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Sample records for melanomas suggests hsp-27

  1. Effect of phosphorylated hsp27 on proliferation of human endothelial and smooth muscle cells.

    Science.gov (United States)

    Trott, Deborah; McManus, Ciara A; Martin, Jody L; Brennan, Bryony; Dunn, Michael J; Rose, Marlene L

    2009-06-01

    Recent studies have suggested a protective role of hsp27 against atherosclerosis and transplant graft vasculopathy. Here we have investigated the effects of over-expression of wild-type hsp27 and its phosphorylation mimics on proliferation of human endothelial cells (ECs) and smooth muscle cells (SMCs). ECs and SMCs cultured from human blood vessels or cells lines (human microvascular endothelial cell line and human telomerase reverse transcriptase subunit SMC) were infected with adenovirus containing DNA from wild-type hsp27, hyper-phosphorylated hsp27 mimic (3D hsp27), hypo-phosphorylated hsp27 mimic (3A hsp27) or anti-sense hsp27, and proliferation measured over the next 5 days. Protein extracts from infected cells were subjected to proteomic analysis using 2-D DIGE. Over-expression of 3D hsp27 and anti-sense hsp27 but not 3A hsp27 mimic caused significant inhibition of proliferation of ECs and SMCs. Proteomic analysis focussed on proteins that were significantly down-regulated by the 3D hsp27 mutant. The cell cycling proteins stathmin, cofilin and ubiquitination enzymes fullfilled these criteria. 1-D Western blots of infected human microvascular endothelial cell line and human telomerase reverse transcriptase subunit SMC confirmed down-regulation of stathmin, cofilin and ubiquitination enzymes by 3D hsp27. The phosphorylation status of hsp27 is an important regulator of proliferation of human vascular ECs and SMCs; possibly contributing to cardiovascular protection.

  2. Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

    Energy Technology Data Exchange (ETDEWEB)

    Guttmann, David M.; Hart, Lori [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Du, Kevin [Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States); Seletsky, Andrew [Department of Biology, Drexel University, Philadelphia, Pennsylvania (United States); Koumenis, Constantinos, E-mail: koumenis@xrt.upenn.edu [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2013-09-01

    Purpose: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and γH2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. Results: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. Conclusions: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

  3. A NETWORK-BASED APPROACH FOR PREDICTING HSP27 KNOCK-OUT TARGETS IN MOUSE SKELETAL MUSCLES

    Directory of Open Access Journals (Sweden)

    Malek Kammoun

    2013-03-01

    Full Text Available Thanks to genomics, we have previously identified markers of beef tenderness, and computed a bioinformatic analysis that enabled us to build an interactome in which we found Hsp27 at a crucial node. Here, we have used a network-based approach for understanding the contribution of Hsp27 to tenderness through the prediction of its interactors related to tenderness. We have revealed the direct interactors of Hsp27. The predicted partners of Hsp27 included proteins involved in different functions, e.g. members of Hsp families (Hsp20, Cryab, Hsp70a1a, and Hsp90aa1, regulators of apoptosis (Fas, Chuk, and caspase-3, translation factors (Eif4E, and Eif4G1, cytoskeletal proteins (Desmin and antioxidants (Sod1. The abundances of 15 proteins were quantified by Western blotting in two muscles of HspB1-null mice and their controls. We observed changes in the amount of most of the Hsp27 predicted targets in mice devoid of Hsp27 mainly in the most oxidative muscle. Our study demonstrates the functional links between Hsp27 and its predicted targets. It suggests that Hsp status, apoptotic processes and protection against oxidative stress are crucial for post-mortem muscle metabolism, subsequent proteolysis, and therefore for beef tenderness.

  4. Localization of heat shock protein 27 (hsp27) in the rat gingiva and its changes with tooth eruption.

    Science.gov (United States)

    Sasaki, Au; Yamada, Tohru; Inoue, Katsuyuki; Momoi, Tomoko; Tokunaga, Hiroshi; Sakiyama, Koji; Kanegae, Haruhide; Suda, Naoto; Amano, Osamu

    2011-02-26

    Heat shock protein 27 kDa (Hsp27) functions as a molecular chaperon to prevent apoptosis as well as to contribute to the regulation of cell proliferation and differentiation during development. In the present study, the localization of Hsp27 in the oral epithelium of rats and its expression change during formation of the gingiva with the tooth eruption were examined immunohistochemically to elucidate the roles of Hsp27 in the oral mucosa.In adult rats, Hsp27-immunoreactivity was localized in the prickle and granular layers but absent in the basal and horny layers of the oral epithelium. On the other hand, in the outer and sulcular epithelia of the free gingival, Hsp27-immunoreactivity was detected in the whole layers, while it was not found in the proliferation zone of the junctional epithelium immunoreactive for Ki67. In immature rats on 10th postnatal day, Hsp27-immunoreactivity was intense in the prickle and granular layers of the oral epithelium, but was not detected in its basal layer. In rats at the eruptive phase on 15th postnatal day, Hsp27-immunoreactivity was detected in sites of the basal layer adjacent to where the dental cusps penetrated through the oral epithelium. Although the immunoreactivity for Ki67 was found in the basal layer of the oral epithelium, it was not localized in the Hsp27-immunopositive sites of tooth-penetration in the basal layer. Just after the tooth-eruption on 20th postnatal day, Hsp27-immunoreactivity was not found in the stratified squamous epithelium at the dentogingival junction, whereas it was intense in a single layer of cuboidal epithelial cells attached to the tooth neck. Ki67-positive cells were scattered in the stratified squamous epithelium at the dentogingival junction, whereas no positive cells were found in the portion of a single layer of cuboidal epithelial cells.These findings suggest that the outer and sulcular epithelia of the free gingiva have a relatively slower rate of proliferation than other gingival and

  5. Localization of Heat Shock Protein 27 (Hsp27) in the Rat Gingiva and its Changes with Tooth Eruption

    International Nuclear Information System (INIS)

    Sasaki, Au; Yamada, Tohru; Inoue, Katsuyuki; Momoi, Tomoko; Tokunaga, Hiroshi; Sakiyama, Koji; Kanegae, Haruhide; Suda, Naoto; Amano, Osamu

    2011-01-01

    Heat shock protein 27 kDa (Hsp27) functions as a molecular chaperon to prevent apoptosis as well as to contribute to the regulation of cell proliferation and differentiation during development. In the present study, the localization of Hsp27 in the oral epithelium of rats and its expression change during formation of the gingiva with the tooth eruption were examined immunohistochemically to elucidate the roles of Hsp27 in the oral mucosa. In adult rats, Hsp27-immunoreactivity was localized in the prickle and granular layers but absent in the basal and horny layers of the oral epithelium. On the other hand, in the outer and sulcular epithelia of the free gingival, Hsp27-immunoreactivity was detected in the whole layers, while it was not found in the proliferation zone of the junctional epithelium immunoreactive for Ki67. In immature rats on 10th postnatal day, Hsp27-immunoreactivity was intense in the prickle and granular layers of the oral epithelium, but was not detected in its basal layer. In rats at the eruptive phase on 15th postnatal day, Hsp27-immunoreactivity was detected in sites of the basal layer adjacent to where the dental cusps penetrated through the oral epithelium. Although the immunoreactivity for Ki67 was found in the basal layer of the oral epithelium, it was not localized in the Hsp27-immunopositive sites of tooth-penetration in the basal layer. Just after the tooth-eruption on 20th postnatal day, Hsp27-immunoreactivity was not found in the stratified squamous epithelium at the dentogingival junction, whereas it was intense in a single layer of cuboidal epithelial cells attached to the tooth neck. Ki67-positive cells were scattered in the stratified squamous epithelium at the dentogingival junction, whereas no positive cells were found in the portion of a single layer of cuboidal epithelial cells. These findings suggest that the outer and sulcular epithelia of the free gingiva have a relatively slower rate of proliferation than other gingival and

  6. αB-crystallin and HSP27 in glial cells in tauopathies.

    Science.gov (United States)

    López-González, Irene; Carmona, Margarita; Arregui, Laura; Kovacs, Gabor G; Ferrer, Isidre

    2014-12-01

    Tauopathies are neurodegenerative diseases characterized by hyper-phosphorylated tau deposition in neurons and glial cells. Chaperones, such as small heat shock proteins αB-crystallin and HSP27 highly expressed in normal glial cells, have been postulated as putative molecules preventing abnormal deposition and folding in glial cells in tauopathies. The objective of this work was to assess the expression of αB-crystallin, phosphorylated αB-crystallin at Ser59 and HSP27 in glial cells with and without tau deposits in progressive supranuclear palsy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick's disease (PiD), Alzheimer's disease, frontotemporal lobar degeneration associated with mutations in the tau gene (FTLD-tau), globular glial tauopathy (GGT) and tauopathy in the elderly. Immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy have been used for this purpose. Increased expression of αB-crystallin and phosphorylated αB-crystallin at Ser59 occurs in a subpopulation of glial cells with and without hyper-phosphorylated tau deposition in all the analyzed tauopathies, but their expression in neurons is restricted to ballooned neurons in CBD, AGD and PiD. HSP27 barely co-localizes with tau and with phosphorylated αB-crystallin at Ser59, thus making the formation of active dimers operating as chaperones unlikely. Results suggest a limited function of αB-crystallin and HSP27 in preventing abnormal tau protein deposition in glial cells and neurons; in addition, the expression of αB-crystallin phosphorylated at Ser59 may act as a protective factor in glial cells. © 2014 Japanese Society of Neuropathology.

