3 tabs.

  6. Malignant rectal melanoma. Case report.

    PubMed

    Morlino, Andrea; La Torre, Giuseppe; Vitagliano, Giulia; Cammarota, Aldo

    2015-03-26

    Il Melanoma Anorettale è una malattia rara e aggressiva ed è il terzo tipo più comune di melanoma maligno dopo quello della cute e della retina. Il sintomo più comune è il sanguinamento rettale, che è spesso scambiato per sanguinamento associato a emorroidi. La diagnosi è molto difficile, e quella iniziale può essere corretta solo in circa 80% dei casi. Il caso clinico che proponiamo riguarda un uomo di 71 anni giunto alla nostra osservazione per dolore anale, tenesmo rettale, sanguinamento. L’eplorazione rettale ci ha mostrato una neofromazione dolorosa, di colorito brunastro nel canale anale. La colonscopia e la endoscopia hanno evidenziato la presenza di una grande massa stenotica interessante il canale anale ed il retto con un diametro di circa 90 mm. La biopsia è positiva per melanoma a cellule maligne pigmentate. La TAC ha mostrato un ispessimento della parete rettale e linfonodi nel tessuto adiposo, nel distretto otturatore bilaterale e metastasi polmonari bilaterali. Il dato di laboratorio del Ca 19-9 è nei livelli normali. Il paziente è stato sottoposto a resezione addomino-perineale con dissezione linfonodale. Non ci sono studi dimostranti che la resezione radicale del melanoma primario ano-rettale è associata ad un miglioramento del controllo locale e della sopravvivenza. I pazienti con malattia localizzata dovrebbero essere sottoposti a escissione locale ogniqualvolta ciò sia tecnicamente fattibile. Il ruolo predominante del trattamento chemio radioterapico preoperatorio è quello di ridurre le recidive locoregionale e della cavità pelvica, e per ottenere un più alto tasso di conservazione dell’apparato sfinteriale. Inoltre facilita la rimozione delle potenziali micrometastasi e riduce le metastasi a distanza.

  7. Children's understanding of posterior probability.

    PubMed

    Girotto, Vittorio; Gonzalez, Michel

    2008-01-01

    Do young children have a basic intuition of posterior probability? Do they update their decisions and judgments in the light of new evidence? We hypothesized that they can do so extensionally, by considering and counting the various ways in which an event may or may not occur. The results reported in this paper showed that from the age of five, children's decisions under uncertainty (Study 1) and judgments about random outcomes (Study 2) are correctly affected by posterior information. From the same age, children correctly revise their decisions in situations in which they face a single, uncertain event, produced by an intentional agent (Study 3). The finding that young children have some understanding of posterior probability supports the theory of naive extensional reasoning, and contravenes some pessimistic views of probabilistic reasoning, in particular the evolutionary claim that the human mind cannot deal with single-case probability. PMID:17391661

  8. Rethinking "posterior" tongue-tie.

    PubMed

    Douglas, Pamela Sylvia

    2013-12-01

    Currently, many clinicians who help with breastfeeding problems are diagnosing "posterior" tongue-tie in infants and performing or referring for frenotomy. In this "Speaking Out" article, I argue that the diagnosis of "posterior" tongue-tie has successfully raised awareness of the importance of impaired tongue function in breastfeeding difficulty. However, the diagnosis of "posterior" tongue-tie also applies a reductionist, medicalized theoretical frame to the complex problem of impaired tongue function, risking unintended outcomes. Impaired tongue function arises out of multiple interacting and co-evolving factors, including the interplay between social behaviors concerning breastfeeding and mother-infant biology. Consideration of theoretical frames is vital if we are to build an evidence base through efficient use of the scarce resources available for clinical breastfeeding research and minimize unintended outcomes.

  9. 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

  10. 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

  11. Melanoma: from mutations to medicine

    PubMed Central

    Tsao, Hensin; Chin, Lynda; Garraway, Levi A.; Fisher, David E.

    2012-01-01

    Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field—breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many—sometimes-related, although also distinct—biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field. PMID:22661227

  12. Unsuccessful outcomes after posterior urethroplasty.

    PubMed

    Engel, Oliver; Fisch, Margit

    2015-03-01

    Posterior urethroplasty is the most common strategy for the treatment of post-traumatic urethral injuries. Especially in younger patients, post-traumatic injuries are a common reason for urethral strictures caused by road traffic accidents, with pelvic fracture or direct trauma to the perineum. In many cases early endoscopic realignment is the first attempt to restore the junction between proximal and distal urethra, but in some cases primary realignment is not possible or not enough to treat the urethral injury. In these cases suprapubic cystostomy alone and delayed repair by stricture excision and posterior urethroplasty is an alternative procedure to minimise the risk of stricture recurrence.

  13. 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.

  14. 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.

  15. Stereolithography for Posterior Fossa Cranioplasty

    PubMed Central

    Agner, Celso; Dujovny, Manuel; Evenhouse, Raymond; Charbel, Fady T.; Sadler, Lewis

    1998-01-01

    Posterior fossa cranioplasty has been suggested for improvement of neurological symptoms following craniectomy. However, there is no particular recommendation in the literature about techniques for prosthesis manufacture and implantation. We report our experience using rapid prototyping technology and stereolithography for pre-surgical implant design and production of cranioplasties. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5 PMID:17171056

  16. Neonatal posterior fossa subdural hematoma.

    PubMed

    Coker, S; Beltran, R; Fine, M

    1987-07-01

    Hemorrhage into the posterior fossa is a rare neurosurgical emergency in neonates. CT scanning is diagnostic. Blood layering under the apex of the tentorium cerebelli, however, may resemble a dilated vascular structure, and the rigidity of the pressured tentorium may prevent upward transmission of increased intracranial pressure, resulting in a soft fontanelle.

  17. Pattern of Melanoma Incidence in Miami, Florida

    PubMed Central

    Aldrich, Tim E.; Garcia, Norberto

    1981-01-01

    Although melanoma causes only 1.4 percent of cancers nationally, it accounts for 3.6 percent of cancers in southern Flordia. The authors conducted an incidence survey to determine if the distribution of melanoma was a function of population density, an outdoors lifestyle, or the presence of an older population. PMID:7277525

  18. Herramienta para distinguir lunares de melanoma.

    Cancer.gov

    “De lunares a melanoma: reconocimiento de las características ABCDE” presenta fotos que muestran cambios en lesions individuales pigmentadas con el tiempo, y describe las diferentes apariencias de lunares, de nevos displásicos y de melanomas.

  19. Malignant melanoma at a scientific laboratory

    SciTech Connect

    Shy, C.M.; Checkoway, H.; Marshall, E.G.

    1985-11-15

    The general consensus of the seven reviewers is that occupational exposures at Lawrence Livermore National Laboratory have not been established as a causal factor for the observed excess of malignant melanoma. Several observations support the impression that some or all of the observed melanoma excess may be attributable to intense surveillance and enhanced detection of early stage melanoma lesions. Since the incidence of melanomas among Laboratory employees has not diminished, an early harvesting effect is unlikely. This suggests the distinct possibility that localized, in situ melanomas that would normally not be detected are being reported, and that in the absence of this enhanced detection, many of these early stage lesions would show little or no clinical progression. This phenomenon would explain the continued high incidence of melanomas in the absence of a physical or chemical inciting cause. A key point in this reasoning is the issue of the rate of growth of early stage melanomas, and this point remains a key question for study. Even if the observed excess cannot be explained by detection bias, the reviewers agree that the Austin and Reynolds' study does not make a convincing case for occupational factors being a cause of the high melanoma incidence. 6 refs.

  20. 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.

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Primary Bile Duct Melanoma Causing Obstructive Jaundice

    PubMed Central

    Addepally, Naga S.; Klair, Jagpal S.; Lai, Keith; Aduli, Farshad

    2016-01-01

    Malignant melanoma is one of the few malignancies that are well known for unusual behavior. Primary malignant melanoma usually originates from squamous epithelium of skin, mucous membranes, retina, and uvea. Although melanoma can metastasize to any part of the body, including biliary tract, primary malignant melanoma of bile ducts is an extremely rare entity. We present a 52-year-old man who presented with 5-month epigastric pain and 15-pound weight loss, with 1-week duration of jaundice, nausea/vomiting, pale stools, and dark urine, blood work suggested cholestatic jaundice. Imaging revealed a large perihilar/peripancreatic mass involving the portal vein and hepatic artery, and intrahepatic biliary dilation. Biliary brushings revealed neoplastic cells strongly suggestive of malignant melanoma. PMID:27807580

  8. Mechanisms of Melanoma Promotion by Ultraviolet Radiation.

    PubMed

    Rünger, Thomas M

    2016-09-01

    The mutagenic properties of ultraviolet radiation drive the initiation of melanoma. Induction of matrix metalloproteinases in melanoma cells by longwave UVA radiation, possibly via a Warburg-like effect, promotes melanoma invasiveness. This is one of several mechanisms by which ultraviolet radiation also promotes further growth of previously established melanomas. PMID:27542295

  9. 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.

  10. Creep of posterior dental composites.

    PubMed

    Papadogianis, Y; Boyer, D B; Lakes, R S

    1985-01-01

    The creep of microspecimens of posterior dental composites was studied using a torsional creep apparatus. Shear stresses were maintained for 3 h and recovery was followed for 50 h. Creep curves were obtained at 21, 37, and 50 degrees C and four torque levels. The effect of conditioning the specimens in water up to 8 weeks was studied. The posterior composites exhibited linear viscoelastic behavior at low deformations. They had higher shear moduli and greater resistance to creep than conventional and microfilled composites. In aging experiments, maximum shear moduli occurred when specimens were 48 h to 1 week old. Subsequent softening was attributed to water absorption. Residual strain was highest when the composites were stressed within 24 h of initiating polymerization. Residual strain was very low in specimens 48 h to 8 weeks of age.

  11. Posterior cruciate ligament of the knee (image)

    MedlinePlus

    The posterior cruciate ligament (PCL) is a powerful ligament extending from the top-rear surface of the tibia to the bottom-front surface of the femur. The ligament prevents the knee joint from posterior instability.

  12. Fas-mediated apoptosis of melanoma cells and infiltrating lymphocytes in human malignant melanomas.

    PubMed

    Shukuwa, Tetsuo; Katayama, Ichiro; Koji, Takehiko

    2002-04-01

    In a rodent system, melanoma cells expressing Fas ligand (FasL) could kill Fas-positive lymphocytes, suggesting that FasL expression was an essential factor for melanoma cell survival in vivo. These findings led us to investigate apoptosis, and to histochemically analyze involvement of Fas and FasL in the induction of apoptosis, in human malignant melanoma tissues. The percentages of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labeling (TUNEL)-positive melanoma cells and of proliferating cell nuclear antigen (PCNA)-positive melanoma cells in melanoma tissues (n = 22) were greater than those in melanocytes in uninvolved skin (n = 6) and nevus cells in nevi tissues (n = 9). The infiltrating lymphocytes around melanomas were also TUNEL positive. Immunohistochemistry revealed expression of Fas and FasL in melanoma cells and lymphocytes, whereas no Fas or FasL expression was detected in normal skin melanocytes and nevus cells. There was significant correlation between Fas-positive indices and TUNEL indices in melanoma tissues. Moreover, TUNEL-, Fas-, and FasL-positive indices of melanoma cells from patients with Stage 3 melanomas were significantly lower than those with Stage 2 melanomas. The PCNA index of Stage 1 melanoma was significantly lower than that of the other stages, although the difference of PCNA index was insignificant among Stages 2 to 4. Among Stages 1 to 4, there was no difference in the PCNA, TUNEL-, and Fas-positive indices of lymphocytes, although the FasL-positive index of lymphocytes from Stage 3 melanomas was significantly lower than in that from Stage 2. These data reveal that melanoma cells and infiltrating lymphocytes have the potential to induce their own apoptosis regulated by Fas and FasL in an autocrine and/or paracrine fashion and that the decline of Fas-mediated apoptosis of melanoma cells, rather than the apoptosis of infiltrating lymphocytes, may affect the prognosis of melanoma patients, possibly through the

  13. Osteosarcoma of the posterior maxilla

    PubMed Central

    Prabhusankar, K.; Karande, Amol; Jerry, Jeethu J.; Rishal, Yousef

    2016-01-01

    Osteosarcoma is a very uncommon tumor of the maxillofacial region. Due to the occurrence of the tumor at a young age and its aggressive nature, radical surgery forms the only modality of treatment. A combination of radiotherapy and postoperative chemotherapy has been used for the management of this tumor. A case report of osteosarcoma of the posterior maxilla in an adolescent with a 1-year disease-free follow-up is presented in this report. PMID:27652252

  14. Osteosarcoma of the posterior maxilla.

    PubMed

    Prabhusankar, K; Karande, Amol; Jerry, Jeethu J; Rishal, Yousef

    2016-08-01

    Osteosarcoma is a very uncommon tumor of the maxillofacial region. Due to the occurrence of the tumor at a young age and its aggressive nature, radical surgery forms the only modality of treatment. A combination of radiotherapy and postoperative chemotherapy has been used for the management of this tumor. A case report of osteosarcoma of the posterior maxilla in an adolescent with a 1-year disease-free follow-up is presented in this report. PMID:27652252

  15. Osteosarcoma of the posterior maxilla

    PubMed Central

    Prabhusankar, K.; Karande, Amol; Jerry, Jeethu J.; Rishal, Yousef

    2016-01-01

    Osteosarcoma is a very uncommon tumor of the maxillofacial region. Due to the occurrence of the tumor at a young age and its aggressive nature, radical surgery forms the only modality of treatment. A combination of radiotherapy and postoperative chemotherapy has been used for the management of this tumor. A case report of osteosarcoma of the posterior maxilla in an adolescent with a 1-year disease-free follow-up is presented in this report.

  16. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation.

    PubMed

    Kaufman, Charles K; Mosimann, Christian; Fan, Zi Peng; Yang, Song; Thomas, Andrew J; Ablain, Julien; Tan, Justin L; Fogley, Rachel D; van Rooijen, Ellen; Hagedorn, Elliott J; Ciarlo, Christie; White, Richard M; Matos, Dominick A; Puller, Ann-Christin; Santoriello, Cristina; Liao, Eric C; Young, Richard A; Zon, Leonard I

    2016-01-29

    The "cancerized field" concept posits that cancer-prone cells in a given tissue share an oncogenic mutation, but only discreet clones within the field initiate tumors. Most benign nevi carry oncogenic BRAF(V600E) mutations but rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCPs) and specifically reexpressed in melanoma. Live imaging of transgenic zebrafish crestin reporters shows that within a cancerized field (BRAF(V600E)-mutant; p53-deficient), a single melanocyte reactivates the NCP state, revealing a fate change at melanoma initiation in this model. NCP transcription factors, including sox10, regulate crestin expression. Forced sox10 overexpression in melanocytes accelerated melanoma formation, which is consistent with activation of NCP genes and super-enhancers leading to melanoma. Our work highlights NCP state reemergence as a key event in melanoma initiation.

  17. Wavelengths effective in induction of malignant melanoma

    SciTech Connect

    Setlow, R.B.; Grist, E.; Thompson, K.; Woodhead, A.D. )

    1993-07-15

    It is generally agreed that sunlight exposure is one of the etiologic agents in malignant melanoma of fair-skinned individuals. However, the wavelengths responsible for tumorigenesis are not known, although DNA is assumed to be the target because individuals defective in the repair of UV damage to DNA are several thousandfold more prone to the disease than the average population. Heavily pigmented back-cross hybrids of the genus Xiphophorus (platyfish and swordtails) are very sensitive to melanoma induction by single exposures to UV. The authors irradiated groups of five 6-day-old fish with narrow wavelength bands at 302, 313, 365, 405, and 436 nm and score the irradiated animals for melanomas 4 months later. They used several exposures at each wavelength to obtain estimates of the sensitivity for melanoma induction as a function of exposure and wavelength. The action spectrum (sensitivity per incident photon as a function of wavelength) for melanoma induction shows appreciable sensitivity at 365, 405, and probably 436 nm, suggesting that wavelengths not absorbed directly in DNA are effective in induction. They interpret the results as indicating that light energy absorbed in melanin is effective in inducing melanomas in this animal model and that, in natural sunlight, 90-95% of melanoma induction may be attributed to wavelengths >320 nm-the UV-A and visible spectral regions. 25 refs., 4 figs., 1 tab.

  18. 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

  19. 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

  20. Wavelengths Effective in Induction of Malignant Melanoma

    NASA Astrophysics Data System (ADS)

    Setlow, Richard B.; Grist, Eleanor; Thompson, Keith; Woodhead, Avril D.

    1993-07-01

    It is generally agreed that sunlight exposure is one of the etiologic agents in malignant melanoma of fair-skinned individuals. However, the wavelengths responsible for tumorigenesis are not known, although DNA is assumed to be the target because individuals defective in the repair of UV damage to DNA are several thousandfold more prone to the disease than the average population. Heavily pigmented backcross hybrids of the genus Xiphophorus (platyfish and swordtails) are very sensitive to melanoma induction by single exposures to UV. We irradiated groups of five 6-day-old fish with narrow wavelength bands at 302, 313, 365, 405, and 436 nm and scored the irradiated animals for melanomas 4 months later. We used several exposures at each wavelength to obtain estimates of the sensitivity for melanoma induction as a function of exposure and wavelength. The action spectrum (sensitivity per incident photon as a function of wavelength) for melanoma induction shows appreciable sensitivity at 365, 405, and probably 436 nm, suggesting that wavelengths not absorbed directly in DNA are effective in induction. We interpret the results as indicating that light energy absorbed in melanin is effective in inducing melanomas in this animal model and that, in natural sunlight, 90-95% of melanoma induction may be attributed to wavelengths > 320 nm-the UV-A and visible spectral regions.

  1. 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

  2. Whole Body Melanoma Transcriptome Response in Medaka

    PubMed Central

    Schartl, Manfred; Shen, Yingjia; Maurus, Katja; Walter, Ron; Tomlinson, Chad; Wilson, Richard K.; Postlethwait, John; Warren, Wesley C.

    2015-01-01

    The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model. PMID

  3. Whole Body Melanoma Transcriptome Response in Medaka.

    PubMed

    Schartl, Manfred; Shen, Yingjia; Maurus, Katja; Walter, Ron; Tomlinson, Chad; Wilson, Richard K; Postlethwait, John; Warren, Wesley C

    2015-01-01

    The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model. PMID

  4. Malignant melanoma--a genetic overview.

    PubMed

    Bloethner, S; Scherer, D; Drechsel, M; Hemminki, K; Kumar, R

    2009-11-01

    Malignant melanoma, a potentially lethal skin neoplasm, is characterized by a complex and heterogeneous etiology. Both incidences and deaths associated with melanoma are increasing in Caucasian populations. While exposure to ultraviolet radiation through sun-exposure is the major risk factor; the host factors including skin type and number of moles are critical in predisposition. The CDKN2A is a high penetrance melanoma susceptibility gene as carriers of the mutations are predisposed to the disease within familial settings. The gene is also somatically altered to varying degrees in sporadic melanoma. The CDK4 gene due to occurrence of activation mutations in a few families worldwide represents another melanoma susceptibility locus. The variants within the melanocortin receptor 1 (MC1R) gene, which encodes a melanocyte specific surface receptor with a key role in pigmentation, are associated with high risk phenotypes and increased risk of melanoma. Melanoma tumors are characterized by activation of the RAS-RAF-MEK-ERK pathway through either autocrine growth factor stimulation or oncogenic mutations in the B-RAF or N-RAS genes. Somatic mutations in the B-RAF gene are complemented by those in the N-RAS gene and represent the major genetic alterations. The mutations in the B-RAF gene in melanoma due to occurrence in melanocytic nevi represent early events that additionally require loss of cell cycle inhibitors like CDKN2A for melanoma progression and development. The sequence of events points to the cooperative collaboration between different genetic pathways in tumor development that can be and are being used as targets for developing specific therapeutic agents. PMID:20096196

  5. Primary Retroperitoneal Melanoma Presented in a Rare Extracutaneous Site for Malignant Melanoma

    PubMed Central

    Alsharedi, Mohamed; Zgheib, Nadim Bou; Khelfa, Yousef; Raufi, Ali; Elmsherghi, Nabiha; Lebowicz, Yehuda

    2016-01-01

    Malignant melanoma, as the name implies, is a malignant tumor of melanocytes, found in the skin, eyes, meningeal lining and the mucosal epithelium of the aero-digestive and genitourinary tracts. Malignant melanoma is typically skin malignancy, which rarely presents at extracutaneous site. Here we present a rare case of primary retroperitoneal melanoma and review the findings in comparison with other cases described in literature. PMID:27746882

  6. [Treatment of BRAF-mutated metastatic melanoma].

    PubMed

    Boyles, Tessa Bystrup; Svane, Inge Marie; Bastholt, Lars; Schmidt, Henrik

    2016-08-29

    Melanoma is an aggressive form of skin cancer which is the cause of a great number of skin cancer-related deaths worldwide and about 300 deaths in Denmark. After several years of failure of treatment of metastatic melanoma, the development of BRAF- and later MEK inhibitors was considered revolutionary. Treatment with BRAF inhibitors alone and especially in combination with a MEK inhibitor improves outcome for patients with BRAF V600-mutated metastatic melanoma. However, even when treated with the combination of the inhibitors, many patients develop acquired resistance within a year. PMID:27592869

  7. Axillary Silicone Granulomas in Patients With Melanoma.

    PubMed

    Fernández Canedo, M I; Blázquez Sánchez, N; Valdés Solís, P; de Troya Martín, M

    2016-05-01

    Subcutaneous lesions may be detected during follow-up of patients with melanoma. The main entities that should be contemplated in the differential diagnosis in such cases are in-transit and regional lymph node metastases. We describe 2 cases of women with breast implants who developed palpable subcutaneous lesions in the axillary region during follow-up of melanoma. In both cases, the ultrasound study showed diffuse hyperechoic signals forming the characteristic snowstorm sign in the subcutaneous tissue. Ultrasound proved to be a key diagnostic tool for ruling out melanoma-related disease, such as in-transit metastases and regional lymph node metastases. PMID:26626499

  8. Myeloid Cells' Evasion of Melanoma Immunity

    PubMed Central

    Wang, Jun; Chen, Lieping

    2015-01-01

    An immune-suppressive role of myeloid-derived suppressor cells (MDSCs) in melanoma has long been speculated, whereas molecular mechanisms underlying this role are not well understood. Here, Chung and colleagues show that dendritic cell-associated, heparan sulfate proteoglycans-dependent integrin ligand (DC-HIL), a cell surface immune-modulatory molecule, is highly expressed on tumor-associated MDSCs. Genetic ablation or antibody blockade of DC-HIL delays the growth of transplantable B16 melanoma in syngeneic mice, which is accompanied by enhanced antitumor T-cell activities. These findings support a role for DC-HIL in immune evasion within the melanoma microenvironment. PMID:25318429

  9. Axillary Silicone Granulomas in Patients With Melanoma.

    PubMed

    Fernández Canedo, M I; Blázquez Sánchez, N; Valdés Solís, P; de Troya Martín, M

    2016-05-01

    Subcutaneous lesions may be detected during follow-up of patients with melanoma. The main entities that should be contemplated in the differential diagnosis in such cases are in-transit and regional lymph node metastases. We describe 2 cases of women with breast implants who developed palpable subcutaneous lesions in the axillary region during follow-up of melanoma. In both cases, the ultrasound study showed diffuse hyperechoic signals forming the characteristic snowstorm sign in the subcutaneous tissue. Ultrasound proved to be a key diagnostic tool for ruling out melanoma-related disease, such as in-transit metastases and regional lymph node metastases.

  10. 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.

  11. 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

  12. Intraepidermal epidermotropic metastatic melanoma: a clinical and histopathological mimicker of melanoma in situ occurring in multiplicity.

    PubMed

    Lestre, Sara; João, Alexandre; Ponte, Pedro; Peixoto, Ana; Vieira, Joana; Teixeira, Manuel R; Fidalgo, Ana

    2011-06-01

    The distinction between primary melanoma and melanoma metastatic to the skin has major prognostic implications. We report a case of a 67-year-old male with a diagnosis of a superficial spreading melanoma (stage IB) rendered 6 years earlier who presented clinically with an atypical nevus on his left thigh. Histopathological examination showed an intraepidermal melanocytic proliferation that was interpreted as melanoma in situ. Subsequently, 45 additional pigmented macules appeared in crops over a 9-month period. Clinically and dermoscopically, these lesions were extremely polymorphic. Histopathological findings were compatible with melanoma in situ, as each lesion consisted of a wholly intraepidermal proliferation of markedly atypical melanocytes arranged singly and in nests. A complete gastrointestinal study showed multiple pigmented metastatic lesions throughout the stomach and small bowel, which supported a diagnosis of metastatic melanoma with gastrointestinal and epidermotropic skin involvement. Monosomy of chromosome 9 and a BRAF V600E mutation were detected in the primary tumor sample and in macro-dissected secondary lesions. No CDKN2A or CDK4 germline mutations were found. Intraepidermal epidermotropic metastases of melanoma have been rarely described in literature. In this case, histopathology alone was insufficient to distinguish metastatic melanoma from multiple in situ melanomas. The recognition of epidermotropic metastases should be based on the correlation between clinical, dermoscopic, histopathological and molecular findings. PMID:21352266

  13. Combined Posterior and Anterior Ankle Arthroscopy

    PubMed Central

    Scholten, Peter E.; van Dijk, C. Niek

    2012-01-01

    Treatment of combined anterior and posterior ankle pathology usually consists of either combined anterior and posterior arthrotomies or anterior ankle arthroscopy with an additional posterolateral portal. The first technique bears the risk of complications associated with the extensive exposure, the latter technique provides limited access to the posterior ankle joint. A case is described of combined anterior and posterior arthroscopy, with the patient lying prone and then turned supine, addressing both anterior and posterior ankle pathologies in one tempo. This minimally invasive combined approach allows quick recovery and early return to work and sports activities. PMID:23227391

  14. Melanoma cell galectin-1 ligands functionally correlate with malignant potential*

    PubMed Central

    Yazawa, Erika M.; Geddes-Sweeney, Jenna E.; Cedeno-Laurent, Filiberto; Walley, Kempland C.; Barthel, Steven R.; Opperman, Matthew J.; Liang, Jennifer; Lin, Jennifer Y.; Schatton, Tobias; Laga, Alvaro C.; Mihm, Martin C.; Qureshi, Abrar A.; Widlund, Hans R.; Murphy, George F.; Dimitroff, Charles J.

    2015-01-01

    Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening anti-tumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely-dysplastic nevi as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAMKD) or ST6GalNAc2-overexpressing (ST6O/E) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAMKD or ST6O/E melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1 – melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy. PMID:25756799

  15. How Is Melanoma Skin Cancer Diagnosed?

    MedlinePlus

    ... medicine doctor injects a small amount of a radioactive substance into the area of the melanoma. After ... one or more sentinel lymph nodes. Once the radioactive area has been marked, the patient is taken ...

  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. Isolated pancreatic metastasis from melanoma. Case report.

    PubMed

    Portale, T R; Di Benedetto, V; Mosca, F; Trovato, M A; Scuderi, M G; Puleo, S

    2011-03-01

    Pancreas is frequently site of isolated metastasis, approximately in the 40% of cases in patient with previous history of malignant neoplasia, more frequently from renal cell carcinoma. The melanoma metastasis can also interest the pancreas in case of disseminated disease (50% of the cases); more rarely the pancreas is site of isolated metastases from melanoma. The treatment of the pancreatic metastases from melanoma is controversial: the therapeutic choices are few and the role of surgery is not well defined. If the metastasis are confined to the pancreas, the surgical treatment can be useful for better long time survival. We report a rare case of melanoma with pancreatic isolated metastasi in a patient with a previous melanotic metastasis to the inguinal lymph nodes without evidence of primitive tumor.

  19. Pembrolizumab for Ipilimumab-Resistant Melanoma

    Cancer.gov

    KEYNOTE-002 was designed to test the safety and efficacy of two doses of pembrolizumab compared with chemotherapy in patients with ipilimumab-resistant melanoma; interim results show that pembrolizumab improves progression-free survival for these patients

  20. The state of melanoma: challenges and opportunities.

    PubMed

    Merlino, Glenn; Herlyn, Meenhard; Fisher, David E; Bastian, Boris C; Flaherty, Keith T; Davies, Michael A; Wargo, Jennifer A; Curiel-Lewandrowski, Clara; Weber, Michael J; Leachman, Sancy A; Soengas, Maria S; McMahon, Martin; Harbour, J William; Swetter, Susan M; Aplin, Andrew E; Atkins, Michael B; Bosenberg, Marcus W; Dummer, Reinhard; Gershenwald, Jeffrey E; Halpern, Allan C; Herlyn, Dorothee; Karakousis, Giorgos C; Kirkwood, John M; Krauthammer, Michael; Lo, Roger S; Long, Georgina V; McArthur, Grant; Ribas, Antoni; Schuchter, Lynn; Sosman, Jeffrey A; Smalley, Keiran S; Steeg, Patricia; Thomas, Nancy E; Tsao, Hensin; Tueting, Thomas; Weeraratna, Ashani; Xu, George; Lomax, Randy; Martin, Alison; Silverstein, Steve; Turnham, Tim; Ronai, Ze'ev A

    2016-07-01

    The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long-term needs of the melanoma field, from basic research to clinical management, are presented in the following report.

  1. 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.

  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. 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.