  7. Effect of HSP27 on Human Breast Tumor Cell Growth and Motility

    National Research Council Canada - National Science Library

    Hickey, Eileen

    1997-01-01

    .... Since Hsp27 regulates actin microfilament dynamics, we hypothesize that cells expressing high levels of Hsp27 will show increased motility and altered chemotactic properties, in addition to increased...

  8. LPS ameliorates renal ischemia/reperfusion injury via Hsp27 up-regulation.

    Science.gov (United States)

    He, Kang; Xia, Lei; Zhang, Jianjun

    2018-03-01

    We have recently reported lipopolysaccharide (LPS) pretreatment attenuated renal ischemia/reperfusion injury (IRI), but the exact mechanism remains to be well elucidated. It was reported that heat shock protein (Hsp) 27 was up-regulated after administration of LPS, but whether a direct link existed between Hsp27 up-regulation and LPS-induced protection against renal IRI is still unknown. Mice were exposed to IRI or sham procedure, with pretreatment of LPS or not. Quercetin, an inhibitor of Hsp27 synthesis, was used, and an RNA interference with adenovirus vector using short hairpin RNA targeting Hsp27 was developed for inhibition of Hsp27 in mice. In addition, mice trans-infected with adenovirus vector encoding Hsp27 were used to testify the role of Hsp27 overexpression in LPS-induced renoprotection. Renal function, histological damage, inflammatory reaction, oxidative stress and apoptosis indices were measured. Western blot analysis was used to detect expression of Hsp27. We found LPS pretreatment stimulated renal up-regulation of Hsp27 and reduced renal IRI proven by less renal dysfunction, histological damage, inflammatory reaction, oxidative stress and apoptosis. It was observed that inhibition of Hsp27 synthesis by Quercetin abolished LPS-induced renoprotective effects. After renal knockdown of Hsp27, LPS-induced tolerance against renal IRI was largely removed. Mice with Hsp27 overexpression showed significantly improved renal function after IRI and LPS combined with Hsp27 overexpression had a synergistic effect on protection against renal IRI. Administration of LPS produces protective effects against renal IRI via Hsp27 up-regulation. Preconditional Hsp27 up-regulation might have a great potential for the treatment of renal IRI via ameliorating apoptosis.

  9. Survival of cancer stem cells under hypoxia and serum depletion via decrease in PP2A activity and activation of p38-MAPKAPK2-Hsp27.

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    Shih-Pei Lin

    Full Text Available Hypoxia and serum depletion are common features of solid tumors that occur upon antiangiogenesis, irradiation and chemotherapy across a wide variety of malignancies. Here we show that tumor cells expressing CD133, a marker for colorectal cancer initiating or stem cells, are enriched and survive under hypoxia and serum depletion conditions, whereas CD133- cells undergo apoptosis. CD133+ tumor cells increase cancer stem cell and epithelial-mesenchymal transition properties. Moreover, via screening a panel of tyrosine and serine/threonine kinase pathways, we identified Hsp27 is constitutively activated in CD133+ cells rather than CD133- cell under hypoxia and serum depletion conditions. However, there was no difference in Hsp27 activation between CD133+ and CD133- cells under normal growth condition. Hsp27 activation, which was mediated by the p38MAPK-MAPKAPK2-Hsp27 pathway, is required for CD133+ cells to inhibit caspase 9 and 3 cleavage. In addition, inhibition of Hsp27 signaling sensitizes CD133+ cells to hypoxia and serum depletion -induced apoptosis. Moreover, the antiapoptotic pathway is also activated in spheroid culture-enriched CD133+ cancer stem cells from a variety of solid tumor cells including lung, brain and oral cancer, suggesting it is a common pathway activated in cancer stem cells from multiple tumor types. Thus, activation of PP2A or inactivation of the p38MAPK-MAPKAPK2-Hsp27 pathway may develop new strategies for cancer therapy by suppression of their TIC population.

  10. Hsp27 binding to the 3′UTR of bim mRNA prevents neuronal death during oxidative stress–induced injury: a novel cytoprotective mechanism

    Science.gov (United States)

    Dávila, David; Jiménez-Mateos, Eva M.; Mooney, Claire M.; Velasco, Guillermo; Henshall, David C.; Prehn, Jochen H. M.

    2014-01-01

    Neurons face a changeable microenvironment and therefore need mechanisms that allow rapid switch on/off of their cytoprotective and apoptosis-inducing signaling pathways. Cellular mechanisms that control apoptosis activation include the regulation of pro/antiapoptotic mRNAs through their 3′-untranslated region (UTR). This region holds binding elements for RNA-binding proteins, which can control mRNA translation. Here we demonstrate that heat shock protein 27 (Hsp27) prevents oxidative stress–induced cell death in cerebellar granule neurons by specific regulation of the mRNA for the proapoptotic BH3-only protein, Bim. Hsp27 depletion induced by oxidative stress using hydrogen peroxide (H2O2) correlated with bim gene activation and subsequent neuronal death, whereas enhanced Hsp27 expression prevented these. This effect could not be explained by proteasomal degradation of Bim or bim promoter inhibition; however, it was associated with a specific increase in the levels of bim mRNA and with its binding to Hsp27. Finally, we determined that enhanced Hsp27 expression in neurons exposed to H2O2 or glutamate prevented the translation of a reporter plasmid where bim-3′UTR mRNA sequence was cloned downstream of a luciferase gene. These results suggest that repression of bim mRNA translation through binding to the 3′UTR constitutes a novel cytoprotective mechanism of Hsp27 during stress in neurons. PMID:25187648

  11. Effects of HSP27 chaperone on THP-1 tumor cell apoptosis.

    Science.gov (United States)

    Kaigorodova, E V; Ryazantseva, N V; Novitskii, V V; Maroshkina, A N; Belkina, M V

    2012-11-01

    The role of Hsp27 (heat shock protein 27) chaperone in regulation of THP-1 tumor cell apoptosis was studied. Realization of tumor cell apoptosis under conditions of in vitro culturing with Hsp27 specific inhibitor (KRIBB3) was evaluated by fluorescent microscopy with FITC-labeled annexin V and propidium iodide. Measurements of Bcl-2 family proteins (Bcl-2, Bax, Bad) in tumor cells incubated with Hsp27 inhibitor were carried out by Western blotting. Chaperone Hsp27 acted as apoptosis inhibitor in THP-1 tumor cells modulating the proportion of antiapoptotic (Bcl-2) and proapoptotic (Bax and Bad) proteins.

  12. Monocyte Proteomics Reveals Involvement of Phosphorylated HSP27 in the Pathogenesis of Osteoporosis

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    Bhavna Daswani

    2015-01-01

    Full Text Available Peripheral monocytes, precursors of osteoclasts, have emerged as important candidates for identifying proteins relevant to osteoporosis, a condition characterized by low Bone Mineral Density (BMD and increased susceptibility for fractures. We employed 4-plex iTRAQ (isobaric tags for relative and absolute quantification coupled with LC-MS/MS (liquid chromatography coupled with tandem mass spectrometry to identify differentially expressed monocyte proteins from premenopausal and postmenopausal women with low versus high BMD. Of 1801 proteins identified, 45 were differentially abundant in low versus high BMD, with heat shock protein 27 (HSP27 distinctly upregulated in low BMD condition in both premenopausal and postmenopausal categories. Validation in individual samples (n=80 using intracellular ELISA confirmed that total HSP27 (tHSP27 as well as phosphorylated HSP27 (pHSP27 was elevated in low BMD condition in both categories (P<0.05. Further, using transwell assays, pHSP27, when placed in the upper chamber, could increase monocyte migration (P<0.0001 and this was additive in combination with RANKL (receptor activator of NFkB ligand placed in the lower chamber (P=0.05. Effect of pHSP27 in monocyte migration towards bone milieu can result in increased osteoclast formation and thus contribute to pathogenesis of osteoporosis. Overall, this study reveals for the first time a novel link between monocyte HSP27 and BMD.

  13. Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture ...

    Indian Academy of Sciences (India)

    Prakash

    2009-12-09

    Dec 9, 2009 ... Colon carcinoma; HSP27; HSP72; MRP; IL-6; nitric oxide; co-culture. Expression of ... [Paduch R, Jakubowicz-Gil J and Kandefer-Szerszeń M 2009 Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture of colon tumour ...... J, Jeannin J-F and Juillerat-Jeanneret L 2005 Evaluation of the.

  14. Hsp27 gene in Drosophila ananassae subgroup was split by a ...

    Indian Academy of Sciences (India)

    heat shock protein 27 (Hsp27) is a critical single-copy intron-free nuclear gene involved in the defense responseagainst fungi and bacteria, and is a regulator of adult lifespan. In the present study, 33 homologousHsp27nucleotide sequencesfrom differentDrosophilaspecies were amplified by PCR and reverse transcription ...