  5. 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

  6. Thigmotropism of malignant melanoma cells.

    PubMed

    Quatresooz, Pascale; Piérard-Franchimont, Claudine; Noël, Fanchon; Piérard, Gérald E

    2012-01-01

    During malignant melanoma (MM) progression including incipient metastasis, neoplastic cells follow some specific migration paths inside the skin. In particular, they progress along the dermoepidermal basement membrane, the hair follicles, the sweat gland apparatus, nerves, and the near perivascular space. These features evoke the thigmotropism phenomenon defined as a contact-sensing growth of cells. This process is likely connected to modulation in cell tensegrity (control of the cell shape). These specifically located paucicellular aggregates of MM cells do not appear to be involved in the tumorigenic growth phase, but rather they participate in the so-called "accretive" growth model. These MM cell collections are often part of the primary neoplasm, but they may, however, correspond to MM micrometastases and predict further local overt metastasis spread. PMID:22203839

  7. Imaging of ocular melanoma metastasis.

    PubMed

    Balasubramanya, Rashmi; Selvarajan, Santosh Kumar; Cox, Mougnyan; Joshi, Ganesh; Deshmukh, Sandeep; Mitchell, Donald G; O'Kane, Patrick

    2016-09-01

    Ocular melanoma is the most common adult primary intraocular tumour. Although <1% of patients have metastatic disease at the time of initial diagnosis, most will develop metastasis at varying lengths of time. Metastasis surveillance is therefore critical in the follow-up of patients with ocular melanoma. Liver is the most common site of metastasis and prognosis is based on the treatment of liver metastasis. Hence, imaging of liver metastasis is vital. MRI is the most specific modality for imaging liver metastasis and is at least as sensitive as CT. Extrahepatic metastasis such as retroperitoneal nodules and bone metastases are also better evaluated on MRI. Gadolinium-based contrast agents are extremely helpful for detecting liver lesions. In particular, newer hepatobiliary contrast agents which offer an additional hepatobiliary phase of excretion help in the detection of even tiny liver metastases. Diffusion-weighted imaging is helpful when an i.v. contrast cannot be administered. Treated lesions are also better evaluated with MRI. CT is useful for evaluating lung nodules, large liver metastasis or in patients in whom MRI is medically contraindicated. The disadvantage lies in its inability to detect small liver metastasis and the radiation dose involved. The lesions treated with iodized oil as part of chemoembolization procedures can be followed on CT. Ultrasound can be used only for detecting hepatic metastases. However, it is heavily operator dependent, technically challenging and time consuming especially in patients who are large. Extrahepatic metastasis cannot be seen on ultrasound. Its utility is primarily for the biopsy of liver lesions. Positron emission tomography (PET)-CT can detect lung nodules and large liver lesions but is insensitive to small liver lesions. Moreover, the high radiation dose is a major disadvantage. PMID:27168029

  8. Melanoma immunotherapy: past, present, and future.

    PubMed

    Saleh, Farid; Renno, Waleed; Klepacek, Ivo; Ibrahim, Ghada; Asfar, Sami; Dashti, Hussein; Romero, Pedro; Dashti, Ali; Behbehani, Abdullah

    2005-01-01

    The incidence of cancer and its related morbidity and mortality remain on the increase in both developing and developed countries. Cancer remains a huge burden on the health and social welfare sectors worldwide and its prevention and cure remain two golden goals that science strives to achieve. Among the treatment options for cancer that have emerged in the past 100 years, cancer vaccine immunotherapy seems to present a promising and relatively safer approach as compared to chemotherapy and radiotherapy. The identification of different tumour antigens in the last fifteen years using a variety of techniques, together with the molecular cloning of cytotoxic T lymphocytes (CTLs)- and tumour infiltrating lymphocytes (TILs)-defined tumour antigens allowed more refining of the cancer vaccines that are currently used in different clinical trials. In a proportion of treated patients, some of these vaccines have resulted in partial or complete tumour regression, while they have increased the disease-free survival rate in others. These outcomes are more evident now in patients suffering from melanoma. This review provides an update on melanoma vaccine immunotherapy. Different cancer antigens are reviewed with a detailed description of the melanoma antigens discovered so far. The review also summarises clinical trials and individual clinical cases in which some of the old and current methods to vaccinate against or treat melanoma were used. These include vaccines made of autologous or allogenic melanoma tumour cells, melanoma peptides, recombinant bacterial or viral vectors, or dendritic cells. PMID:16248801

  9. Phytochemicals for the Management of Melanoma

    PubMed Central

    Pal, Harish Chandra; Hunt, Katherine Marchiony; Diamond, Ariana; Elmets, Craig A.; Afaq, Farrukh

    2016-01-01

    Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma. PMID:26864554

  10. 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

  11. 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

  12. Phytochemicals for the Management of Melanoma.

    PubMed

    Pal, Harish Chandra; Hunt, Katherine Marchiony; Diamond, Ariana; Elmets, Craig A; Afaq, Farrukh

    2016-01-01

    Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma. PMID:26864554

  13. 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

  14. 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.

  15. 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

  16. Longevity of Posterior Composite Restorations

    PubMed Central

    Opdam, N.J.M.; van de Sande, F.H.; Bronkhorst, E.; Cenci, M.S.; Bottenberg, P.; Pallesen, U.; Gaengler, P.; Lindberg, A.; Huysmans, M.C.D.N.J.M.; van Dijken, J.W.

    2014-01-01

    The aim of this meta-analysis, based on individual participant data from several studies, was to investigate the influence of patient-, materials-, and tooth-related variables on the survival of posterior resin composite restorations. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a search resulting in 12 longitudinal studies of direct posterior resin composite restorations with at least 5 years’ follow-up. Original datasets were still available, including placement/failure/censoring of restorations, restored surfaces, materials used, reasons for clinical failure, and caries-risk status. A database including all restorations was constructed, and a multivariate Cox regression method was used to analyze variables of interest [patient (age; gender; caries-risk status), jaw (upper; lower), number of restored surfaces, resin composite and adhesive materials, and use of glass-ionomer cement as base/liner (present or absent)]. The hazard ratios with respective 95% confidence intervals were determined, and annual failure rates were calculated for subgroups. Of all restorations, 2,816 (2,585 Class II and 231 Class I) were included in the analysis, of which 569 failed during the observation period. Main reasons for failure were caries and fracture. The regression analyses showed a significantly higher risk of failure for restorations in high-caries-risk individuals and those with a higher number of restored surfaces. PMID:25048250

  17. Huge interparietal posterior fontanel meningohydroencephalocele

    PubMed Central

    Dos Santos, Manuel Filipe Dias; de Santa Barbara, Rita de Cassia

    2015-01-01

    Congenital encephalocele is a neural tube defect characterized by a sac-like protrusion of the brain, meninges, and other intracranial structures through the skull, which is caused by an embryonic development abnormality. The most common location is at the occipital bone, and its incidence varies according to different world regions. We report a case of an 1-month and 7-day-old male child with a huge interparietal-posterior fontanel meningohydroencephalocele, a rare occurrence. Physical examination and volumetric computed tomography were diagnostic. The encephalocele was surgically resected. Intradural and extradural approaches were performed; the bone defect was not primarily closed. Two days after surgery, the patient developed hydrocephaly requiring ventriculoperitoneal shunting. The surgical treatment of the meningohydroencephalocele of the interparietal-posterior fontanel may be accompanied by technical challenges and followed by complications due to the presence of large blood vessels under the overlying skin. In these cases, huge sacs herniate through large bone defects including meninges, brain, and blood vessels. The latter present communication with the superior sagittal sinus and ventricular system. A favorable surgical outcome generally follows an accurate strategy taking into account individual features of the lesion. PMID:26484324

  18. Posterior cerebral artery territory infarctions.

    PubMed

    Cereda, Carlo; Carrera, Emmanuel

    2012-01-01

    Infarctions in the territory of the posterior cerebral artery (PCA) occur in about 5-10% of all ischemic strokes. The PCA can be divided into 'deep' (P1 and P2 segments) and 'superficial' (P3 and P4) segments. Occlusion of paramedian perforating arteries arising from P1 causes rostral midbrain infarction with or without thalamic lesion. The classical clinical triad after thalamomesencephalic infarcts is hypersomnolence, cognitive deficits and vertical oculomotor paresis. Two main arterial groups arise from P2: infarction in the territory of the thalamogeniculate arteries causes severe contralateral hypesthesia and ataxia, whereas infarction in the territory of the posterior choroidal arteries results in sectoranopia with involvement of the lateral geniculate body. After superficial PCA infarcts, visual field defects and somatosensory deficits are the most frequent signs. Additionally, disorders of reading may be seen after unilateral left infarction and disorientation for place and visual neglect after right lesion. After bilateral PCA infarcts, amnesia, cortical blindness (the patient cannot see but pretend he can) may occur. Acute thrombolysis is as useful after PCA infarctions as after anterior circulation strokes. Mortality after PCA strokes is low, but long-term behavioral and cognitive deficits are underestimated.

  19. 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

  20. Melanoma

    MedlinePlus

    ... are essential for reducing exposure to harmful ultraviolet (UV) light. These protective measures are especially important in children because 80% of our lifetime exposure to UV light occurs before age 18. Once a month, you ...

  1. Melanoma

    MedlinePlus

    ... Fitness Diseases & Conditions Infections Q&A School & Jobs Drugs & Alcohol Staying Safe Recipes En Español Making a Change – Your Personal Plan Hot Topics Meningitis Choosing Your Mood Prescription Drug Abuse Healthy School Lunch Planner How Can I ...

  2. Melanoma

    MedlinePlus

    ... following tips can also help: Apply high-quality sunscreen with a sun protection factor (SPF) rating of ... a short time. Apply a large amount of sunscreen on all exposed areas, including ears and feet. ...

  3. Melanoma

    MedlinePlus

    ... edges are ragged, blurred or irregular Color - the color is uneven and may include shades of black, brown and tan Diameter - there is a change in size, usually an increase Evolving - the mole has changed over the past ...

  4. Cloning and in vitro expression of a melanoma-associated antigen immunogenic in patients with melanoma.

    PubMed

    Hayashibe, K; Mishima, Y; Ferrone, S

    1991-08-01

    The purpose of this study was to identify human melanoma-associated Ag (MAA) that are immunogenic in patients, because these molecules may be useful immunogens to implement active specific immunotherapy. To this end, an expression cDNA library constructed from the human melanoma cell line A375 was screened with sera from patients with melanoma. A 1029-bp cDNA (designated D-1) was isolated. Its nucleotide sequence showed no significant homology with viral and mammalian sequences stored in GE-NETYX. cDNA D-1 hybridized to a 2.0-kb mRNA species from human melanoma, neuroblastoma, erythroleukemia, B lymphoid, and T lymphoid cell lines but not from a renal carcinoma cell line, PBL, and cultured skin fibroblasts. The D-1 clone produced a fusion protein that displayed a significantly higher reactivity with sera from patients with melanoma than from healthy controls. Furthermore, D-1 fusion protein induced in mice antibodies that immunoprecipitated a 50-kDa component from cultured human melanoma cells. The structural properties of D-1 MAA are different from those of previously described MAA. These results suggest that the approach we have applied may be useful to identify novel MAA expressed by melanoma cells. Furthermore, the immunogenicity of recombinant D-1 protein suggests that it may be a valuable immunogen to implement active specific immunotherapy in patients with melanoma, if additional experiments show that it has the appropriate tissue distribution.

  5. High LIFr expression stimulates melanoma cell migration and is associated with unfavorable prognosis in melanoma.

    PubMed

    Guo, Hongwei; Cheng, Yabin; Martinka, Magdalena; McElwee, Kevin

    2015-09-22

    Increased or decreased expression of LIF receptor (LIFr) has been reported in several human cancers, including skin cancer, but its role in melanoma is unknown. In this study, we investigated the expression pattern of LIFr in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 441 melanomas and 96 nevi, we found that no normal nevi showed high LIFr expression. LIFr staining was significantly increased in primary melanoma compared to dysplastic nevi (P = 0.0003) and further increased in metastatic melanoma (P = 0.0000). Kaplan-Meier survival curve and univariate Cox regression analyses showed that increased expression of LIFr was correlated with poorer 5-year patient survival (overall survival, P = 0.0000; disease-specific survival, P = 0.0000). Multivariate Cox regression analyses indicated that increased LIFr expression was an independent prognostic marker for primary melanoma (P = 0.036). LIFr knockdown inhibited melanoma cell migration in wound healing assays and reduced stress fiber formation. LIFr knockdown correlated with STAT3 suppression, but not YAP, suggesting that LIFr activation might stimulate melanoma cell migration through the STAT3 pathway. Our data indicate that strong LIFr expression identifies potentially highly malignant melanocytic lesions at an early stage and LIFr may be a potential target for the development of early intervention therapeutics. PMID:26329521

  6. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

    PubMed

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

    2016-03-01

    Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

  7. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

    PubMed

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

    2016-03-01

    Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis. PMID:26892650

  8. 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.

  9. Standard melanoma-associated markers do not identify the MM127 metastatic melanoma cell line

    PubMed Central

    Haridas, Parvathi; McGovern, Jacqui A.; Kashyap, Abhishek S.; McElwain, D. L. Sean; Simpson, Matthew J.

    2016-01-01

    Reliable identification of different melanoma cell lines is important for many aspects of melanoma research. Common markers used to identify melanoma cell lines include: S100; HMB-45; and Melan-A. We explore the expression of these three markers in four different melanoma cell lines: WM35; WM793; SK-MEL-28; and MM127. The expression of these markers is examined at both the mRNA and protein level. Our results show that the metastatic cell line, MM127, cannot be detected using any of the commonly used melanoma-associated markers. This implies that it would be very difficult to identify this particular cell line in a heterogeneous sample, and as a result this cell line should be used with care. PMID:27087056

  10. 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

  11. Gene Network Rewiring to Study Melanoma Stage Progression and Elements Essential for Driving Melanoma

    PubMed Central

    Kaushik, Abhinav; Bhatia, Yashuma; Ali, Shakir; Gupta, Dinesh

    2015-01-01

    Metastatic melanoma patients have a poor prognosis, mainly attributable to the underlying heterogeneity in melanoma driver genes and altered gene expression profiles. These characteristics of melanoma also make the development of drugs and identification of novel drug targets for metastatic melanoma a daunting task. Systems biology offers an alternative approach to re-explore the genes or gene sets that display dysregulated behaviour without being differentially expressed. In this study, we have performed systems biology studies to enhance our knowledge about the conserved property of disease genes or gene sets among mutually exclusive datasets representing melanoma progression. We meta-analysed 642 microarray samples to generate melanoma reconstructed networks representing four different stages of melanoma progression to extract genes with altered molecular circuitry wiring as compared to a normal cellular state. Intriguingly, a majority of the melanoma network-rewired genes are not differentially expressed and the disease genes involved in melanoma progression consistently modulate its activity by rewiring network connections. We found that the shortlisted disease genes in the study show strong and abnormal network connectivity, which enhances with the disease progression. Moreover, the deviated network properties of the disease gene sets allow ranking/prioritization of different enriched, dysregulated and conserved pathway terms in metastatic melanoma, in agreement with previous findings. Our analysis also reveals presence of distinct network hubs in different stages of metastasizing tumor for the same set of pathways in the statistically conserved gene sets. The study results are also presented as a freely available database at http://bioinfo.icgeb.res.in/m3db/. The web-based database resource consists of results from the analysis presented here, integrated with cytoscape web and user-friendly tools for visualization, retrieval and further analysis. PMID

  12. Endoscopic management of posterior epistaxis: a review.

    PubMed

    McClurg, S W; Carrau, R

    2014-02-01

    The paradigm for the management of epistaxis, specifically posterior epistaxis, has undergone significant changes in the recent past. Recent prospective and retrospective data has shown that the endonasal surgical management of posterior epistaxis is superior to posterior nasal packing and angiography/embolization with regards to various factors including pain, cost-effectiveness, risk and overall control of bleeding. Endonasal endoscopic surgical techniques for posterior epistaxis include direct cauterization and transnasal endoscopic sphenopalatine/ posterior nasal artery ligation or cauterization with or without control of the anterior ethmoidal artery. Despite the evidence provided by the current literature, a universal treatment protocol has not yet been established. This review article provides an up-to-date assessment of the available literature, and presents a structured paradigm for the management of posterior epistaxis.