  15. Hsp27 gene in Drosophila ananassae subgroup was split by a ...

    Indian Academy of Sciences (India)

    Abstract. In Drosophila, heat shock protein 27 (Hsp27) is a critical single-copy intron-free nuclear gene involved in the defense response against fungi and bacteria, and is a regulator of adult lifespan. In the present study, 33 homologous Hsp27 nucleotide sequences from different Drosophila species were amplified by PCR ...

  16. Upregulation of Phosphorylated HSP27, PRDX2, GRP75, GRP78 and GRP94 in Acquired Middle Ear Cholesteatoma Growth

    Science.gov (United States)

    Ho, Kuen Yao; Yeh, Tai Sheng; Huang, Han Hsiang; Hung, Kuo Feng; Chai, Chee Yin; Chen, Wan Tzu; Tsai, Shih Meng; Chang, Ning Chia; Chien, Chen Yu; Wang, Hsun Mo; Wu, Yu Jen

    2013-01-01

    Cholesteatoma is a destructive and expanding growth of keratinizing squamous epithelium in the middle ear or petrous apex. The molecular and cellular processes of the pathogenesis of acquired middle ear cholesteatoma have not been fully understood. In this study, comparative proteomic analysis was conducted to investigate the roles of specific proteins in the pathways regarding keratinocyte proliferation in cholesteatoma. The differential proteins were detected by comparing the two-dimension electrophoresis (2-DE) maps of the epithelial tissues of 12 attic cholesteatomas with those of retroauricular skins. There were 14 upregulated proteins in the epithelial tissues of cholesteatoma in comparison with retroauricular skin. The modulation of five crucial proteins, HSP27, PRDX2, GRP75, GRP78 and GRP94, was further determined by RT-PCR, Western blot and immunohistochemistry. Phosphorylation of HSP27 at Ser-82 was identified by mass spectroscopy. The results of this study suggested that phosphorylated HSP27 is the end expression of two potential signal-transduction pathways, and together with PRDX2, they are very likely involved in the proliferation of keratinocytes in cholesteatoma. Upregulations of GRP75, GRP78 and GRP94 in keratinocytes may be able to counter endoplasmic reticulum stress, to inhibit cell apoptosis, to prevent protein unfolding and to promote cholesteatoma growth. PMID:23852020

  17. Proteomic Characterization of Annexin l (ANX1 and Heat Shock Protein 27 (HSP27 as Biomarkers for Invasive Hepatocellular Carcinoma Cells.

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    Ruo-Chiau Wang

    Full Text Available To search for reliable biomarkers and drug targets for management of hepatocellular carcinoma (HCC, we performed a global proteomic analysis of a pair of HCC cell lines with distinct differentiation statuses using 2-DE coupled with MALDI-TOF MS. In total, 106 and 55 proteins were successfully identified from the total cell lysate and the cytosolic, nuclear and membrane fractions in well-differentiated (HepG2 and poorly differentiated (SK-Hep-1 HCC clonal variants, respectively. Among these proteins, nine spots corresponding to proteins differentially expressed between HCC cell types were selected and confirmed by immunofluorescence staining and western blotting. Notably, Annexin 1 (ANX1, ANX-2, vimentin and stress-associated proteins, such as GRP78, HSP75, HSC-70, protein disulfide isomerase (PDI, and heat shock protein-27 (HSP27, were exclusively up-regulated in SK-Hep-1 cells. Elevated levels of ANX-4 and antioxidant/metabolic enzymes, such as MnSOD, peroxiredoxin, NADP-dependent isocitrate dehydrogenase, α-enolase and UDP-glucose dehydrogenase, were observed in HepG2 cells. We functionally demonstrated that ANX1 and HSP27 were abundantly overexpressed only in highly invasive types of HCC cells, such as Mahlavu and SK-Hep-1. Knockdown of ANX1 or HSP27 in HCC cells resulted in a severe reduction in cell migration. The in-vitro observations of ANX1 and HSP27 expressions in HCC sample was demonstrated by immunohistochemical stains performed on HCC tissue microarrays. Poorly differentiated HCC tended to have stronger ANX1 and HSP27 expressions than well-differentiated or moderately differentiated HCC. Collectively, our findings suggest that ANX1 and HSP27 are two novel biomarkers for predicting invasive HCC phenotypes and could serve as potential treatment targets.

  18. Hsp27 binding to the 3'UTR of bim mRNA prevents neuronal death during oxidative stress-induced injury: a novel cytoprotective mechanism.

    Science.gov (United States)

    Dávila, David; Jiménez-Mateos, Eva M; Mooney, Claire M; Velasco, Guillermo; Henshall, David C; Prehn, Jochen H M

    2014-11-01

    Neurons face a changeable microenvironment and therefore need mechanisms that allow rapid switch on/off of their cytoprotective and apoptosis-inducing signaling pathways. Cellular mechanisms that control apoptosis activation include the regulation of pro/antiapoptotic mRNAs through their 3'-untranslated region (UTR). This region holds binding elements for RNA-binding proteins, which can control mRNA translation. Here we demonstrate that heat shock protein 27 (Hsp27) prevents oxidative stress-induced cell death in cerebellar granule neurons by specific regulation of the mRNA for the proapoptotic BH3-only protein, Bim. Hsp27 depletion induced by oxidative stress using hydrogen peroxide (H2O2) correlated with bim gene activation and subsequent neuronal death, whereas enhanced Hsp27 expression prevented these. This effect could not be explained by proteasomal degradation of Bim or bim promoter inhibition; however, it was associated with a specific increase in the levels of bim mRNA and with its binding to Hsp27. Finally, we determined that enhanced Hsp27 expression in neurons exposed to H2O2 or glutamate prevented the translation of a reporter plasmid where bim-3'UTR mRNA sequence was cloned downstream of a luciferase gene. These results suggest that repression of bim mRNA translation through binding to the 3'UTR constitutes a novel cytoprotective mechanism of Hsp27 during stress in neurons. © 2014 Dávila et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  19. Radiotherapy of primary human melanomas - experiences and suggestions

    International Nuclear Information System (INIS)

    Elsmann, H.J.; Ernst, K.; Suter, L.

    1991-01-01

    We treated 60 invasive primary human melanomas by soft X-rays. In 23 additional cases radiotherapy was applied after total excision of a primary melanoma. Only in two cases was a tumor observed in the field of irradiation during the follow-up period: A recurrence of a primary melanoma and a skin metastasis. Radioresistance cannot be unequivocally assumed in either case. Since deeply situated in-transit metastases cannot be destroyed by soft X-rays in spite of our good results we regard radiotherapy of invasive primary melanomas as a second choice treatment to be administered if impaired general health, excessive tumor growth in certain localisations or refusal of the patient to not allow a major operation. Nodular parts of primary melanomas should be excised before radiotherapy to obtain material for histopathological confirmation of the diagnosis and to determine the thickness of the tumor. X-rays of lower hardness can subsequently be applied. (orig.) [de

  20. Radiotherapy of primary human melanomas - experiences and suggestions

    Energy Technology Data Exchange (ETDEWEB)

    Elsmann, H.J.; Ernst, K.; Suter, L. (Muenster Univ. (Germany). Fachklinik Hornheide fuer Tumoren, Tuberkulose und Wiederherstellung an Gesicht und Haut)

    1991-07-01

    We treated 60 invasive primary human melanomas by soft X-rays. In 23 additional cases radiotherapy was applied after total excision of a primary melanoma. Only in two cases was a tumor observed in the field of irradiation during the follow-up period: A recurrence of a primary melanoma and a skin metastasis. Radioresistance cannot be unequivocally assumed in either case. Since deeply situated in-transit metastases cannot be destroyed by soft X-rays in spite of our good results we regard radiotherapy of invasive primary melanomas as a second choice treatment to be administered if impaired general health, excessive tumor growth in certain localisations or refusal of the patient to not allow a major operation. Nodular parts of primary melanomas should be excised before radiotherapy to obtain material for histopathological confirmation of the diagnosis and to determine the thickness of the tumor. X-rays of lower hardness can subsequently be applied. (orig.).

  1. Characterization of HSP27 phosphorylation sites in human atherosclerotic plaque secretome

    DEFF Research Database (Denmark)

    Durán, Mari-Carmen; Boeri-Erba, Elisabetta; Mohammed, Shabaz

    2007-01-01

    spectrometry (MS). Among the identified proteins, two isoforms of heat shock protein 27 (HSP27), a protein recently described as a potential biomarker of atherosclerosis, were detected. However, the putative mechanisms in which HSP27 isoforms could be involved in the atherosclerotic process are unknown. Thus......, the role that phosphorylated HSP27 could play in the atherosclerotic process is actually under study. The present work shows the strategies employed to characterize the phosphorylation in the HSP27 secreted by atheroma plaque samples. The application of liquid chromatography tandem mass spectrometry (MS......-lymphocytes). These interactions can be mediated by proteins secreted from these cells, which therefore exert an important role in the atherosclerotic process. We recently described a novel strategy for the characterization of the human atherosclerotic plaque secretome, combining two-dimensional gel electrophoresis and mass...