  13. Placement technique for direct posterior composite restorations.

    PubMed

    Javaheri, D S

    2001-04-01

    Due to improved materials, instrumentation, and placement techniques, composite resins have overcome the traditional complications associated with wear resistance, microleakage, sensitivity, and tight anatomical contacts. Composite resins have been utilized with increased frequency for direct posterior restorations capable of satisfying the growing aesthetic expectations of contemporary dental patients. When properly placed, posterior composites can provide successful and predictable restorations. This article presents clinical considerations for the aesthetic conservation of posterior restorations with composite resin materials.

  14. Spontaneous melanoma formation in nonhybrid Xiphophorus.

    PubMed

    Schartl, A; Malitschek, B; Kazianis, S; Borowsky, R; Schartl, M

    1995-01-01

    Melanoma in hybrids of Xiphophorus is due to the unrestricted activity of a cellular oncogene locus, Tu, encoding the growth factor receptor gene Xmrk. In nonhybrid parental fish, Tu is controlled by a tumor suppressor gene. Thus, its restricted activity leads there only to a nonmalignant, species- and population-specific macromelanophore spot pattern. Prompted by enigmatic reports on nonhybrid Xiphophorus with pigmentation abnormalities resembling melanoma, we have studied pigmentation in descendants of wild-caught fish and purebred laboratory stocks derived from wild populations. Whereas most stocks exhibiting macromelanophore patterns never developed pigmentation abnormalities, an exceptional situation for some nonhybrids was found. In X. variatus carrying the macromelanophore pattern "punctatus-2" and in X. cortezi with "spotted caudal," expressivity of the pigmentation gene ranges from a few black spots to extreme melanosis and eventually to malignant melanoma. In X. maculatus with the mutant pigmentation gene striped" carrying in addition the micromelanophore pattern "anal fin black" or "lower comet," testosterone-dependent melanoma develop originating from the corresponding micromelanophore pattern. The tumors are highly malignant and express a melanoma-associated antigen. Overexpression of the Xmrk oncogene appears as the underlying molecular mechanism for tumor induction. These findings clearly demonstrate that tumors can also develop in purebred wild-type fish. The classical model for formation of hereditary melanoma in Xiphophorus hybrids does not explain the development of melanoma in the absence of hybridization. However, their existence gives additional support to the reasoning that the Xmrk oncogene associated with the macromelanophore locus is potentially injurious. PMID:7805027

  15. 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.

  16. 3D MRI-based tumor delineation of ocular melanoma and its comparison with conventional techniques.

    PubMed

    Daftari, Inder k; Aghaian, Elsa; O'Brien, Joan M; Dillon, William; Phillips, Theodore L

    2005-11-01

    . with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.

  17. Solar radiation and malignant melanoma of the skin.

    PubMed

    Houghton, A N; Viola, M V

    1981-10-01

    Several observations suggest that a majority of cases of malignant melanoma of the skin are linked to sun exposure. Evidence includes higher occurrence of melanoma on anatomic areas heavily exposed during recreation, development of melanoma more frequently in lightly pigmented persons, and correlation of melanoma incidence and mortality with proximity to the equator. The role of the sun exposure in the pathogenesis of melanoma remains unclear, however. Many cases of melanoma may be related to heavy doses of solar radiation received during recreation. Chronic sun exposure is not so clearly linked to the development of melanoma (except in the uncommon lentigo maligna variety). Sunspot cycles have been associated with changes in melanoma incidence; an excess of melanoma cases has been observed every 9 to 12 years after peak sunspot activity. These excess cases may be caused by more intense exposure to solar ultraviolet radiation during sunspot maxima, perhaps related to changes in the stratospheric ozone layer. These epidemiologic and clinical clues suggest that many cases of melanoma are related to sun exposure triggering the appearance of clinically evident melanoma. In this regard, solar radiation behaves as a cocarcinogen or promoter, rather than a dose-dependent carcinogen. These observations also suggest that other factors may be involved in the pathogenesis of melanoma, e.g., nevi, heredity, or exposure to chemical carcinogens.

  18. Indium-111 labeled anti-melanoma monoclonal antibodies

    DOEpatents

    Srivastava, S.C.; Fawwaz, R.A.; Ferrone, S.

    1984-04-30

    A monoclonal antibody to a high molecular weight melanoma-associated antigen was chelated and radiolabeled with indium-111. This material shows high affinity for melanoma and thus can be used in the detection, localization and imaging of melanoma. 1 figure.

  19. 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.

  20. Community Perceptions of Specific Skin Features of Possible Melanoma

    ERIC Educational Resources Information Center

    Baade, Peter D.; Balanda, Kevin P.; Stanton, Warren R.; Lowe, John B.; Del Mar, Chris B.

    2004-01-01

    Background: Melanoma can be curable if detected early. One component of detecting melanoma is an awareness of the important features of the disease. It is currently not clear which features the community view as indicative of melanoma. Objective: To investigate which features of the skin members of an urban community believe may indicate skin…

  1. Solar radiation and malignant melanoma of the skin

    SciTech Connect

    Houghton, A.N.; Viola, M.V.

    1981-01-01

    Several observations suggest that a majority of cases of malignant melanoma of the skin are linked to sun exposure. Evidence includes higher occurrence of melanoma on anatomic areas heavily exposed during recreation, development of melanoma more frequently in lightly pigmented persons, and correlation of melanoma incidence and mortality with proximity to the equator. The role of the sun exposure in the pathogenesis of melanoma remains unclear, however. Many cases of melanoma may be related to heavy doses of solar radiation received during recreation. Chronic sun exposure is not so clearly linked to the development of melanoma (except in the uncommon lentigo maligna variety). Sunspot cycles have been associated with changes in melanoma incidence; an excess of melanoma cases has been observed every 9 to 12 years after peak sunspot activity. These excess cases may be caused by more intense exposure to solar ultraviolet radiation during sunspot maxima, perhaps related to changes in the stratospheric ozone layer. These epidemiologic and clinical clues suggest that many cases of melanoma are related to sun exposure triggering the appearance of clinically evident melanoma. In this regard, solar radiation behaves as a cocarcinogen or promoter, rather than a dose-dependent carcinogen. These observations also suggest that other factors may be involved in the pathogenesis of melanoma, e.g., nevi, heredity, or exposure to chemical carcinogens.

  2. 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

  3. Antioxidants can increase melanoma metastasis in mice.

    PubMed

    Le Gal, Kristell; Ibrahim, Mohamed X; Wiel, Clotilde; Sayin, Volkan I; Akula, Murali K; Karlsson, Christin; Dalin, Martin G; Akyürek, Levent M; Lindahl, Per; Nilsson, Jonas; Bergo, Martin O

    2015-10-01

    Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.

  4. 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

  5. MicroRNA dysregulation in melanoma.

    PubMed

    Latchana, Nicholas; Ganju, Akaansha; Howard, J Harrison; Carson, William E

    2016-09-01

    Melanoma is the deadliest form of skin cancer. Current challenges facing the management of melanoma include accurate prediction of individuals who will respond to adjuvant therapies as well as early detection of recurrences. These and other challenges have prompted investigation into biomarkers that could be used as diagnostic, prognostic and therapeutic aids. MicroRNAs (miRs) are small 19-22 nucleotide RNA inhibitors of protein translation. Over 800 different miRs are present within cells and importantly miR expression profiles may vary across different cells types and stages of malignancy. Unique expression profiles have been described for malignant melanoma; however, this work has yet to be translated into routine clinical practice. We highlight pertinent studies involving common miRs implicated in the oncogenesis of melanoma including miR-21, miR-125b, miR-150, miR-155, miR-205, and miR-211. In particular, emphasis is placed upon differential expression across different stages of melanoma progression, prognostic implications and potential mechanistic involvement. Focused efforts on inhibition of these miRs could be the most efficient method of translating preclinical endeavors into clinically meaningful applications. PMID:27566021

  6. Circulating melanoma cells as a predictive biomarker.

    PubMed

    Karakousis, Giorgos; Yang, Ruifeng; Xu, Xiaowei

    2013-06-01

    The prognosis of patients with metastatic melanoma has improved significantly with targeted therapeutic agents and immunotherapies. Detection of early melanoma recurrence after treatment will be beneficial to switch patients who fail on one therapy to different modalities. Circulating tumor cells (CTCs) are cancer cells released by a tumor into the peripheral blood. These cells hold potential as prognostic, predictive, and pharmacodynamic biomarkers for treatment. In this issue, Khoja et al. report that melanoma CTCs can be detected using Melcam and high molecular weight melanoma-associated antibody. They found that in 101 stage IV melanoma patients, CTC numbers ranged between 0 and 36/7.5 ml blood; 26% of the patients had ≥ 2 CTCs at baseline. The CTC number (≥ 2 CTCs) at baseline was significantly prognostic for median overall survival (OS) in univariate and multivariate analysis. Patients receiving treatment where CTC numbers remained ≥ 2 CTCs during their treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, hazard ratio 0.34, 95% confidence interval 0.14-0.81, log-rank test P=0.015). The implications of this work are substantial in counseling patients about their prognosis and in helping to assess responses to systemic therapies. PMID:23673501

  7. 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.

  8. The Epidemiology, Prevention, and Detection of Melanoma

    PubMed Central

    Riker, Adam I.; Zea, Nicolas; Trinh, Tan

    2010-01-01

    We are seeing a record number of newly diagnosed skin cancers worldwide, with the incidence of melanoma increasing at a faster rate than almost all other cancers. As clinicians, we will have, by far, the greatest impact on reducing this incidence through better methods of early detection of melanoma and proven prevention methods and techniques. The medical community must enhance its efforts to increase its training of new health care personnel who are capable of diagnosing and treating this record number of patients with skin cancer. We must also try to increase the access to our limited number of dermatologists and provide novel ways of patient education such as through skin self-examinations, total body photography, and improved education for our children. By providing easier access to skin examinations, we will increase our chances of detecting melanoma in its earliest and most curable form. The dangers of indoor tanning beds and salons must be transparent to those that use them, focusing on expanding the oversight of such facilities by our local and federal governmental agencies while establishing legislation in several states to further limit their use to our youth, who are especially at high risk for developing melanoma in the future. This review will focus on the epidemiology, prevention, and detection of melanoma. PMID:21603359

  9. 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

  10. A Landscape of Driver Mutations in Melanoma

    PubMed Central

    Hodis, Eran; Watson, Ian R.; Kryukov, Gregory V.; Arold, Stefan T.; Imielinski, Marcin; Theurillat, Jean-Philippe; Nickerson, Elizabeth; Auclair, Daniel; Li, Liren; Place, Chelsea; DiCara, Daniel; Ramos, Alex H.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey; Voet, Douglas; Saksena, Gordon; Stransky, Nicolas; Onofrio, Robert C.; Winckler, Wendy; Ardlie, Kristin; Wagle, Nikhil; Wargo, Jennifer; Chong, Kelly; Morton, Donald L.; Stemke-Hale, Katherine; Chen, Guo; Noble, Michael; Meyerson, Matthew; Ladbury, John E.; Davies, Michael A.; Gershenwald, Jeffrey E.; Wagner, Stephan N.; Hoon, Dave S.B.; Schadendorf, Dirk; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Garraway, Levi A.; Chin, Lynda

    2012-01-01

    SUMMARY Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis. PMID:22817889

  11. 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

  12. Impact of melanoma genetic test reporting on perceived control over melanoma prevention.

    PubMed

    Aspinwall, Lisa G; Stump, Tammy K; Taber, Jennifer M; Kohlmann, Wendy; Leaf, Samantha L; Leachman, Sancy A

    2015-10-01

    To determine whether receiving melanoma genetic test results undermines perceived control over melanoma prevention, control-related beliefs were examined among 60 adults from melanoma-prone families receiving CDKN2A/p16 test results (27 unaffected noncarriers, 15 unaffected carriers, 18 affected carriers; response rate at 2 years = 64.9 % of eligible respondents). Multilevel modeling of perceived control ratings over a 2-year period revealed significant variation in individual trajectories: most participants showed increases (45 %) or no change (38.3 %), while 16.7 % showed decreases. At the group level, noncarriers reported sustained increases through the 2-year follow-up (ps < .05); unaffected carriers reported significant short-term increases (ps < .05); and affected carriers reported no change. Participants in all groups continued to rate photoprotection as highly effective in reducing melanoma risk and reported decreased beliefs that carrying the p16 mutation would inevitably lead to the development of melanoma. Qualitative responses immediately following counseling and test reporting corroborated these findings, as 93 % indicated it was possible to either prevent (64.9 %) or decrease the likelihood (28.1 %) of future melanomas. Thus, genetic test reporting does not generally undermine perceived control over melanoma prevention, though variability in response to positive results warrants future study.

  13. Melanoma staging: facts and controversies.

    PubMed

    Forschner, Andrea; Eigentler, Thomas Kurt; Pflugfelder, Annette; Leiter, Ulrike; Weide, Benjamin; Held, Laura; Meier, Friedegund; Garbe, Claus

    2010-01-01

    The value of staging examinations remains controversial for the initial staging in melanoma patients at the time of the primary diagnosis and for surveillance. Issues concerning tumor recurrences and progression must be discussed separately for different risk groups. For low-risk patients (stage IA; tumor thickness less than 1 mm), staging examinations like sentinel lymph node biopsy (SLNB), blood tests, or imaging can generally be abandoned. Baseline staging with simple techniques is at the discretion of the physician. In intermediate-risk patients (stages IB and IIA), an initial staging examination involving SLNB and computed tomography (CT) scans is recommended. Further follow-up may be restricted to physical examinations, blood tests of tumor marker protein S100beta, and to lymph node ultrasonography. If findings are suspicious, further imaging procedures may be involved. In high-risk patients (stages IIB to III), an initial staging examination with CT is recommended, and regular follow-up every 6 months with whole body imaging by CT or magnetic resonance imaging seems useful. Physical examinations, blood tests of tumor marker protein S100beta, and lymph node ultrasound imaging should be routine. This intense follow-up may enable surgical treatments with complete removal of all recognizable metastases in about 15% to 25% of patients and improve their prognosis. The risk of recurrence or tumor progression is very high in stage IV patients, and their management is individualized. PMID:20541679

  14. Assessment of melanoma extent and melanoma metastases invasion using electron paramagnetic resonance and bioluminescence imaging.

    PubMed

    Godechal, Quentin; Defresne, Florence; Danhier, Pierre; Leveque, Philippe; Porporato, Paolo Ettore; Sonveaux, Pierre; Baurain, Jean-François; Feron, Olivier; Gallez, Bernard

    2011-01-01

    The clinical outcome of melanoma depends on the local and distant spread of the disease at the time of diagnosis, as the estimated 5-year survival rate is about 100% for superficial melanoma diagnosed early, but less than 10% for melanoma that has disseminated to major organs such as lungs. There is a crucial need for new effective methods for the detection and the characterization of melanomas. In the pre-clinical setting, this will help to understand the factors that contribute to the malignancy while the transfer into the clinic will contribute to an early effective treatment of patients. Melanoma lesions can be detected by electron paramagnetic resonance (EPR) using paramagnetic properties of melanin pigments. As part of the development of EPR imaging to characterize melanomas, we evaluated in the present study the usefulness of EPR to report on the extension of lung metastases by comparing the method with bioluminescence imaging using B16 melanoma cells expressing luciferase. B16 melanoma cells were injected subcutaneously or intravenously in C57/BL6 mice. The primary tumors or the lung colonization by melanoma cells was measured after several delay periods to obtain several degrees of invasiveness. The animals were measured in-vivo with bioluminescence after i.v. injection of luciferin. The primary tumors or lungs were then excised. After freeze-drying, the content of melanin in lungs was measured and imaged by EPR at 9 GHz. We observed a direct relationship between the EPR intensity and the bioluminescence intensity. Another tumor model (KHT sarcoma), non-pigmented but expressing luciferase, was used to confirm that the EPR signal was directly linked to the melanin pigment present in the tumors. PMID:21861288

  15. Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression

    PubMed Central

    Eriksson, Johanna; Le Joncour, Vadim; Nummela, Pirjo; Jahkola, Tiina; Virolainen, Susanna; Laakkonen, Pirjo; Saksela, Olli; Hölttä, Erkki

    2016-01-01

    Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to develop more effective therapies and to identify new markers to predict disease behavior. Here, we compared the gene expression profiles of benign nevi, and non-metastatic and metastatic primary melanomas to identify any common changes in disease progression. We identified several genes associated with inflammation, angiogenesis, and extracellular matrix modification to be upregulated in metastatic melanomas. We selected one of these genes, collagen triple helix repeat containing 1 (CTHRC1), for detailed analysis, and found that CTHRC1 was expressed in both melanoma cells and the associated fibroblasts, as well as in the endothelium of tumor blood vessels. Knockdown of CTHRC1 expression by shRNAs in melanoma cells inhibited their migration in Transwell assays and their invasion in three-dimensional collagen and Matrigel matrices. We also elucidated the possible down-stream effectors of CTHRC1 by gene expression profiling of the CTHRC1-knockdown cells. Our analyses showed that CTHRC1 is regulated coordinately with fibronectin and integrin β3 by the pro-invasive and -angiogenic transcription factor NFATC2. We also found CTHRC1 to be a target of TFGβ and BRAF. These data highlight the importance of tumor stroma in melanoma progression. Furthermore, CTHRC1 was recognized as an important mediator of melanoma cell migration and invasion, providing together with its regulators—NFATC2, TGFβ, and BRAF—attractive therapeutic targets against metastatic melanomas. PMID:26918341

  16. Pseudoaneurysm of the Posterior Tibial Artery After Posterior Tibial Tendon Transfer.

    PubMed

    Elabdi, Monsef; Roukhsi, Redouane; Tijani, Youssef; Chtata, Hassan; Jaafar, Abdeloihab

    2016-01-01

    Pseudoaneurysm of the posterior tibial artery is an uncommon condition that, left untreated, can lead to hemorrhage, thrombosis, or emboli. We present the case of a 54-year-old male who developed pseudoaneurysm of the posterior tibial artery 4 months after undergoing tibialis posterior tendon transfer for management of peroneal nerve palsy, which had developed as a complication of hip arthroplasty. PMID:26972754

  17. Consistently inconsistent, the posterior vaginal wall.

    PubMed

    Hale, Douglass S; Fenner, Dee

    2016-03-01

    Posterior vaginal wall prolapse is one of the most common prolapses encountered by gynecological surgeons. What appears to be a straightforward condition to diagnose and treat surgically for physicians has proven to be frustratingly unpredictable with regard to symptom relief for patients. Functional disorders such as dyssynergic defecation and constipation are often attributed to posterior vaginal wall prolapse. Little scientific evidence supports this assumption, emphasizing that structure and function are not synonymous when treating posterior vaginal wall prolapse. Rectoceles, enteroceles, sigmoidoceles, peritoneoceles, rectal and intraanal intussusception, rectal prolapse, and descending perineal syndrome are all conditions that have an impact on the posterior vaginal wall. All too often these different anatomic conditions are treated with the same surgical approach, addressing a posterior vaginal wall bulge with a traditional posterior colporrhaphy. Studies that examine the correlation between stage of posterior wall prolapse and patient symptoms have failed to reliably do so. Surgical outcomes measured by prolapse staging appear successful, yet patient expectations are often not met. As increasing attention is being placed on patient satisfaction outcomes concerning surgical treatments, this fact will need to be addressed. Surgeons will have to clearly communicate what can and what cannot be expected with surgical repair of posterior vaginal wall prolapse.

  18. Postoperative rehabilitation of the posterior cruciate ligament.

    PubMed

    Edson, Craig J; Fanelli, Gregory C; Beck, John D

    2010-12-01

    Diagnosis and management of posterior cruciate ligament injuries has evolved, and now the treatment often includes surgical intervention. The purpose of this paper is to define the current approach to postsurgical management after the posterior cruciate ligament reconstruction, review conservative management, and discuss surgical outcomes using a specified program.

  19. Neurolinguistic Aspects of Finnish Posterior Aphasia.

    ERIC Educational Resources Information Center

    Niemi, Jussi; Koivuselka-Sallinen, Paivi

    Examination of the lexical errors (phonological paraphasias and neologisms) of two posterior aphasic patients who are speakers of Finnish, a highly synthetic language, revealed that the lexical difficulties generally typical of posterior aphasics were found in these patients as well. The typical lexical difficulties clustered around open class…

  20. Report from the Melanoma Independent Board First Melanoma MIB Conference, 21–22 October 2013

    PubMed Central

    Testori, A; Ascierto, P; Chiarion Sileni, V; De Lorenzo, F; Pelicci, PG; Rossi, CR

    2014-01-01

    The Melanoma Independent Board (MIB) held its first conference from 21 to 22 October, 2013, in Rome, Italy. Like the MIB itself, the conference brought together specialists from all aspects of cancer care: doctors, patient associations, journalists, and representatives from local government, hospitals, and pharma to encourage an interdisciplinary discussion on the future of melanoma. It was hoped that the conference would be an opportunity for all participants to see and understand each other’s points of view. In memoriam of melanoma pioneer Natalie Cascinelli, the conference focussed on innovation and sustainability as well as the latest drug developments. PMID:25075214

  1. Bioelectric Applications for Treatment of Melanoma

    PubMed Central

    Beebe, Stephen J.; Schoenbach, Karl H.; Heller, Richard

    2010-01-01

    Two new cancer therapies apply bioelectric principles. These methods target tumor structures locally and function by applying millisecond electric fields to deliver plasmid DNA encoding cytokines using electrogene transfer (EGT) or by applying rapid rise-time nanosecond pulsed electric fields (nsPEFs). EGT has been used to locally deliver cytokines such as IL-12 to activate an immune response, resulting in bystander effects. NsPEFs locally induce apoptosis-like effects and affect vascular networks, both promoting tumor demise and restoration of normal vascular homeostasis. EGT with IL-12 is in melanoma clinical trials and nsPEFs are used in models with B16F10 melanoma in vitro and in mice. Applications of bioelectrics, using conventional electroporation and extensions of it, provide effective alternative therapies for melanoma. PMID:24281185

  2. Conjunctival malignant melanoma in a horse.

    PubMed

    Moore, C.P.; Collins, B.K.; Linton, L.L.; Collier, L.L.

    2000-01-01

    A case of malignant melanoma originating from the conjunctiva of a horse is reported. The tumor exhibited locally aggressive behavior as evidenced clinically by recurrence following two treatment episodes including surgical excision on each occasion and one application of cryotherapy. The orbit was subsequently exenterated and histologically malignant conjunctival melanoma was confirmed. Histopathologic features included variable pigmentation with amelanotic sites demonstrating marked cellular and nuclear pleomorphism with high numbers of mitotic figures. Cords of neoplastic cells invaded the sclera and cornea. Following exenteration, the horse exhibited no recurrence of the tumor for five years before being lost to follow-up. To our knowledge, this is the first report of primary malignant conjunctival melanoma in a horse.

  3. 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

  4. Bioelectric applications for treatment of melanoma.

    PubMed

    Beebe, Stephen J; Schoenbach, Karl H; Heller, Richard

    2010-09-27

    Two new cancer therapies apply bioelectric principles. These methods target tumor structures locally and function by applying millisecond electric fields to deliver plasmid DNA encoding cytokines using electrogene transfer (EGT) or by applying rapid rise-time nanosecond pulsed electric fields (nsPEFs). EGT has been used to locally deliver cytokines such as IL-12 to activate an immune response, resulting in bystander effects. NsPEFs locally induce apoptosis-like effects and affect vascular networks, both promoting tumor demise and restoration of normal vascular homeostasis. EGT with IL-12 is in melanoma clinical trials and nsPEFs are used in models with B16F10 melanoma in vitro and in mice. Applications of bioelectrics, using conventional electroporation and extensions of it, provide effective alternative therapies for melanoma.

  5. 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.

  6. Ensemble approach for differentiation of malignant melanoma

    NASA Astrophysics Data System (ADS)

    Rastgoo, Mojdeh; Morel, Olivier; Marzani, Franck; Garcia, Rafael

    2015-04-01

    Melanoma is the deadliest type of skin cancer, yet it is the most treatable kind depending on its early diagnosis. The early prognosis of melanoma is a challenging task for both clinicians and dermatologists. Due to the importance of early diagnosis and in order to assist the dermatologists, we propose an automated framework based on ensemble learning methods and dermoscopy images to differentiate melanoma from dysplastic and benign lesions. The evaluation of our framework on the recent and public dermoscopy benchmark (PH2 dataset) indicates the potential of proposed method. Our evaluation, using only global features, revealed that ensembles such as random forest perform better than single learner. Using random forest ensemble and combination of color and texture features, our framework achieved the highest sensitivity of 94% and specificity of 92%.

  7. 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

  8. 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

  9. 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

  10. Continence after posterior sagittal anorectoplasty.

    PubMed

    Langemeijer, R A; Molenaar, J C

    1991-05-01

    Posterior sagittal anorectoplasty (PSARP) was introduced in 1982 by Peña and De Vries as a new operation for patients with a high anorectal malformation. The degree of postoperative continence is reported to be high. During the past decade, too, new insights have been gained into the embryology of anorectal malformations. Evaluation of PSARP in relation to current understanding of the development and anatomy of the anorectum and the pelvic floor has led us to conclude that optimal continence cannot be expected. Fifty patients with a high anorectal malformation underwent PSARP between June 1983 and May 1990. Postoperative follow-up consisted of anamnesis (subjective) and electrostimulation, defecography, and anorectal manometry (objective). All patients are alive, and all but one are being evaluated regularly. Subjectively, the majority of patients were more or less incontinent, with soiling of pants at least once a day. On the basis of objective criteria, virtually all patients appeared to be incontinent, and in only one patient was the mechanism of defecation almost unimpaired after PSARP. From this study, we conclude that although PSARP provides a good aesthetic result, patients will never acquire normal continence.

  11. Postoperative posterior spinal wound infections.

    PubMed

    Massie, J B; Heller, J G; Abitbol, J J; McPherson, D; Garfin, S R

    1992-11-01

    The incidence of postoperative spinal infections increases with the complexity of the procedure. Diskectomy is associated with less than a 1% risk of infection; spinal fusion without instrumentation is associated with a 1%-5% risk; and fusion with instrumentation may be associated with a risk of 6% or more. Twenty-two postoperative posterior spinal infections that occurred during a three-year period were reviewed for this report. Staphylococcus aureus was the most frequent organism cultured (more than 50% of the cases). Other recurring organisms were Staphylococcus epidermis, Peptococcus, Enterobacter cloacae, and Bacteroides. Many patients had multiple organisms. Risk factors appeared to include advanced age, prolonged hospital bed rest, obesity, diabetes, immunosuppression, and infection at remote sites. Operative factors included prolonged surgery (greater than five hours), high volume of personnel moving through the operating room, and instrumentation. Postoperative contamination may occur and may be related to prolonged postoperative bed rest, skin maceration (thoracolumbosacral orthoses), and drainage tubes exiting distally from lumbar wounds (toward the rectum). Effective treatment includes early diagnosis, surgical debridement and irrigation, and parenteral antibiotics. Superficial infections were treated successfully with wound closure over outflow tubes, and deep infections with inflow-outflow systems. Maintaining the instrumentation in place was possible in most cases. Parenteral antibiotics were maintained for six weeks in every case. PMID:1395319

  12. In vivo melanoma depth detection by a handheld photoacoustic microscope

    NASA Astrophysics Data System (ADS)

    Zhou, Yong; Xing, Wenxin; Maslov, Konstantin I.; Cornelius, Lynn A.; Wang, Lihong V.

    2015-03-01

    We developed a handheld photoacoustic microscope (PAM) to detect melanoma and determine tumor depth in nude mice in vivo. Compared to our previous PAM system for melanoma imaging, a new light delivery mechanism is introduced to improve light penetration. We show that melanomas with 4.1 mm and 3.3 mm thicknesses can be successfully detected in phantom and in vivo experiments, respectively. With its deep melanoma imaging ability and novel handheld design, this system is promising for clinical melanoma diagnosis, prognosis, and surgical planning for patients at the bedside.

  13. Historical summary and recommendations on Melanoma in the LLNL workforce

    SciTech Connect

    Moore, D.H. II; Hatch, F.

    1994-12-01

    This document provides a historical summary and recommendations on melanoma in the Lawrence Livermore National Laboratory (LLNL) workforce. Melanoma of the skin comprises about 3.5% of the incidence (38,000 new cases in 1991) and 1.7% of the mortality (8500 deaths in 1991) of all cancer in the U.S. However, for several decades it has shown the fastest rate of increase of any cancer site. The following areas are discussed: background and recognition of increased melanoma at LLNL, history of melanoma studies at LLNL, results from occupational factors study, overall conclusion on increased melanoma incidence, and recommendations for future management.

  14. 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.

  15. 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

  16. Malignant Melanoma Arising in Red Tattoo Ink

    PubMed Central

    Duff, Gerald; McKenna, Dermot; Regan, Padraic James

    2015-01-01

    We report the case of a 33-year-old male who presented with a malignant melanoma on his anterior chest wall. The lesion was only found in the red ink pigment of the tattoo, as were several in-transit dermal metastases. Possible explanations include a pre-existing lesion which was seeded with red ink or the possibility of the red ink causing an inflammatory reaction leading to malignant transformation. This is the first reported case of a melanoma developing in the red ink pigment of a multi-colored tattoo. PMID:26217569

  17. 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

  18. 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.