  2. Integrative genetic analysis suggests that skin color modifies the genetic architecture of melanoma.

    Science.gov (United States)

    Hulur, Imge; Skol, Andrew D; Gamazon, Eric R; Cox, Nancy J; Onel, Kenan

    2017-01-01

    Melanoma is the deadliest form of skin cancer and presents a significant health care burden in many countries. In addition to ultraviolet radiation in sunlight, the main causal factor for melanoma, genetic factors also play an important role in melanoma susceptibility. Although genome-wide association studies have identified many single nucleotide polymorphisms associated with melanoma, little is known about the proportion of disease risk attributable to these loci and their distribution throughout the genome. Here, we investigated the genetic architecture of melanoma in 1,888 cases and 990 controls of European non-Hispanic ancestry. We estimated the overall narrow-sense heritability of melanoma to be 0.18 (P < 0.03), indicating that genetics contributes significantly to the risk of sporadically-occurring melanoma. We then demonstrated that only a small proportion of this risk is attributable to known risk variants, suggesting that much remains unknown of the role of genetics in melanoma. To investigate further the genetic architecture of melanoma, we partitioned the heritability by chromosome, minor allele frequency, and functional annotations. We showed that common genetic variation contributes significantly to melanoma risk, with a risk model defined by a handful of genomic regions rather than many risk loci distributed throughout the genome. We also demonstrated that variants affecting gene expression in skin account for a significant proportion of the heritability, and are enriched among melanoma risk loci. Finally, by incorporating skin color into our analyses, we observed both a shift in significance for melanoma-associated loci and an enrichment of expression quantitative trait loci among melanoma susceptibility variants. These findings suggest that skin color may be an important modifier of melanoma risk. We speculate that incorporating skin color and other non-genetic factors into genetic studies may allow for an improved understanding of melanoma

  3. Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis

    DEFF Research Database (Denmark)

    Zhuang, Hongqin; Jiang, Weiwei; Cheng, Wei

    2010-01-01

    Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL...... siRNA on drug sensitization of A549 cells to TRAIL treatment. The results showed that treatment of A549 cells with HSP27 siRNA down-regulated HSP27 expression but did not induce significant apoptosis. However, combination of HSP27 siRNA with TRAIL-induced significant apoptosis in TRAIL-resistant A549...... cells. In addition to inducing caspases activation and apoptosis, combined treatment with HSP27 siRNA and TRAIL also increased JNK and p53 expression and activity. Collectively, these findings provide a conclusion that siRNA targeting of the HSP27 gene specifically down-regulated HSP27 expression in A...

  4. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1.

    Directory of Open Access Journals (Sweden)

    Jonathan T Sims

    Full Text Available Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec, reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline

  5. Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

    Science.gov (United States)

    Sims, Jonathan T.; Ganguly, Sourik S.; Bennett, Holly; Friend, J. Woodrow; Tepe, Jessica; Plattner, Rina

    2013-01-01

    Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis. PMID:23383209

  6. Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture ...

    Indian Academy of Sciences (India)

    Logo of the Indian Academy of Sciences ... Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture of colon tumour cell spheroids with normal cells after incubation with rhTGF-1 and/or ... rhTGF-1 and/or CPT-11 decreased NO production both in tumour and normal cell monocultures and their co-cultures.

  7. Heat shock proteins (HSP70 and HSP27) as markers of epithelial dysplasia in oral leukoplakia.

    Science.gov (United States)

    Seoane, Juan M; Varela-Centelles, Pablo I; Ramirez, José R; Cameselle-Teijeiro, José; Romero, Maria A; Aguirre, José Manuel

    2006-10-01

    Heat shock proteins (HSPs) play a significant role in cell proliferation, differentiation, and oncogenesis. HSP70 and HSP27 are constitutively and gradually expressed in a broad range of normal tissues and neoplasms, and their expression has been assessed as markers for oral epithelial dysplasia. The study involved 43 patients with oral leukoplakia (OL): 23 were categorized as nondysplastic and 20 as dysplastic OLs. Immunohistochemistry was carried out with the monoclonal antibodies HSP70 and HSP27. The presence of epithelial dysplasia and its histologic grading was evaluated according to the World Health Organization classification: mild, moderate, and severe squamous epithelial dysplasia. Expression of HSPs within the epithelium was also evaluated. The difference in the percentage of HSP70 positive nuclei in nondysplastic and dysplastic OL reached statistical significance(Equation is included in full-text article.)95% confidence interval = 17.74-43.82; P = 0.000). None of the 43 specimens analyzed showed positive nuclear immunostaining for anti-HSP27 antibody. No significant difference for HSP27 cytoplasmic expression could be identified between OL with or without epithelial dysplasia(Equation is included in full-text article.)95% confidence interval = 0.44-3.95; P = 0.89). It is concluded that the nuclear HSP70 immunoexpression could be an objective marker for the presence of the epithelial dysplasia in OL.

  8. Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture ...

    Indian Academy of Sciences (India)

    We studied the expression of inducible heat shock protein (HSP27, HSP72) and multidrug-resistance protein (MRP) in co-cultures of human colon carcinoma cell spheroids obtained from different grades of tumour with normal human colon epithelium, myofibroblast and endothelial cell monolayers. We also measured the ...

  9. Heat-shock-protein-27(HSP27) expression in ovarian carcinoma : Relation in response to chemotherapy and prognosis

    NARCIS (Netherlands)

    Arts, HJG; Hollema, H; Lemstra, W; Willemse, PHB; De Vries, EGE; Kampinga, HH; Van der Zee, AGJ

    1999-01-01

    Heat-shock protein 27 (hsp27) is one of the small heat-shock proteins. Its expression in ovarian- and breast-cancer cell lines has been associated with resistance to cisplatin and doxorubicin. In addition, hsp27 expression appears to facilitate cellular growth, differentiation and motility. In

  10. Melanoma

    Science.gov (United States)

    ... Lentigo maligna melanoma; Melanoma in situ; Superficial spreading melanoma; Nodular melanoma; Acral lentiginous melanoma ... and brown. It is most common in Caucasians. Nodular melanoma usually starts as a raised area that is ...

  11. HOXC13 and HSP27 Expression in Skin and the Periodic Growth of Secondary Fiber Follicles from Longdong Cashmere Goats Raised in Different Production Systems.

    Science.gov (United States)

    Wang, Jiqing; Yu, Ping; Wang, Haifang; He, Yanyu

    2018-04-01

    This experiment was conducted to identify periodic changes in secondary follicles (SFs) over one year of extensive (grazed) and intensive (housed and fed supplement) farming of Longdong cashmere goats. One-year old goats (n = 24, 12 extensively fed and 12 intensively fed) were studied. The diameter, depth, density, activity, and ultra-structural features of SFs were assessed using light microscopy and transmission electron microscopy. HOXC13 and HSP27 expression were studied using immunohistochemistry and immunofluorescence method. The anagen stage in the extensively grazed goats was from April to September, but was longer (April to October) in the housed, supplementary fed group. The depth and activity of the SF in anagen and catagen differed (P HOXC13 protein were present in both the epidermis and dermis, with HSP27 immunoreactivity highest in the hair shaft (HS), outer root sheath (ORS) and inner root sheath (IRS). HOXC13 expression was prominent in both the eprdermis and ORS. HSP27 and HOXC13 expression were prominent during anagen, and less so during catagen and telogen. In anagen, HSP27 expression in the HS, IRS, and ORS of the extensively fed group was higher than in the intensively fed group (p HOXC13 expression in HS, IRS and ORS of the extensively fed group was lower than in the intensively fed group (P < 0.05). This suggests the growth of cashmere is influenced by nutrition and that housed goats could be used in cashmere production. Anat Rec, 301:742-752, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    International Nuclear Information System (INIS)

    Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

    2011-01-01

    Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of sulfur mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FT TM ). In both systems, administration of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100-1000 μM) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-β-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity.

  13. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27.

    Science.gov (United States)

    Freshney, N W; Rawlinson, L; Guesdon, F; Jones, E; Cowley, S; Hsuan, J; Saklatvala, J

    1994-09-23

    An IL-1-stimulated protein kinase cascade resulting in phosphorylation of the small heat shock protein hsp27 has been identified in KB cells. It is distinct from the p42 MAP kinase cascade. An upstream activator kinase phosphorylated a 40 kDa kinase (p40) upon threonine and tyrosine residues, which in turn phosphorylated a 50 kDa kinase (p50) upon threonine (and some serine) residues. p50 phosphorylated hsp27 upon serine. p40 and p50 were purified to near homogeneity. All three components were inactivated by protein phosphatase 2A, and p40 was inactivated by protein tyrosine phosphatase 1B. The substrate specificity of p40 differed from that of p42 and p54 MAP kinases. The upstream activator was not a MAP kinase kinase. p50 resembled MAPKAPK-2 and may be identical.