  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. 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

  1. Malignant melanoma in a grey horse: case presentation and review of equine melanoma treatment options.

    PubMed

    Metcalfe, Lucy Va; O'Brien, Peter J; Papakonstantinou, Stratos; Cahalan, Stephen D; McAllister, Hester; Duggan, Vivienne E

    2013-01-01

    A 15 year-old grey Thoroughbred gelding presented for investigation of chronic weight loss and recent onset of respiratory difficulty. Clinical examination confirmed tachypnoea with increased respiratory effort. Thoracic ultrasound examination detected pleural effusion. The dyspnoea was related to the large volume of pleural effusion and, following post-mortem examination, to the presence of a large mediastinal mass. Multiple pigmented masses, likely melanomas, were detected peri-anally. Thoracic radiography, cytological examination of the pleural fluid and a fine needle aspirate of a thoracic mass led to a presumptive diagnosis of malignant melanoma and this was confirmed at post mortem examination. Further metastatic spread to the central nervous system and right guttural pouch was also identified. In conclusion this case manifests the potential malignant behaviour of equine melanomas, and a review of proposed therapies for melanoma treatment highlights the therapeutic options and current areas of research. PMID:24196087

  2. 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

  3. Posterior labral injury in contact athletes.

    PubMed

    Mair, S D; Zarzour, R H; Speer, K P

    1998-01-01

    Nine athletes (seven football offensive linemen, one defensive lineman, and one lacrosse player) were found at arthroscopy to have posterior labral detachment from the glenoid. In our series, this lesion is specific to contact athletes who engage their opponents with arms in front of the body. All patients had pain with bench pressing and while participating in their sport, diminishing their ability to play effectively. Conservative measures were ineffective in relieving their symptoms. Examination under anesthesia revealed symmetric glenohumeral translation bilaterally, without evidence of posterior instability. Treatment consisted of glenoid rim abradement and posterior labral repair with a bioabsorbable tack. All patients returned to complete at least one full season of contact sports and weightlifting without pain (minimum follow-up, > or = 2 years). Although many injuries leading to subluxation of the glenohumeral joint occur when an unanticipated force is applied, contact athletes ready their shoulder muscles in anticipation of impact with opponents. This leads to a compressive force at the glenohumeral joint. We hypothesize that, in combination with a posteriorly directed force at impact, the resultant vector is a shearing force to the posterior labrum and articular surface. Repeated exposure leads to posterior labral detachment without capsular injury. Posterior labral reattachment provides consistently good results, allowing the athlete to return to competition.

  4. 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.

  5. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation

    PubMed Central

    Kaufman, Charles K.; Mosimann, Christian; Fan, Zi Peng; Yang, Song; Thomas, Andrew; Ablain, Julien; Tan, Justin L.; Fogley, Rachel D.; van Rooijen, Ellen; Hagedorn, Elliott; Ciarlo, Christie; White, Richard; Matos, Dominick; Puller, Ann-Christin; Santoriello, Cristina; Liao, Eric; Young, Richard A.; Zon, Leonard I.

    2016-01-01

    The “cancerized field” concept posits that cells in a given tissue share an oncogenic mutation or insult and are thus cancer-prone, yet only discreet clones within the field initiate tumors. Nearly all benign nevi carry oncogenic BRAFV600E mutations, but they only rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCP’s) and is specifically re-expressed in melanoma. We show by live imaging of transgenic zebrafish crestin reporters that, within a cancerized field (BRAFV600E-mutant; p53-deficient), a single melanocyte reactivates the NCP state, and this establishes that a fate change occurs at melanoma initiation in this model. We show the crestin element is regulated by NCP transcription factors, including sox10. Forced sox10 overexpression in melanocytes accelerated melanoma formation, consistent with activation of a NCP gene signature and super-enhancers leading to melanoma. Our work highlights the importance of NCP state reemergence as a key event in melanoma initiation. PMID:26823433

  6. 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

  7. PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells

    PubMed Central

    George, Andrea L.; Suriano, Robert; Rajoria, Shilpi; Osso, Maria C.; Tuli, Neha; Hanly, Elyse; Geliebter, Jan; Arnold, Angelo N.; Wallack, Marc; Tiwari, Raj K.

    2015-01-01

    Over expression of various immunogenic melanoma associated antigens (MAAs) has been exploited in the development of immunotherapeutic melanoma vaccines. Expression of MAAs such as MART-1 and gp100 is modulated by the MAPK signaling pathway, which is often deregulated in melanoma. The protein BRAF, a member of the MAPK pathway, is mutated in over 60% of melanomas providing an opportunity for the identification and approval by the FDA of a small molecule MAPK signaling inhibitor PLX4032 that functions to inactivate mutant BRAFV600E. To this end, we characterized five patient derived primary melanoma cell lines with respect to treatment with PLX4032. Cells were treated with 5μM PLX4032 and harvested. Western blotting analysis, RT-PCR and in vitro transwell migration and invasion assays were utilized to determine treatment effects. PLX4032 treatment modulated phosphorylation of signaling proteins belonging to the MAPK pathway including BRAF, MEK, and ERK and abrogated cell phenotypic characteristics such as migration and invasion. Most significantly, PLX4032 led to an up regulation of many MAA proteins in three of the four BRAF mutated cell lines, as determined at the protein and RNA level. Interestingly, MAGE-A1 protein and mRNA levels were reduced upon PLX4032 treatment in two of the primary lines. Taken together, our findings suggest that the BRAFV600E inhibitor PLX4032 has therapeutic potential over and above its known target and in combination with specific melanoma targeting vaccine strategies may have further clinical utility. PMID:26640592

  8. Interpretation of Melanoma Risk Feedback in First-Degree Relatives of Melanoma Patients

    PubMed Central

    Hay, Jennifer L.; Baguer, Carlos; Li, Yuelin; Orlow, Irene; Berwick, Marianne

    2012-01-01

    Little is known about how individuals might interpret brief genetic risk feedback. We examined interpretation and behavioral intentions (sun protection, skin screening) in melanoma first-degree relatives (FDRs) after exposure to brief prototypic melanoma risk feedback. Using a 3 by 2 experimental pre-post design where feedback type (high-risk mutation, gene environment, and nongenetic) and risk level (positive versus negative findings) were systematically varied, 139 melanoma FDRs were randomized to receive one of the six scenarios. All scenarios included an explicit reminder that melanoma family history increased their risk regardless of their feedback. The findings indicate main effects by risk level but not feedback type; positive findings led to heightened anticipated melanoma risk perceptions and anticipated behavioral intentions. Yet those who received negative findings often discounted their family melanoma history. As such, 25%, 30%, and 32% of those who received negative mutation, gene-environment, and nongenetic feedback, respectively, reported that their risk was similar to the general population. Given the frequency with which those who pursue genetic testing may receive negative feedback, attention is needed to identify ideal strategies to present negative genetic findings in contexts such as direct to consumer channels where extensive genetic counseling is not required. PMID:22888347

  9. Acidic tumor microenvironment in human melanoma.

    PubMed

    Böhme, Ines; Bosserhoff, Anja Katrin

    2016-09-01

    One characteristic of solid tumors such as malignant melanoma is the acidification of the tumor microenvironment. The deregulation of cancer cell metabolism is considered a main cause of extracellular acidosis. Here, cancer cells utilize aerobic glycolysis instead of oxidative phosphorylation even under normoxic conditions, as originally described by Otto Warburg. These metabolic alterations cause enhanced acid production, especially of lactate and carbon dioxide (CO2 ). The extensive production of acidic metabolites and the enhanced acid export to the extracellular space cause a consistent acidification of the tumor microenvironment, thus promoting the formation of an acid-resistant tumor cell population with increased invasive and metastatic potential. As melanoma is one of the deadliest and most metastatic forms of cancer, understanding the effects of this extracellular acidosis on human melanoma cells with distinct metastatic properties is important. The aim of this review was to summarize recent studies of the acidification of the tumor microenvironment, focusing on the specific effects of the acidic milieu on melanoma cells and to give a short overview of therapeutic approaches. PMID:27233233

  10. 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

  11. Melanoma and the Unfolded Protein Response

    PubMed Central

    Sykes, Erin K.; Mactier, Swetlana; Christopherson, Richard I.

    2016-01-01

    The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and poor outcome in melanoma patients. The proliferative burden of cancer induces stress and activates several cellular stress responses. The UPR is a tightly orchestrated stress response that is activated upon the accumulation of unfolded proteins within the ER (endoplasmic reticulum). The UPR is designed to mediate two conflicting outcomtes, recovery and apoptosis. As a result, the UPR initiates a widespread signaling cascade to return the cell to homeostasis and failing to achieve cellular recovery, initiates UPR-induced apoptosis. There is evidence that ER stress and subsequently the UPR promote tumourigenesis and metastasis. The complete role of the UPR has yet to be defined. Understanding how the UPR allows for adaption to stress and thereby assists in cancer progression is important in defining an archetype of melanoma pathology. In addition, elucidation of the mechanisms of the UPR may lead to development of effective treatments of metastatic melanoma. PMID:26927180

  12. [Primary malignant melanoma of the vagina].

    PubMed

    Lomeo, A M; Iacobellis, G; Martoccia, G; Manzione, L; De Sanctis, D; Maglietta, R; Vita, G

    1993-03-01

    We report two cases of primary malignant melanoma of the vagina explaining the essential clinical pathological and therapeutic features. They themselves, added those represented in literature, might constitute a further contribution to best definition of the unusual genital pathology, especially as regards prognostic and therapeutic aspects.

  13. 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.

  14. 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

  15. Thiourea as a melanoma targeting agent.

    PubMed

    Mårs, U; Larsson, B S

    1996-04-01

    It has previously been shown that various thiourea derivatives are incorporated into nascent melanin, and a few of these substances, e.g. 2-thiouracil and its radioiodinated analogue, have been used for selective targeting of melanotic melanoma. Possible localization of thiourea itself in melanoma, however, has not been investigated so far. We have therefore performed the present autoradiographic and impulse counting study on the disposition of 14C-thiourea in mice transplanted with B16 melanoma. The results demonstrated a pronounced, but partly heterogeneous, uptake of radioactivity in the melanoma tissue, with the highest concentration 4 h after the injection. Four days after the administration of a single dose, the retention of label was still high in certain tumoral areas. The lung was the only normal tissue with a similarly high uptake of radioactivity. Additional experiments in vitro showed that the incorporation of thiourea into melanin was dose-dependent. The binding to performed melanin was found to be low, which strongly indicates that the incorporation of thiourea into melanin mainly is due to interaction with intermediates of the melanin synthetic pathway.

  16. Malignant melanoma of the lacrimal sac.

    PubMed

    Yamade, S; Kitagawa, A

    1978-01-01

    A case of malignant melanoma of the lacrimal sac in a 41-year-old woman is reported, which is propably the 12th one in the world literature. Dacryocystectomy is advisable at a localized stage. The importance of early diagnosis is discussed. PMID:714368

  17. 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.

  18. Instantánea del melanoma

    Cancer.gov

    Información sobre las tendencias de incidencia, mortalidad y financiamiento del NCI sobre el melanoma; así como ejemplos de actividades del NCI y adelantos en la investigación de este tipo de cáncer.

  19. [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

  20. p16 Mutations in hereditary melanomas

    SciTech Connect

    Hussussian, C.J.; Struewing, J.P.; Goldstein, A.M.

    1994-09-01

    The p16 gene (CDK4 inhibitor) is located in chromosome 9p21, a region that shows linkage to hereditary melanoma and is deleted in many different tumors. p16 was analyzed in 19 families with hereditary melanoma by amplifying the entire coding region in 5 short segments and screening by SSCP under several conditions that should resolve >95% of polymorphisms. A total of 10 variants were detected in 15 families. The mutations detected included 7 missense, 1 silent, 1 nonsense, and one that destroyed a consensus splice donor site. One of the missense mutations was present in 5/21 spouses in these families, giving an estimated allele frequency of 0.12. Therefore the {triangle}436 [G{yields}A] variant is a common polymorphism and is not involved in the development of melanoma. However, there was strong evidence for the involvement of the other p16 mutations in five 9p21 linked families. In these families, a total of 17/19 individuals with melanoma inherited the mutant allele, while only 2/26 unaffected family members (1 with dysplastic nevi) and 0/13 spouses had the mutant alleles. In two additional 9p21 linked families, one segregated a silent mutation in 3/4 of the affected individuals, and the second only contained the common {triangle}436 [G{yields}A] mutation. In the two families with strong evidence of linkage to chromosome 1p36 and exclusion of linkage to 9p21, no SSCP variants were detected at p16 among 11 melanoma cases, except for a single affected individual who inherited the variant from an unaffected parent. These data confirm the existence of genetic heterogeneity in families with hereditary melanoma. Most (5/7) of the families with strong linkage to 9p21 had p16 missense mutations that segregated with the disease, while 2 families with strong linkage to chromosome 1p36 did not have any detectable p16 mutations that segregated with the disease. Further functional analyses of these mutations will clarify which are causally related to hereditary melanoma.

  1. Primary Malignant Melanoma in the Pineal Region

    PubMed Central

    Hong, Yong-Kil

    2014-01-01

    A 59-year-old male patient had 5-month history of gait disturbance and memory impairment. His initial brain computed tomography scan showed 3.5×2.8 cm sized mass with high density in the pineal region. The tumor was hypointense on T2 weighted magnetic resonance images and hyperintense on T1 weighted magnetic resonance images with heterogenous enhancement of central portion. The tumor was totally removed via the occipital transtentorial approach. Black mass was observed in the operation field, and after surgery, histopathological examination confirmed the diagnosis of malignant melanoma. Whole spine magnetic resonance images and whole body 18-fluoro-deoxyglucose positron emission tomography could not demonstrate the primary site of this melanoma. Scrupulous physical examination of his skin and mucosa was done and dark pigmented lesion on his left leg was found, but additional studies including magnetic resonance images and skin biopsy showed negative finding. As a result, final diagnosis of primary pineal malignant melanoma was made. He underwent treatment with the whole brain radiotherapy and extended local boost irradiation without chemotherapy. His preoperative symptoms were disappeared, and no other specific neurological deficits were founded. His follow-up image studies showed no recurrence or distant metastasis until 26 weeks after surgery. Primary pineal malignant melanomas are extremely rare intracranial tumors, and only 17 cases have been reported since 1899. The most recent case report showed favorable outcome by subtotal tumor resection followed by whole brain and extended local irradiation without chemotherapy. Our case is another result to prove that total tumor resection with radiotherapy can be the current optimal treatment for primary malignant melanoma in the pineal region. PMID:25628812

  2. Blue light inhibits proliferation of melanoma cells

    NASA Astrophysics Data System (ADS)

    Becker, Anja; Distler, Elisabeth; Klapczynski, Anna; Arpino, Fabiola; Kuch, Natalia; Simon-Keller, Katja; Sticht, Carsten; van Abeelen, Frank A.; Gretz, Norbert; Oversluizen, Gerrit

    2016-03-01

    Photobiomodulation with blue light is used for several treatment paradigms such as neonatal jaundice, psoriasis and back pain. However, little is known about possible side effects concerning melanoma cells in the skin. The aim of this study was to assess the safety of blue LED irradiation with respect to proliferation of melanoma cells. For that purpose we used the human malignant melanoma cell line SK-MEL28. Cell proliferation was decreased in blue light irradiated cells where the effect size depended on light irradiation dosage. Furthermore, with a repeated irradiation of the melanoma cells on two consecutive days the effect could be intensified. Fluorescence-activated cell sorting with Annexin V and Propidium iodide labeling did not show a higher number of dead cells after blue light irradiation compared to non-irradiated cells. Gene expression analysis revealed down-regulated genes in pathways connected to anti-inflammatory response, like B cell signaling and phagosome. Most prominent pathways with up-regulation of genes were cytochrome P450, steroid hormone biosynthesis. Furthermore, even though cells showed a decrease in proliferation, genes connected to the cell cycle were up-regulated after 24h. This result is concordant with XTT test 48h after irradiation, where irradiated cells showed the same proliferation as the no light negative control. In summary, proliferation of melanoma cells can be decreased using blue light irradiation. Nevertheless, the gene expression analysis has to be further evaluated and more studies, such as in-vivo experiments, are warranted to further assess the safety of blue light treatment.