  14. HSP27 Inhibits Homocysteine-Induced Endothelial Apoptosis by Modulation of ROS Production and Mitochondrial Caspase-Dependent Apoptotic Pathway

    Directory of Open Access Journals (Sweden)

    Xin Tian

    2016-01-01

    Full Text Available Objectives. Elevated plasma homocysteine (Hcy could lead to endothelial dysfunction and is viewed as an independent risk factor for atherosclerosis. Heat shock protein 27 (HSP27, a small heat shock protein, is reported to exert protective effect against atherosclerosis. This study aims to investigate the protective effect of HSP27 against Hcy-induced endothelial cell apoptosis in human umbilical vein endothelial cells (HUVECs and to determine the underlying mechanisms. Methods. Apoptosis, reactive oxygen species (ROS, and mitochondrial membrane potential (MMP of normal or HSP27-overexpressing HUVECs in the presence of Hcy were analyzed by flow cytometry. The mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR and western blot. Results. We found that Hcy could induce cell apoptosis with corresponding decrease of nitric oxide (NO level, increase of endothelin-1 (ET-1, intracellular adhesion molecule-1 (ICAM-1, vascular cellular adhesion molecule-1 (VCAM-1, and monocyte chemoattractant protein-1 (MCP-1 levels, elevation of ROS, and dissipation of MMP. In addition, HSP27 could protect the cell against Hcy-induced apoptosis and inhibit the effect of Hcy on HUVECs. Furthermore, HSP27 could increase the ratio of Bcl-2/Bax and inhibit caspase-3 activity. Conclusions. Therefore, we concluded that HSP27 played a protective role against Hcy-induced endothelial apoptosis through modulation of ROS production and the mitochondrial caspase-dependent apoptotic pathway.

  15. Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability

    Directory of Open Access Journals (Sweden)

    Kong Sun-Young

    2008-10-01

    Full Text Available Abstract Background Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer. Methods To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR cells. Results Heat-shock protein 27 (HSP27 expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex. Conclusion Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.

  16. Hsp27 promotes ABCA1 expression and cholesterol efflux through the PI3K/PKCζ/Sp1 pathway in THP-1 macrophages.

    Science.gov (United States)

    Kuang, Hai-Jun; Zhao, Guo-Jun; Chen, Wu-Jun; Zhang, Min; Zeng, Gao-Feng; Zheng, Xi-Long; Tang, Chao-Ke

    2017-09-05

    Heat shock protein 27 (Hsp27) is a putative biomarker and therapeutic target in atherosclerosis. This study was to explore the potential mechanisms underlying Hsp27 effects on ATP-binding cassette transporter A1 (ABCA1) expression and cellular cholesterol efflux. THP-1 macrophage-derived foam cells were infected with adenovirus to express wild-type Hsp27, hyper-phosphorylated Hsp27 mimic (3D Hsp27), antisense Hsp27 or hypo-phosphorylated Hsp27 mimic (3A Hsp27). Wild-type and 3D Hsp27 were found to up-regulate ABCA1 mRNA and protein expression and increase cholesterol efflux from cells. Expression of antisense or 3A Hsp27 suppressed the expression of ABCA1 and cholesterol efflux. Furthermore, over-expression of wild-type and 3D Hsp27 significantly increased the levels of phosphorylated specificity protein 1 (Sp1), protein kinase C ζ (PKCζ) and phosphatidylinositol 3-kinase (PI3K). In addition, the up-regulation of ABCA1 expression and cholesterol efflux induced by 3D Hsp27 was suppressed by inhibition of Sp1, PKCζ and PI3K with specific kinase inhibitors. Taken together, our results revealed that Hsp27 may up-regulate the expression of ABCA1 and promotes cholesterol efflux through activation of the PI3K/PKCζ/Sp1 signal pathway in THP-1 macrophage-derived foam cells. Our findings may partly explain the mechanisms underlying the anti-atherogenic effect of Hsp27. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Melanoma

    Science.gov (United States)

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

  18. Stage and cell-specific expression and intracellular localization of the small heat shock protein Hsp27 during oogenesis and spermatogenesis in the Mediterranean fruit fly, Ceratitis capitata.

    Science.gov (United States)

    Economou, Katerina; Kotsiliti, Elena; Mintzas, Anastassios C

    2017-01-01

    The cell-specific expression and intracellular distribution of the small heat protein Hsp27 was investigated in the ovaries and testes of the Mediterranean fruit fly, Ceratitis capitata (medfly), under both normal and heat shock conditions. For this study, a gfp-hsp27 strain was used to detect the chimeric protein by confocal microscopy. In unstressed ovaries, the protein was expressed throughout egg development in a stage and cell-specific pattern. In germarium, the protein was detected in the cytoplasm of the somatic cells in both unstressed and heat-shocked ovaries. In the early stages of oogenesis of unstressed ovaries, the protein was mainly located in the perinuclear region of the germ cells and in the cytoplasm of the follicle cells, while in later stages (9-10) it was distributed in the cytoplasm of the germ cells. In late stages (12-14), the protein changed localization pattern and was exclusively associated with the nuclei of the somatic cells. In heat shocked ovaries, the protein was mainly located in the nuclei of the somatic cells throughout egg chamber's development. In unstressed testes, the chimeric protein was detected in the nuclei of primary spermatocytes and in the filamentous structures of spermatid bundles, called actin cones. Interestingly, after a heat shock, the protein presented the same cell-specific localization pattern as in unstressed testes. Furthermore, the protein was also detected in the nuclei of the epithelial cells of the deferent duct, the accessory glands and the ejaculatory bulb. Our data suggest that medfly Hsp27 may have cell-specific functions, especially in the nucleus. Moreover, the association of this protein to actin cones during spermatid individualization, suggests a possible role of the protein in the formation and stabilization of actin cones. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Cadmium stimulates MAPKs and Hsp27 phosphorylation in bovine adrenal chromaffin cells

    International Nuclear Information System (INIS)

    Leal, Rodrigo B.; Posser, Thais; Rigon, Ana Paula; Oliveira, Camila S.; Goncalves, Carlos Alberto; Gelain, Daniel P.; Dunkley, Peter R.

    2007-01-01

    Cadmium (Cd 2+ ) is a common environmental pollutant, which is widely used in industry and is a constituent of tobacco smoke. Exposure to this heavy metal has been linked to a wide range of detrimental effects on mammalian cells. In this study, the action of Cd 2+ on protein phosphorylation in bovine adrenal chromaffin cells (BACCs) was examined. Cells were incubated with 32 Pi in the presence of Cd 2+ (1-50 μM) and proteins were separated by one- or two-dimensional electrophoresis. An increase in the phosphorylation of BACCs proteins, without changing cell viability, was observed in response to Cd 2+ (5-50 μM). Particularly at three spots, with molecular weight of 25 kDa and isoeletric point range 4.0-4.5, which were identified as phosphorylated isoforms of the heat shock protein of 27 kDa (Hsp27). Phosphorylation of the p38 MAPK , a member of mitogen-activated protein kinase (MAPK) family, was stimulated by Cd 2+ over the same concentration range and it was the major upstream protein kinase involved in the phosphorylation of all three spots of Hsp27. Cd 2+ also stimulated the phosphorylation of other MAPK family member, the extracellular signal-regulated kinase (ERK)-1/2. Therefore, primary adrenal chromaffin cells are a target for Cd 2+ and both the ERK1/2 and the p38 MAPK are activated. Additionally, Hsp27 is highly phosphorylated in response to the metal exposure, due to p38 MAPK activation. These biochemical effects of Cd 2+ might disrupt the normal secretory function of these cells

  20. Effect of the standardized Cimicifuga foetida extract on Hsp 27 expression in the MCF-7 cell line

    Directory of Open Access Journals (Sweden)

    Maritza C Soler

    2011-01-01

    Full Text Available Cimicifuga foetida, an Asian Cimicifuga species, has been employed as a cooling and detoxification agent in traditional Chinese medicine since ancient times. For this herb, two cycloartane triterpene glycosides isolated from the rhizomes have demonstrated cytotoxicity on rat tumor and human cancer cell lines. Since human Hsp27 is increased in various human cancers and exhibits cytoprotective activity that affects tumorigenesis and the susceptibility of tumours to cancer treatment, the purpose of this research was to study the expression of this protein in MCF-7 breast cancer cells. To accomplish this aim, MCF-7 cells were exposed to different concentrations of Cimicifuga foetida extract showing a reduction in cell number measured by the sulforhodamine assay. In addition, the expression of Hsp-27 mRNA detected by RT-PCR and Hsp-27 protein detected by immnofluorescence was present in all conditions, except when using the highest concentration of Cimicifuga foetida extract (2,000 jig /L. We conclude that Hsp 27 expression at 2,000 jig /L Cimicifuga foetida extract is diminished. This is the first report showing the Hsp-27 expression after exposure to Cimicifuga foetida extract in MCF-7 cells.

  1. Effect of the standardized Cimicifuga foetida extract on Hsp 27 expression in the MCF-7 cell line.

    Science.gov (United States)

    Soler, Maritza C; Molina, Jessica L; Díaz, Hugo A; Pinto, Vivian C; Barrios, Yasenka L; He, Kan; Roller, Marc; Weinstein-Oppenheimer, Caroline R

    2011-01-01

    Cimicifuga foetida, an Asian Cimicifuga species, has been employed as a cooling and detoxification agent in traditional Chinese medicine since ancient times. For this herb, two cycloartane triterpene glycosides isolated from the rhizomes have demonstrated cytotoxicity on rat tumor and human cancer cell lines. Since human Hsp27 is increased in various human cancers and exhibits cytoprotective activity that affects tumorigenesis and the susceptibility of tumours to cancer treatment, the purpose of this research was to study the expression of this protein in MCF-7 breast cancer cells. To accomplish this aim, MCF-7 cells were exposed to different concentrations of Cimicifuga foetida extract showing a reduction in cell number measured by the sulforhodamine assay. In addition, the expression of Hsp-27 mRNA detected by RT-PCR and Hsp-27 protein detected by immnofluorescence was present in all conditions, except when using the highest concentration of Cimicifuga foetida extract (2,000 jig /L). We conclude that Hsp 27 expression at 2,000 jig /L Cimicifuga foetida extract is diminished. This is the first report showing the Hsp-27 expression after exposure to Cimicifuga foetida extract in MCF-7 cells.

  2. [Apoptosis-modulating effects of heat shock proteins: the influence of Hsp27 chaperone on TBA Bcl-2 family proteins in Jurkat cell line].

    Science.gov (United States)

    Riazantseva, N V; Kaĭgorodova, E V; Maroshkina, A N; Belkina, M V; Novitskiĭ, V V

    2012-01-01

    The in vitro phosphorylated and non-phosphorylated Hsp27 forms concentrations and Bcl-2 proteins affected by Hsp27 inhibition were studied in Jurkat-line tumor cells and healthy donor mononuclear lymphocytes by Western blotting technique. The Hsp27 inhibition causes the increase of intracellular Bax protein concentration and the decrease of Bcl-2 level leading to an increase of apoptotic changes in Jurkat line cells.

  3. Expression times for hsp27 and hsp70 as an indicator of thermal stress during death due to fire.

    Science.gov (United States)

    Doberentz, E; Genneper, L; Wagner, R; Madea, B

    2017-11-01

    The expression of heat shock proteins (hsps) increases in cases of hyperthermal cellular stress in order to protect cellular structures. Hsps can be visualized with immunohistochemical staining. We examined 48 cases of death from fire and excessive heat and a control group of 100 deaths without any perimortem thermal stress, measuring both the hsp27 and hsp70 expressions in myocardial, pulmonary, and renal tissues. The results revealed a correlation between hsp expression and survival time. Hsps are expressed rapidly within seconds or minutes after exposure to heat stress. In particular, hsp27 is expressed fast in high levels, whereas hsp70 expression is higher in the pulmonary and renal tissue of long-term survivors. In the myocardial tissue, hsp27 expression dominated in both short- and long-term survival. The expression pattern is strongly dependent on the organ structure and the survival time, which should be considered in future postmortem studies on hsps.

  4. Effects of protein transduction domain (PTD) selection and position for improved intracellular delivery of PTD-Hsp27 fusion protein formulations.

    Science.gov (United States)

    Ul Ain, Qurrat; Lee, Jong Hwan; Woo, Young Sun; Kim, Yong-Hee

    2016-09-01

    Protein drugs have attracted considerable attention as therapeutic agents due to their diversity and biocompatibility. However, hydrophilic proteins possess difficulty in penetrating lipophilic cell membrane. Although protein transduction domains (PTDs) have shown effectiveness in protein delivery, the importance of selection and position of PTDs in recombinant protein vector constructs has not been investigated. This study intends to investigate the significance of PTD selection and position for therapeutic protein delivery. Heat shock protein 27 (Hsp27) would be a therapeutic protein for the treatment of ischemic heart diseases, but itself is insufficient to prevent systemic degradation and overcoming biochemical barriers during cellular transport. Among all PTD-Hsp27 fusion proteins we cloned, Tat-Hsp27 fusion protein showed the highest efficacy. Nona-arginine (9R) conjugation to the N-terminal of Hsp27 (Hsp27-T) showed higher efficacy than C-terminal. To test the synergistic effect of two PTDs, Tat was inserted to the N-terminal of Hsp27-9R. Tat-Hsp27-9R exhibited enhanced transduction efficiency and significant improvement against oxidative stress and apoptosis. PTD-Hsp27 fusion proteins have strong potential to be developed as therapeutic proteins for the treatment of ischemic heart diseases and selection and position of PTDs for improved efficacy of PTD-fusion proteins need to be optimized considering protein's nature, transduction efficiency and stability.

  5. Hsp27 inhibits 6-hydroxydopamine-induced cytochrome c release and apoptosis in PC12 cells

    International Nuclear Information System (INIS)

    Gorman, Adrienne M.; Szegezdi, Eva; Quigney, Declan J.; Samali, Afshin

    2005-01-01

    Cellular stress may stimulate cell survival pathways or cell death depending on its severity. 6-Hydroxydopamine (6-OHDA) is a neurotoxin that targets dopaminergic neurons that is often used to induce neuronal cell death in models of Parkinson's disease. Here we present evidence that 6-OHDA induces apoptosis in rat PC12 cells that involves release of cytochrome c and Smac/Diablo from mitochondria, caspase-3 activation, cleavage of PARP, and nuclear condensation. 6-OHDA also induced the heat shock response, leading to increased levels of Hsp25 and Hsp70. Increased Hsp25 expression was associated with cell survival. Prior heat shock or overexpression of Hsp27 (human homologue of Hsp25) delayed cytochrome c release, caspase activation, and reduced the level of apoptosis caused by 6-OHDA. We conclude that 6-OHDA induces a variety of responses in cultured PC12 cells ranging from cell survival to apoptosis, and that induction of stress proteins such as Hsp25 may protect cells from undergoing 6-OHDA-induced apoptosis

  6. Proline isomerization in the C-terminal region of HSP27.

    Science.gov (United States)

    Alderson, T Reid; Benesch, Justin L P; Baldwin, Andrew J

    2017-07-01

    In mammals, small heat-shock proteins (sHSPs) typically assemble into interconverting, polydisperse oligomers. The dynamic exchange of sHSP oligomers is regulated, at least in part, by molecular interactions between the α-crystallin domain and the C-terminal region (CTR). Here we report solution-state nuclear magnetic resonance (NMR) spectroscopy investigations of the conformation and dynamics of the disordered and flexible CTR of human HSP27, a systemically expressed sHSP. We observed multiple NMR signals for residues in the vicinity of proline 194, and we determined that, while all observed forms are highly disordered, the extra resonances arise from cis-trans peptidyl-prolyl isomerization about the G193-P194 peptide bond. The cis-P194 state is populated to near 15% at physiological temperatures, and, although both cis- and trans-P194 forms of the CTR are flexible and dynamic, both states show a residual but differing tendency to adopt β-strand conformations. In NMR spectra of an isolated CTR peptide, we observed similar evidence for isomerization involving proline 182, found within the IPI/V motif. Collectively, these data indicate a potential role for cis-trans proline isomerization in regulating the oligomerization of sHSPs.

  7. Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment

    Energy Technology Data Exchange (ETDEWEB)

    Jakubowicz-Gil, Joanna, E-mail: jjgil@poczta.umcs.lublin.pl [Department of Comparative Anatomy and Anthropology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin (Poland); Langner, Ewa [Department of Medical Biology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950 Lublin (Poland); Bądziul, Dorota [Department of Comparative Anatomy and Anthropology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin (Poland); Wertel, Iwona [1st Department of Gynaecology, University School of Medicine, Staszica 16, 20-081 Lublin (Poland); Rzeski, Wojciech [Department of Medical Biology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950 Lublin (Poland); Department of Immunology and Virology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin (Poland)

    2013-12-15

    The aim of the present study was to investigate whether silencing of Hsp27 or Hsp72 expression in glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cells increases their sensitivity to programmed cell death induction upon temozolomide and/or quercetin treatment. Transfection with specific siRNA was performed for the Hsp gene silencing. As revealed by microscopic observation and flow cytometry, the inhibition of Hsp expression was correlated with severe apoptosis induction upon the drug treatment studied. No signs of autophagy were detected. This was correlated with a decreased mitochondrial membrane potential, increased level of cytochrome c in the cytoplasm, and activation of caspase 3 and caspase 9. All these results suggest that the apoptotic signal was mediated by an internal pathway. Additionally, in a large percentage of cells treated with temozolomide, with or without quercetin, granules within the ER system were found, which was accompanied by an increased level of caspase 12 expression. This might be correlated with ER stress. Quercetin and temozolomide also changed the shape of nuclei from circular to “croissant like” in both transfected cell lines. Our results indicate that blocking of Hsp27 and Hsp72 expression makes T98G cells and MOGGCCM cells extremely vulnerable to apoptosis induction upon temozolomide and quercetin treatment and that programmed cell death is initiated by an internal signal. - Highlights: • Hsps gene silencing induced severe apoptosis upon temozolomide–quercetin treatment • Apoptosis in transfected glioma cells was initiated by internal signal • Programmed cell death was preceded by ER stress • Temozolomide–quercetin treatment changed nuclei shape in transfected glioma cells.

  8. Effect of the standardized Cimicifuga foetida extract on Hsp 27 expression in the MCF-7 cell line

    OpenAIRE

    Maritza C Soler; Jessica L Molina; Hugo A Díaz; Vivian C Pinto; Yasenka L Barrios; Kan He; Marc Roller; Caroline R Weinstein-Oppenheimer

    2011-01-01

    Cimicifuga foetida, an Asian Cimicifuga species, has been employed as a cooling and detoxification agent in traditional Chinese medicine since ancient times. For this herb, two cycloartane triterpene glycosides isolated from the rhizomes have demonstrated cytotoxicity on rat tumor and human cancer cell lines. Since human Hsp27 is increased in various human cancers and exhibits cytoprotective activity that affects tumorigenesis and the susceptibility of tumours to cancer treatment, the purpose...