  3. Posterior Hip Pain in an Athletic Population

    PubMed Central

    Frank, Rachel M.; Slabaugh, Mark A.; Grumet, Robert C.; Virkus, Walter W.; Bush-Joseph, Charles A.; Nho, Shane J.

    2010-01-01

    Context: Posterior hip pain is a relatively uncommon but increasingly recognized complaint in the orthopaedic community. Patient complaints and presentations are often vague or nonspecific, making diagnosis and subsequent treatment decisions difficult. The purposes of this article are to review the anatomy and pathophysiology related to posterior hip pain in the athletic patient population. Evidence Acquisition: Data were collected through a thorough review of the literature via a MEDLINE search of all relevant articles between 1980 and 2010. Results: Many patients who complain of posterior hip pain actually have pain referred from another part of the body—notably, the lumbar spine or sacroiliac joint. Treatment options for posterior hip pain are typically nonoperative; however, surgery is warranted in some cases. Conclusions: Recent advancements in the understanding of hip anatomy, pathophysiology, and treatment options have enabled physicians to better diagnosis athletic hip injuries and select patients for appropriate treatment. PMID:23015944

  4. Congenital abnormalities of the posterior fossa.

    PubMed

    Bosemani, Thangamadhan; Orman, Gunes; Boltshauser, Eugen; Tekes, Aylin; Huisman, Thierry A G M; Poretti, Andrea

    2015-01-01

    The frequency and importance of the evaluation of the posterior fossa have increased significantly over the past 20 years owing to advances in neuroimaging. Nowadays, conventional and advanced neuroimaging techniques allow detailed evaluation of the complex anatomic structures within the posterior fossa. A wide spectrum of congenital abnormalities has been demonstrated, including malformations (anomalies due to an alteration of the primary developmental program caused by a genetic defect) and disruptions (anomalies due to the breakdown of a structure that had a normal developmental potential). Familiarity with the spectrum of congenital posterior fossa anomalies and their well-defined diagnostic criteria is crucial for optimal therapy, an accurate prognosis, and correct genetic counseling. The authors discuss the spectrum of posterior fossa malformations and disruptions, with emphasis on neuroimaging findings (including diagnostic criteria), neurologic presentation, systemic involvement, prognosis, and risk of recurrence.

  5. Congenital abnormalities of the posterior fossa.

    PubMed

    Bosemani, Thangamadhan; Orman, Gunes; Boltshauser, Eugen; Tekes, Aylin; Huisman, Thierry A G M; Poretti, Andrea

    2015-01-01

    The frequency and importance of the evaluation of the posterior fossa have increased significantly over the past 20 years owing to advances in neuroimaging. Nowadays, conventional and advanced neuroimaging techniques allow detailed evaluation of the complex anatomic structures within the posterior fossa. A wide spectrum of congenital abnormalities has been demonstrated, including malformations (anomalies due to an alteration of the primary developmental program caused by a genetic defect) and disruptions (anomalies due to the breakdown of a structure that had a normal developmental potential). Familiarity with the spectrum of congenital posterior fossa anomalies and their well-defined diagnostic criteria is crucial for optimal therapy, an accurate prognosis, and correct genetic counseling. The authors discuss the spectrum of posterior fossa malformations and disruptions, with emphasis on neuroimaging findings (including diagnostic criteria), neurologic presentation, systemic involvement, prognosis, and risk of recurrence. PMID:25590398

  6. 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

  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. [Utilization of melanin precursors for experimental chemotherapy of malignant melanoma].

    PubMed

    Jimbow, K; Miura, S; Ito, Y; Kasuga, T; Ito, S

    1984-10-01

    Melanin synthesis is a metabolic pathway unique and specific to melanocytes. It occurs by conversion of tyrosine to dopa and dopaquinone in the presence of tyrosinase. It is highly accelerated in malignant melanoma with a marked increase of tyrosinase activity. This study summarizes the recent progress in experimental chemotherapeutic approaches to malignant melanoma by utilizing melanin precursors, and presents our current results. Our studies indicated (a) that hydroquinone and 4-isopropylcatechol are selectively toxic to melanocytes and melanoma cells, (b) that their actions are mediated through tyrosinase, and (c) that dopa is selectively and highly incorporated into melanoma cells and melanocytes depending on the tyrosinase activity. In addition, our new compounds, i.e., 4-S-cysteinylphenol and 4-S-cysteaminylphenol were highly toxic to melanoma cells, increasing the life span of B16 melanoma bearing mice and decreasing melanoma growth in C57 BL mice. Other synthetic compounds, e.g., cysteinylcatechols and their devivatives, were, however, not toxic to melanoma cells. 4-S-cysteinylphenol and 4-S-cysteaminylphenol appeared to exert their cytotoxicity through the action of tyrosinase present in melanoma cells, thus providing a kind of "guided missile" approach to melanoma chemotherapy. PMID:6435538

  9. Canine malignant melanoma alpha-3 integrin binding peptides

    PubMed Central

    Aina, Olulanu H.; Maeda, Yoshiko; Harrison, Matthew; Zwingenberger, Allison L.; Walker, Naomi J.; Lam, Kit S.; Kent, Michael S.

    2014-01-01

    There is a need to develop novel targeted imaging and therapeutic agents that can aid in early diagnosis, detection of metastasis and treatment of melanoma. Alpha-3 integrin is overexpressed in 82% of metastatic melanomas in humans and may be a potential target for peptide ligands carrying therapeutic agents. Five melanoma cell lines were generated from canine primary oral and metastatic canine tumors, grown in mice, and validated with melanoma markers Melan A, S-100, Micropthalmia transcription factor (MITF), Tyrosinase, and MART-1. The melanoma cell lines were tested for binding affinity to previously published alpha-3 integrin-binding peptides containing the cdGXGXXc motif. Fluorescent conjugates of the alpha-3 integrin binding OA02 peptide were used to quantify receptor affinity in the cell lines, a specimen of canine primary oral melanoma, and melanoma xenografts. Alpha-3 integrin was expressed by all 5 canine melanoma cell lines. Four of the 5 lines as well as the primary canine tumor showed affinity to alpha-3 integrin binding peptides with the cdGXGXXc motif. Optical imaging of canine melanoma xenografts in nude mice indicates rapid, strong uptake of the optical tracer in the tumor with an average persistence of approximately 48 hours. Ex vivo images showed high tumor-to-background ratio, with tumor signals more than twice that of the kidney and other vital organs. We propose that integrin alpha-3 integrin binding ligands could potentially become useful probes for imaging and delivery of cytotoxic agents for the treatment of melanoma. PMID:21722969

  10. Comparative Metabolic Flux Profiling of Melanoma Cell Lines

    PubMed Central

    Scott, David A.; Richardson, Adam D.; Filipp, Fabian V.; Knutzen, Christine A.; Chiang, Gary G.; Ronai, Ze'ev A.; Osterman, Andrei L.; Smith, Jeffrey W.

    2011-01-01

    Metabolic rewiring is an established hallmark of cancer, but the details of this rewiring at a systems level are not well characterized. Here we acquire this insight in a melanoma cell line panel by tracking metabolic flux using isotopically labeled nutrients. Metabolic profiling and flux balance analysis were used to compare normal melanocytes to melanoma cell lines in both normoxic and hypoxic conditions. All melanoma cells exhibited the Warburg phenomenon; they used more glucose and produced more lactate than melanocytes. Other changes were observed in melanoma cells that are not described by the Warburg phenomenon. Hypoxic conditions increased fermentation of glucose to lactate in both melanocytes and melanoma cells (the Pasteur effect). However, metabolism was not strictly glycolytic, as the tricarboxylic acid (TCA) cycle was functional in all melanoma lines, even under hypoxia. Furthermore, glutamine was also a key nutrient providing a substantial anaplerotic contribution to the TCA cycle. In the WM35 melanoma line glutamine was metabolized in the “reverse” (reductive) direction in the TCA cycle, particularly under hypoxia. This reverse flux allowed the melanoma cells to synthesize fatty acids from glutamine while glucose was primarily converted to lactate. Altogether, this study, which is the first comprehensive comparative analysis of metabolism in melanoma cells, provides a foundation for targeting metabolism for therapeutic benefit in melanoma. PMID:21998308

  11. 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.

  12. Higher Expression of the Heterogeneous Nuclear Ribonucleoprotein K in Melanoma

    PubMed Central

    Wen, Fushi; Shen, Alex; Shanas, Reneé; Bhattacharyya, Achyut; Lian, Fangru; Hostetter, Galen; Shi, Jiaqi

    2010-01-01

    Background The heterogeneous nuclear ribonucleoprotein (hnRNP) K is an essential RNA and DNA binding protein involved in gene expression and signal transduction. The role of hnRNP K in cancer is relatively understudied. However, several cellular functions strongly indicate that hnRNP K is involved in tumorigenesis. Oncogenes c-Src, c-myc, and eIF4E are regulated by hnRNP K. We have shown an increased cytoplasmic hnRNP K in pancreatic cancer. In the present study, we investigated the altered expression of hnRNP K protein and its correlation with p-ERK in melanoma using human melanoma cell lines and tissue microarray. Materials and Methods The protein levels of hnRNP K and p-ERK in 8 human melanoma cell lines and a melanoma progression tissue microarray containing 80 melanoma, 23 dysplastic nevi, and 14 benign nevi specimens were analyzed using Western blot and immunohistochemistry analysis. hnRNP K was knocked down by siRNA, and its effect on melanoma cells was assessed. Results We showed a higher hnRNP K protein level in both melanoma cell lines and melanoma tissue specimens, which correlated with a higher c-myc expression. An increase in the cytoplasmic hnRNP K and eIF4E protein levels in melanoma cells is also seen. p-ERK level was also higher in dysplastic nevi and melanoma tissues, but did not correlate with hnRNP K protein level. We then demonstrated that knocking down of hnRNP K by siRNA inhibited melanoma cell growth and colony formation, as well as c-myc expression. Conclusions hnRNP K expression correlated with melanoma and may play a role in melanoma tumorigenesis. PMID:20499280

  13. [Pathogenesis of posterior capsule opacification in pseudophakia].

    PubMed

    Łukaszewska-Smyk, Agnieszka; Kałuzny, Józef

    2009-01-01

    The lens epithelial cells of A and E type are involved in pathogenesis of posterior capsule opacification (PCO). They undergo metaplasia into microfibroblasts, then migrate towards posterior capsule where they proliferate and form opacification. These processes are stimulated by cytokines and interleukines. The extracellular matrix which constitutes a scaffold for migration and attachment of epithelial cells plays an important role in PCO formation. Integrines intercede in this process.

  14. Posterior Wnts Have Distinct Roles in Specification and Patterning of the Planarian Posterior Region.

    PubMed

    Sureda-Gómez, Miquel; Pascual-Carreras, Eudald; Adell, Teresa

    2015-11-05

    The wnt signaling pathway is an intercellular communication mechanism essential in cell-fate specification, tissue patterning and regional-identity specification. A βcatenin-dependent signal specifies the AP (Anteroposterior) axis of planarians, both during regeneration of new tissues and during normal homeostasis. Accordingly, four wnts (posterior wnts) are expressed in a nested manner in central and posterior regions of planarians. We have analyzed the specific role of each posterior wnt and the possible cooperation between them in specifying and patterning planarian central and posterior regions. We show that each posterior wnt exerts a distinct role during re-specification and maintenance of the central and posterior planarian regions, and that the integration of the different wnt signals (βcatenin dependent and independent) underlies the patterning of the AP axis from the central region to the tip of the tail. Based on these findings and data from the literature, we propose a model for patterning the planarian AP axis.

  15. Vertigo due to posterior circulation stroke.

    PubMed

    Kim, Ji Soo; Lee, Hyung

    2013-07-01

    Stroke in the distribution of the posterior circulation may present as acute onset spontaneous vertigo and imbalance. Although vertigo due to posterior circulation stroke is usually associated with other neurologic symptoms or signs, small infarcts in the cerebellum or brainstem can present with vertigo without other localizing symptoms. Approximately 17% of patients with isolated posterior inferior cerebellar artery territory infarction presented with isolated vertigo, nystagmus, and postural unsteadiness. A head impulse test can differentiate acute isolated vertigo associated with cerebellar stroke from more benign disorders involving the inner ear. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the anterior inferior cerebellar artery). In this case, evaluation of isolated audiovestibular loss may prevent the progression of acute vertigo and hearing loss into more widespread areas of infarction in the posterior circulation. In this article, the clinical syndromes and signs of acute vestibular syndrome due to posterior circulation stroke involving the brainstem and cerebellum are summarized.

  16. Immunohistochemical Analysis of Collagen IV and Laminin Expression in Spontaneous Melanoma Regression in the Melanoma-Bearing Libechov Minipig.

    PubMed

    Planska, Daniela; Burocziova, Monika; Strnadel, Jan; Horak, Vratislav

    2015-01-01

    Spontaneous regression (SR) of human melanoma is a rare, well-documented phenomenon that is not still fully understood. Its detailed study cannot be performed in patients due to ethical reasons. Using the Melanoma-bearing Libechov Minipig (MeLiM) animals of various ages (from 3 weeks to 8 months) we implemented a long-term monitoring of melanoma growth and SR. We focused on immunohistochemical detection of two important extracellular matrix proteins, collagen IV and laminin, which are associated with cancer. We showed that SR of melanoma is a highly dynamic process. The expression of collagen IV and laminin correlated with changes in population of melanoma cells. Tumours of 3-week-old animals consisted primarily of melanoma cells with a granular expression of collagen IV and laminin around them. Thereafter, melanoma cells were gradually destroyed and tumour tissue was rebuilt into the connective tissue. Collagen IV expression slightly increased in tumours of 10-week-old pigs showing extracellular fibrous appearance. In tumours of older animals, areas lacking melanoma cells demonstrated a low expression and areas still containing melanoma cells a high expression of both proteins. We considered the age of 10 weeks as a turning point in the transition between tumour growth and SR of the MeLiM melanoma.

  17. Posterior urethral polyp with type I posterior urethral valves: a rare association in a neonate.

    PubMed

    Kesan, Krushnakumar V; Gupta, Rahul Kumar; Kothari, Paras; Gupta, Abhaya; Mudkhedkar, Kedar; Kamble, Ravikiran; Dikshit, K Vishesh

    2014-06-01

    Urethral polyp is a rare cause of bladder outlet obstruction, voiding dysfunction, and hematuria in the pediatric age group. Urethral polyps are rarely associated with other congenital urinary tract anomalies. In this study, we report a case of solitary posterior urethral polyp with type I posterior urethral valve in a 7-day-old neonate presented with urinary retention and deranged renal function. The polyp was diagnosed on cystoscopy. Transurethral resection of the polyp with posterior urethral valve fulguration was performed. Pathologic assessment revealed a fibroepithelial lesion, which was consistent with congenital posterior urethral polyp.

  18. 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.