  9. Oligomerization and chaperone-like activity of Drosophila melanogaster small heat shock protein DmHsp27 and three arginine mutants in the alpha-crystallin domain.

    Science.gov (United States)

    Moutaoufik, Mohamed Taha; Morrow, Geneviève; Maaroufi, Halim; Férard, Céline; Finet, Stéphanie; Tanguay, Robert M

    2017-07-01

    The small Hsp DmHsp27 from Drosophila melanogaster is one of the few small heat shock proteins (sHsps) found within the nucleus. We report that its dimerization is independent of disulfide bond formation and seems to rely on salt bridges. Unlike metazoan sHsps, DmHsp27 forms two populations of oligomers not in equilibrium. Mutations at highly conserved arginine residues in mammalian sHsps have been reported to be associated with protein conformational defects and intracellular aggregation. Independent mutation of three highly conserved arginines (R122, R131, and R135) to glycine in DmHsp27 results in only one population of higher molecular weight form. In vitro, the chaperone-like activity of wild-type DmHsp27 was comparable with that of its two isolated populations and to the single population of the R122G, R131G, and R135G using luciferase as substrate. However, using insulin, the chaperone-like activity of wild-type DmHsp27 was lower than that of R122G and R131G mutants. Altogether, the results characterize wild-type DmHsp27 and its alpha-crystallin domain (ACD) arginine mutants and may give insight into protection mechanism of sHsps.

  10. Study Suggests Smaller Melanoma Excision Margins May Be Option for Some Patients

    Science.gov (United States)

    A randomized controlled trial of patients with stage IIA–C cutaneous melanoma thicker than 2-mm found that a 2-cm surgical resection margin is sufficient and is as safe for patients as a 4-cm margin.

  11. Interleukin 1 and tumor necrosis factor stimulate two novel protein kinases that phosphorylate the heat shock protein hsp27 and beta-casein.

    Science.gov (United States)

    Guesdon, F; Freshney, N; Waller, R J; Rawlinson, L; Saklatvala, J

    1993-02-25

    We have partially purified and characterized two protein kinases that were strongly activated by interleukin-1 (IL-1) or tumor necrosis factor (TNF) in MRC-5 fibroblasts. The kinases were separated by anion exchange chromatography of cytosolic fractions. They phosphorylated in vitro the small heat shock protein (hsp27) or beta-casein and were stimulated 3- and 4.5-fold, respectively, in cells that had been exposed to IL-1 or TNF for 10 min. They were distinct from the mitogen-activated protein kinases, whose activation by IL-1 or TNF has been reported recently. The hsp27 kinase phosphorylated its substrate on serine residues. Its molecular mass was estimated to be 45-kDa by gel filtration. It is probably involved in the increase in hsp27 phosphorylation seen in intact cells. The beta-casein kinase behaved as a 65-kDa protein. It phosphorylated its substrate on serine and threonine residues and had little activity on alpha-casein. The hsp27 and beta-casein kinases were not activated after stimulation of the cells with phorbol myristate acetate (PMA). In contrast, the MAP kinases were activated to a similar extent (2-3-fold) by the cytokines and by PMA. The hsp27- and beta-casein kinases probably correspond to novel enzymes whose mechanisms of activation may be independent of protein kinase C or MAP kinases.

  12. Melanoma

    Science.gov (United States)

    ... if they're dark skinned, young, and have no family history. Even for them, behaviors like too much sun exposure and not enough skin protection are important risk factors. How Do People Know They Have It? Many melanomas start out as a mole or a bump ...

  13. Expression of heat shock proteins (hsp) 27 and 70 in various organ systems in cases of death due to fire.

    Science.gov (United States)

    Doberentz, E; Genneper, L; Böker, D; Lignitz, E; Madea, B

    2014-11-01

    The expression of heat shock proteins (hsp) increases in case of variable types of endogenous and exogenous cellular stress, as for example thermal stress. Immunohistochemical staining with hsp antibodies can visualize these stress proteins. Fifty-three cases of death due to heat and a control group of 100 deaths without any antemortem thermic stress were examined regarding hsp27 and hsp70 expression in myocardial, pulmonary, and renal tissues. The results revealed a correlation between hsp expression, survival time, and cause of death. In cases of death due to fire, the expression of hsp is more extensive than in the control group, especially in pulmonary and renal tissues. The immunohistochemical investigation of an hsp expression can support the proof of vitality in cases of death related to fire.

  14. Effect of vibrational stress and spaceflight on regulation of heat shock proteins hsp70 and hsp27 in human lymphocytes (Jurkat)

    Science.gov (United States)

    Cubano, L. A.; Lewis, M. L.

    2001-01-01

    Heat shock protein levels are increased in cells as a result of exposure to stress. To determine whether heat shock protein regulation could be used to evaluate stress in cells during spaceflight, the response of Jurkat cells to spaceflight and simulated space shuttle launch vibration was investigated by evaluating hsp70 and hsp27 gene expression. Gene expression was assessed by reverse transcription-polymerase chain reaction using mRNA extracted from vibrated, nonvibrated, space-flown, and ground control cells. Results indicate that mechanical stresses of vibration and low gravity do not up-regulate the mRNA for hsp70, although the gene encoding hsp27 is up-regulated by spaceflight but not by vibration. In ground controls, the mRNA for hsp70 and hsp27 increased with time in culture. We conclude that hsp70 gene expression is a useful indicator of stress related to culture density but is not an indicator of the stresses of launch vibration or microgravity. Up-regulation of hsp27 gene expression in microgravity is a new finding.

  15. Targeting Hsp27/eIF4E interaction with phenazine compound: a promising alternative for castration-resistant prostate cancer treatment.

    Science.gov (United States)

    Hajer, Ziouziou; Claudia, Andrieu; Erik, Laurini; Sara, Karaki; Maurizio, Fermeglia; Ridha, Oueslati; David, Taieb; Michel, Camplo; Olivier, Siri; Sabrina, Pricl; Maria, Katsogiannou; Palma, Rocchi

    2017-09-29

    The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo .

  16. Melanoma genetics

    DEFF Research Database (Denmark)

    Read, Jazlyn; Wadt, Karin A W; Hayward, Nicholas K

    2015-01-01

    Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of herita......Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence...... in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely...... polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed...

  17. Hsp27, Hsp70 and mismatch repair proteins hMLH1 and hMSH2 expression in peripheral blood lymphocytes from healthy subjects and cancer patients.

    Science.gov (United States)

    Nadin, Silvina Beatriz; Vargas-Roig, Laura M; Drago, Gisela; Ibarra, Jorge; Ciocca, Daniel R

    2007-07-08

    Mismatch repair (MMR) deficiency and higher expression levels of heat shock proteins (Hsps) have been implicated with drug resistance to topoisomerase II poisons (doxorubicin) and to platinum compounds (cisplatin). This study was designed to determine individual influences of doxorubicin and cisplatin treatment on the expression of Hsp27, Hsp70, hMLH1 and hMSH2 proteins and in the DNA damage status in peripheral blood lymphocytes (PBLs). In addition, we studied whether these proteins and the DNA damage correlated with the survival of cancer patients. PBLs from 10 healthy donors and 25 cancer patients (before and after three cycles of chemotherapy) were exposed to in vitro treatments: C (control), HS (heat shock at 42 degrees C), Do or Pt (doxorubicin or cisplatin alone), and HS+Do or HS+Pt (heat shock+doxorubicin or heat shock+cisplatin). PBLs were collected at time 0 (T0: immediately after drug treatment) and after 24h of repair (T24). Hsp27, Hsp70, hMLH1 and hMSH2 were studied by immunocytochemistry and the DNA damage by alkaline comet assay. Immunofluorescence studies and confocal microscopy revealed that hMLH1 and hMSH2 colocalized with Hsp27 and Hsp72 (inducible form of Hsp70). hMLH1 and hMSH2 were significantly induced by Pt and HS+Pt at T24 in cancer patients, but only modestly influenced by Do. Cancer patients presented higher basal expression of total and nuclear Hsp27 and Hsp70 than controls, and these proteins were also increased by HS, Do and HS+Do. The Hsp70 induction by Pt and HS+Pt was noted in cancer patients, especially nuclear Hsp70. In cancer patients, basal DNA damage was slightly higher than in healthy persons; and after Pt and HS+Pt treatments, DNA migration and number of apoptotic cells were higher than controls. Hsps accomplished a cytoprotective function in pre-chemotherapy PBLs (HS before Do or Pt), but not in post-chemotherapy samples. In Pt-treated patients the ratio N/C (nuclear/cytoplasmic) of Hsp27 was related to disease free survival

  18. l-glutamine and l-alanine supplementation increase glutamine-glutathione axis and muscle HSP-27 in rats trained using a progressive high-intensity resistance exercise.