  19. Therapeutic Interventions to Disrupt the Protein Synthetic Machinery in Melanoma

    PubMed Central

    Kardos, Gregory R.; Robertson, Gavin P.

    2015-01-01

    Control of the protein synthetic machinery is deregulated in many cancers, including melanoma, in order to increase protein production. Tumor suppressors and oncogenes play key roles in protein synthesis from the transcription of rRNA and ribosome biogenesis to mRNA translation initiation and protein synthesis. Major signaling pathways are altered in melanoma to modulate the protein synthetic machinery thereby promoting tumor development. However, despite the importance of this process in melanoma development, involvement of the protein synthetic machinery in this cancer type is an underdeveloped area of study. Here, we review the coupling of melanoma development to deregulation of the protein synthetic machinery. We examine existing knowledge regarding RNA Polymerase I inhibition and mRNA translation focusing on their inhibition for therapeutic applications in melanoma. Furthermore, the contribution of amino acid biosynthesis and involvement of ribosomal proteins are also reviewed as future therapeutic strategies to target deregulated protein production in melanoma. PMID:26139519

  20. 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

  1. Transgenic mouse model of malignant skin melanoma.

    PubMed Central

    Mintz, B; Silvers, W K

    1993-01-01

    Tyr-SV40E transgenic mice are specifically susceptible to melanoma due to expression of the oncogene in pigment cells. Mice of the more susceptible lines die young of early-onset eye melanomas, when skin melanomas are still infrequent and benign. To surmount this obstacle, skin from donors of two high-susceptibility lines was grafted to Tyr-SV40E hosts of a low-susceptibility line of the same inbred strain, thereby enabling the skin to outlive the donors and continue to grow in immunocompetent but tolerant hosts. Unexpectedly, donor pigment cells in all the grafts soon selectively proliferated close to areas of greatest wound healing, forming a dense black tracery, especially at the outer rim of the grafts. These lesions slowly grew radially within the grafts, producing irregular greyish patches. Local vertical thickenings then appeared and developed into small melanomas, which soon ulcerated through the epidermis. The tumors rapidly enlarged and became deeply invasive. Discrete black nevi also arose, with many becoming larger and distinctly blue, but those not near areas of pronounced wound healing did not progress to malignancy. In this first series, malignant melanoma resulted in all the grafts from the more susceptible of two donor lines and in some grafts from the other line. Distant metastases occurred in some cases from each line. Most tumors were hypomelanotic and heterogeneous, with lobes or areas differing in melanization. The results strongly suggest that growth factors and cytokines--known to be produced in wound repair--are triggering the growth and malignant conversion of these genetically susceptible melanocytes and that in the graft situation we are merely witnessing a caricature--a usefully exaggerated manifestation of the true events underlying the genesis of melanomas. The striking resemblance to the human malignancy, the genetic uniformity and different susceptibilities of the transgenic lines, and the experimental possibilities in the grafted

  2. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice.

    PubMed

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  3. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

    PubMed Central

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K.; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  4. [Molecular biology of familial cases of human melanoma].

    PubMed

    Kit, O I; Vodolazhsky, D L; Timoshkina, N N; Przhedetsky, Yu V; Khokhlova, O V

    2015-01-01

    Skin melanoma is an etiologically heterogeneous disease, the development of which is related to a complex interaction of environmental factors and individual genetic characteristics. This article provides current molecular-genetic aspects of familial cases of melanoma and polymorphism of genes directly related to the risk of developing this hereditary disease. The studies of hereditary cancer cases add our knowledge of mechanisms oncotransformation, genetic changes in signaling pathways, which are responsible for invasiveness, metastasis and drug resistance of melanoma cells of the skin.

  5. Proton beam radiotherapy of choroidal melanoma: The Liverpool-Clatterbridge experience

    SciTech Connect

    Damato, Bertil . E-mail: Bertil@damato.co.uk; Kacperek, Andrzej; Chopra, Mona; Campbell, Ian R.; Errington, R. Douglas

    2005-08-01

    Purpose To report on outcomes after proton beam radiotherapy of choroidal melanoma using a 62-MeV cyclotron in patients considered unsuitable for other forms of conservative therapy. Methods and Materials A total of 349 patients with choroidal melanoma referred to the Liverpool Ocular Oncology Centre underwent proton beam radiotherapy at Clatterbridge Centre for Oncology (CCO) between January 1993 and December 2003. Four daily fractions of proton beam radiotherapy were delivered, with a total dose of 53.1 proton Gy, and with lateral and distal safety margins of 2.5 mm. Outcomes measured were local tumor recurrence; ocular conservation; vision; and metastatic death according to age, gender, eye, visual acuity, location of anterior and posterior tumor margins, quadrant, longest basal tumor dimension, tumor height, extraocular extension, and retinal invasion. Results The 5-year actuarial rates were 3.5% for local tumor recurrence, 9.4% for enucleation, 79.1% for conservation of vision of counting fingers or better, 61.1% for conservation of vision of 20/200 or better, 44.8% for conservation of vision of 20/40 or better, and 10.0% for death from metastasis. Conclusion Proton beam radiotherapy with a 62 MeV cyclotron achieves high rates of local tumor control and ocular conservation, with visual outcome depending on tumor size and location.

  6. 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

  7. 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.

  8. 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

  9. Metastatic melanoma mimicking solitary fibrous tumor: report of two cases.

    PubMed

    Bekers, Elise M; van Engen-van Grunsven, Adriana C H; Groenen, Patricia J T A; Westdorp, Harm; Koornstra, Rutger H T; Bonenkamp, Johannes J; Flucke, Uta; Blokx, Willeke A M

    2014-02-01

    Malignant melanomas are known for their remarkable morphological variation and aberrant immunophenotype with loss of lineage-specific markers, especially in recurrences and metastases. Hot spot mutations in BRAF, NRAS, GNAQ, and GNA11 and mutations in KIT are oncogenic events in melanomas. Therefore, genotyping can be a useful ancillary diagnostic tool. We present one case each of recurrent and metastatic melanoma, both showing histological and immunohistochemical features of solitary fibrous tumor (SFT). Mutational analysis detected BRAF and NRAS mutations in the primary and secondary lesions, respectively. This result confirmed the diagnosis of recurrent/metastastic melanoma.

  10. Melanoma miRNA trafficking controls tumour primary niche formation.

    PubMed

    Dror, Shani; Sander, Laureen; Schwartz, Hila; Sheinboim, Danna; Barzilai, Aviv; Dishon, Yuval; Apcher, Sebastien; Golan, Tamar; Greenberger, Shoshana; Barshack, Iris; Malcov, Hagar; Zilberberg, Alona; Levin, Lotan; Nessling, Michelle; Friedmann, Yael; Igras, Vivien; Barzilay, Ohad; Vaknine, Hananya; Brenner, Ronen; Zinger, Assaf; Schroeder, Avi; Gonen, Pinchas; Khaled, Mehdi; Erez, Neta; Hoheisel, Jörg D; Levy, Carmit

    2016-09-01

    Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche. PMID:27548915

  11. Serpine2, a potential novel target for combating melanoma metastasis

    PubMed Central

    Wu, Qi Wei

    2016-01-01

    Early stages of melanoma can be treated by surgical resection of tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both metastasis promoting and metastasis suppressor genes have been reported, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating cancer. In the present study, we found that Serpin Peptidase Inhibitor 2, Serpine2 was involved in the metastasis of melanoma cells. The requirement of Serpine2 in the migration of melanoma cells was confirmed by gene silencing and over-expression in vitro. Moreover, down-regulation of Serpine2 expression strikingly inhibited melanoma cellular metastasis in vivo. Finally, we found that Serpine2 promotes melanoma metastasis through the glycogen synthesis kinase 3β, GSK-3β signaling pathway. To conclude, our findings suggested a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. PMID:27347308

  12. Melanoma of the sellar region mimicking pituitary adenoma.

    PubMed

    Sidiropoulos, Michael; Syro, Luis V; Rotondo, Fabio; Scheithauer, Bernd W; Penagos, Luis Carlos; Uribe, Humberto; Ramirez, Maria Del Pilar; Horvath, Eva; Goth, Miklos; Kovacs, Kalman

    2013-04-01

    We report here the case of an 82-year-old woman who presented with visual disturbance. MRI demonstrated a sellar mass. The diagnosis of pituitary adenoma was made. She underwent transnasal surgery. Histologic, immunohistochemical and ultrastructural studies indicated that the tumor was a melanoma. Despite an exhaustive search for a primary lesion elsewhere, none was found. The sellar tumor was considered a primary lesion, although extrasellar primary tumor imaging cannot be excluded with 100% certainty. Reported examples of melanoma affecting the sellar region are few. They exhibit morphologic features identical to those of melanomas arising elsewhere. Although very rare, primary melanomas enter into the differential diagnosis of sellar lesions. PMID:22624497

  13. Rarity of CDK4 germline mutations in familial melanoma.

    PubMed

    Goldstein, A M; Chidambaram, A; Halpern, A; Holly, E A; Guerry IV, D; Sagebiel, R; Elder, D E; Tucker, M A

    2002-02-01

    To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma.

  14. Identification of donor melanoma in a renal transplant recipient.

    PubMed

    Wilson, L J; Horvat, R T; Tilzer, L; Meis, A M; Montag, L; Huntrakoon, M

    1992-12-01

    A patient with chronic renal failure received a closely matched cadaveric kidney. Approximately 3 months after transplantation, the patient developed a metastatic malignant melanoma. A large retroperitoneal mass consisting of large pleomorphic polygonal neoplastic cells was found close to the donated kidney. This tumor was diagnosed as a malignant melanoma. DNA analysis of this tumor, the donated kidney, and the recipient indicated that the melanoma originated from the donor. Although this is not the first report of a donated melanoma, it is the first report of definitive DNA analysis of the origin of the malignant cells.

  15. SEOM guidelines for the management of Malignant Melanoma 2015.

    PubMed

    Berrocal, A; Arance, A; Espinosa, E; Castaño, A G; Cao, M G; Larriba, J L G; Martín, J A L; Márquez, I; Soria, A; Algarra, S M

    2015-12-01

    All melanoma patients must be confirmed histologically and resected according to Breslow. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon must be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 therapy. Up to 10 years follow up is recommended for melanoma patients with dermatologic examinations and physical exams.

  16. TET2 Negatively Regulates Nestin Expression in Human Melanoma.

    PubMed

    Gomes, Camilla B F; Zechin, Karina G; Xu, Shuyun; Stelini, Rafael F; Nishimoto, Ines N; Zhan, Qian; Xu, Ting; Qin, Gungwei; Treister, Nathaniel S; Murphy, George F; Lian, Christine G

    2016-06-01

    Although melanoma is an aggressive cancer, the understanding of the virulence-conferring pathways involved remains incomplete. We have demonstrated that loss of ten-eleven translocation methylcytosine dioxygenase (TET2)-mediated 5-hydroxymethylcytosine (5-hmC) is an epigenetic driver of melanoma growth and a biomarker of clinical virulence. We also have determined that the intermediate filament protein nestin correlates with tumorigenic and invasive melanoma growth. Here we examine the relationships between these two biomarkers. Immunohistochemistry staining of nestin and 5-hmC in 53 clinically annotated primary and metastatic patient melanomas revealed a significant negative correlation. Restoration of 5-hmC, as assessed in a human melanoma cell line by introducing full-length TET2 and TET2-mutated constructs, decreased nestin gene and protein expression in vitro. Genome-wide mapping using hydroxymethylated DNA immunoprecipitation sequencing disclosed significantly less 5-hmC binding in the 3' untranslated region of the nestin gene in melanoma compared to nevi, and 5-hmC binding in this region was significantly increased after TET2 overexpression in human melanoma cells in vitro. Our findings provide evidence suggesting that nestin regulation is negatively controlled epigenetically by TET2 via 5-hmC binding at the 3' untranslated region of the nestin gene, providing one potential pathway for understanding melanoma growth characteristics. Studies are now indicated to further define the interplay between 5-hmC, nestin expression, and melanoma virulence. PMID:27102770

  17. Preoperative nuclear scans in patients with melanoma

    SciTech Connect

    Au, F.C.; Maier, W.P.; Malmud, L.S.; Goldman, L.I.; Clark, W.H. Jr.

    1984-05-15

    One hundred forty-one liver scans, 137 brain scans, and 112 bone scans were performed in 192 patients with clinical Stage 1 melanoma. One liver scan was interpreted as abnormal; liver biopsy of that patient showed no metastasis. There were 11 suggestive liver scans; three of the patients with suggestive liver scans had negative liver biopsies. The remaining eight patients were followed from 4 to 6 years and none of those patients developed clinical evidence of hepatic metastases. All of the brain scans were normal. Five patients had suggestive bone scans and none of those patients had manifested symptoms of osseous metastases with a follow-up of 2 to 4.5 years. This study demonstrates that the use of preoperative liver, brain and bone scan in the evaluation of patients with clinical Stage 1 melanoma is virtually unproductive.

  18. Pathways and therapeutic targets in melanoma

    PubMed Central

    Shtivelman, Emma; Davies, Michael A.; Hwu, Patrick; Yang, James; Lotem, Michal; Oren, Moshe; Flaherty, Keith T.; Fisher, David E.

    2014-01-01

    This review aims to summarize the current knowledge of molecular pathways and their clinical relevance in melanoma. Metastatic melanoma was a grim diagnosis, but in recent years tremendous advances have been made in treatments. Chemotherapy provided little benefit in these patients, but development of targeted and new immune approaches made radical changes in prognosis. This would not have happened without remarkable advances in understanding the biology of disease and tremendous progress in the genomic (and other “omics”) scale analyses of tumors. The big problems facing the field are no longer focused exclusively on the development of new treatment modalities, though this is a very busy area of clinical research. The focus shifted now to understanding and overcoming resistance to targeted therapies, and understanding the underlying causes of the heterogeneous responses to immune therapy. PMID:24743024

  19. [Systemic treatment of melanoma brain metastases].

    PubMed

    Le Rhun, É; Mateus, C; Mortier, L; Dhermain, F; Guillot, B; Grob, J-J; Lebbe, C; Thomas, M; Jouary, T; Leccia, M-T; Robert, C

    2015-02-01

    Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

  20. Relationship between Latitude and Melanoma in Italy.

    PubMed

    Crocetti, Emanuele; Buzzoni, Carlotta; Chiarugi, Alessandra; Nardini, Paolo; Pimpinelli, Nicola

    2012-01-01

    Objective. Evaluate the ecological relationship between skin melanoma epidemiology and latitude in Italy. Methods. We used data from the Italian network of cancer registries (Airtum). In a Poisson model, we evaluated the effect on incidence, mortality, and survival of latitude, adjusting for some demographic, social, phenotypic, and behavioural variables. Results. Incidence increased in Italy by 17% for each degree of increase in latitude. The effect of latitude was statistically significantly present also adjusting for other variables (incidence rate ratio = 1.08). The effect of latitude on increasing mortality (mortality rate ratio = 1.27) and improving survival (relative excess risk of death = 0.93) was no longer present in the multivariate model. Conclusion. Melanoma incidence, mortality, and survival vary in Italy according to latitude. After adjustment for several confounders, incidence still grows with growing latitude. Presumably, latitude expresses other variables that might be related to individual susceptibility and/or local care.