    Science.gov (United States)

    Leite, Jaqueline Santos Moreira; Raizel, Raquel; Hypólito, Thaís Menezes; Rosa, Thiago Dos Santos; Cruzat, Vinicius Fernandes; Tirapegui, Julio

    2016-08-01

    In this study we investigated the chronic effects of oral l-glutamine and l-alanine supplementation, either in their free or dipeptide form, on glutamine-glutathione (GLN-GSH) axis and cytoprotection mediated by HSP-27 in rats submitted to resistance exercise (RE). Forty Wistar rats were distributed into 5 groups: sedentary; trained (CTRL); and trained supplemented with l-alanyl-l-glutamine, l-glutamine and l-alanine in their free form (GLN+ALA), or free l-alanine (ALA). All trained animals were submitted to a 6-week ladder-climbing protocol. Supplementations were offered in a 4% drinking water solution for 21 days prior to euthanasia. Plasma glutamine, creatine kinase (CK), myoglobin (MYO), and erythrocyte concentration of reduced GSH and glutathione disulfide (GSSG) were measured. In tibialis anterior skeletal muscle, GLN-GSH axis, thiobarbituric acid reactive substances (TBARS), and the expression of heat shock factor 1 (HSF-1), 27-kDa heat shock protein (HSP-27), and glutamine synthetase were determined. In CRTL animals, high-intensity RE reduced muscle glutamine levels and increased GSSG/GSH rate and TBARS, as well as augmented plasma CK and MYO levels. Conversely, l-glutamine-supplemented animals showed an increase in plasma and muscle levels of glutamine, with a reduction in GSSG/GSH rate, TBARS, and CK. Free l-alanine administration increased plasma glutamine concentration and lowered muscle TBARS. HSF-1 and HSP-27 were high in all supplemented groups when compared with CTRL (p alanine, in both a free or dipeptide form, improve the GLN-GSH axis and promote cytoprotective effects in rats submitted to high-intensity RE training.

  19. Hsp27, Hsp70, and metallothionein in MDCK and LLC-PK1 renal epithelial cells: effects of prolonged exposure to cadmium

    International Nuclear Information System (INIS)

    Bonham, Rita T.; Fine, Michael R.; Pollock, Fiona M.; Shelden, Eric A.

    2003-01-01

    Cadmium is a widely distributed industrial and environmental toxin. The principal target organ of chronic sublethal cadmium exposure is the kidney. In renal epithelial cells, acute high-dose cadmium exposure induces differential expression of proteins, including heat shock proteins. However, few studies have examined heat shock protein expression in cells after prolonged exposure to cadmium at sublethal concentrations. Here, we assayed total cell protein, neutral red uptake, cell death, and levels of metallothionein and heat shock proteins Hsp27 and inducible Hsp70 in cultures of MDCK and LLC-PK1 renal epithelial cells treated with cadmium for 3 days. Treatment with cadmium at concentrations equal to or greater than 10 μM (LLC-PK1) or 25 μM (MDCK) reduced measures of cell vitality and induced cell death. However, a concentration-dependent increase in Hsp27 was detected in both cell types treated with as little as 5 μM cadmium. Accumulation of Hsp70 was correlated only with cadmium treatment at concentrations also causing cell death. Metallothionein was maximally detected in cells treated with cadmium at concentrations that did not reduce cell vitality, and further increases were not detected at greater concentrations. These results reveal that heat shock proteins accumulate in renal epithelial cells during prolonged cadmium exposure, that cadmium induces differential expression of heat shock protein in epithelial cells, and that protein expression patterns in epithelial cells are specific to the cadmium concentration and degree of cellular injury. A potential role for Hsp27 in the cellular response to sublethal cadmium-induced injury is also implicated by our results

  20. Heat shock proteins HSP70 and HSP27 in the cerebral spinal fluid of patients undergoing thoracic aneurysm repair correlate with the probability of postoperative paralysis.

    Science.gov (United States)

    Hecker, James G; Sundram, Hari; Zou, Shaomin; Praestgaard, Amy; Bavaria, Joseph E; Ramchandren, Sindhu; McGarvey, Michael

    2008-12-01

    An understanding of the time course and correlation with injury of heat shock proteins (HSPs) released during brain and/or spinal cord cellular stress (ischemia) is critical in understanding the role of the HSPs in cellular survival, and may provide a clinically useful biomarker of severe cellular stress. We have analyzed the levels of HSPs in the cerebrospinal fluid (CSF) from patients who are undergoing thoracic aneurysm repair. Blood and CSF samples were collected at regular intervals, and CSF was analyzed by enzyme-linked immunosorbent assay for HSP70 and HSP27. These results were correlated with intraoperative somatosensory-evoked potentials measurements and postoperative paralysis. We find that the levels of these proteins in many patients are elevated and that the degree of elevation correlates with the risk of permanent paralysis. We hypothesize that sequential measurement intraoperatively of the levels of the heat shock proteins HSP70 and HSP27 in the CSF can predict those patients who are at greatest risk for paralysis during thoracic aneurysm surgery and will allow us to develop means of preventing or attenuating this severe and often fatal complication.

  1. Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemo-resistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

    Science.gov (United States)

    Cui, Yun; Sun, Yin; Hu, Shuai; Luo, Jie; Li, Lei; Li, Xin; Yeh, Shuyuan; Jin, Jie; Chang, Chawnshang

    2016-01-01

    Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa. PMID:27375022

  2. Sinclair swine melanoma

    International Nuclear Information System (INIS)

    Hook, R.R.; Berkelhammer, J.; Hamby, C.V.

    1986-01-01

    Sinclair(S-1) miniature swine spontaneously develop melanomas which have many biologic and histologic features in common with human superficial spreading melanoma. Host control of this neoplasm was indicated by the high incidence of spontaneous regression, a decrease in tumor development with age and a decrease in progressive growth of the tumor as age of tumor development increases. Immunologic mechanisms were implicated in host control by histologic observation of a mononuclear inflammatory infiltration of tumors which lead to depigmentation and fibrosis. In vitro immunologic studies revealed that leukocytes from melanoma swine were sensitized specifically to a tumor associated antigen like substance present in extracts of cutaneous melanomas and cultured swine melanoma cells and that melanoma swine leukocytes were cytotoxic for swine melanoma cells. Furthermore, these studies suggested the existence of a common cross reactive, melanoma associated antigen shared by human and swine melanomas. Antigenic analyses of swine melanomas with mouse monoclonal antibodies developed to a single swine melanoma cell culture and with rabbit antisera developed to pooled extracts of cutaneous melanomas demonstrated the presence of tumor associated antigens in swine melanoma cell culture and cutaneous melanomas. The failure of mouse monoclonal antibodies to detect antigens in cutaneous melanoma extracts and the failure of rabbit antisera to detect antigens in melanoma cell culture extracts suggested a differential in antigen expression between swine melanoma cells grown in vitro and in vivo

  3. SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation.

    Directory of Open Access Journals (Sweden)

    Gopinathan Pillai Sreekanth

    Full Text Available Dengue virus (DENV infection causes organ injuries, and the liver is one of the most important sites of DENV infection, where viral replication generates a high viral load. The molecular mechanism of DENV-induced liver injury is still under investigation. The mitogen activated protein kinases (MAPKs, including p38 MAPK, have roles in the hepatic cell apoptosis induced by DENV. However, the in vivo role of p38 MAPK in DENV-induced liver injury is not fully understood. In this study, we investigated the role of SB203580, a p38 MAPK inhibitor, in a mouse model of DENV infection. Both the hematological parameters, leucopenia and thrombocytopenia, were improved by SB203580 treatment and liver transaminases and histopathology were also improved. We used a real-time PCR microarray to profile the expression of apoptosis-related genes. Tumor necrosis factor α, caspase 9, caspase 8, and caspase 3 proteins were significantly lower in the SB203580-treated DENV-infected mice than that in the infected control mice. Increased expressions of cytokines including TNF-α, IL-6 and IL-10, and chemokines including RANTES and IP-10 in DENV infection were reduced by SB203580 treatment. DENV infection induced the phosphorylation of p38MAPK, and its downstream signals including MAPKAPK2, HSP27 and ATF-2. SB203580 treatment did not decrease the phosphorylation of p38 MAPK, but it significantly reduced the phosphorylation of MAPKAPK2, HSP27, and ATF2. Therefore, SB203580 modulates the downstream signals to p38 MAPK and reduces DENV-induced liver injury.

  4. The stress kit: A new method based on competitive reverse transcriptase-polymerase chain reaction to quantify the expression of human αB-crystallin, Hsp27, and Hsp60

    NARCIS (Netherlands)

    Bajramović, J.J.; Geutskens, S.B.; Bsibsi, M.; Boot, M.; Hassankhan, R.; Verhulst, K.C.; Noort, J.M. van

    2000-01-01

    We describe a reverse transcriptase-polymerase chain reaction method for the semiquantitative detection of mRNAs encoding the human heat shock proteins αβ-crystallin, Hsp27, and Hsp60. The method involves the coamplification of cellular mRNA-derived cDNA with a dilution series of a competitor

  5. Predicción computacional de estructura terciaria de las proteínas humanas Hsp27, αB-cristalina y HspB8

    Directory of Open Access Journals (Sweden)

    Homero Saenz-Suárez

    2011-03-01

    Full Text Available Objetivo. Realizar predicciones computacionales de estructura de las proteínas humanas Hsp27, αB cristalina y HspB8. Materiales y métodos. La predicción de la estructura secundaria se obtuvo mediante un consenso de los programas de predicción secundaria GOR 4,nnPred,Sspro, APSSP2, JPredict, Porter, Prof, SOPMA, HNN y Psi-Pred. Los modelos de estructura terciaria se elaboraron a partir de fragmentos homólogos de proteínas con estructura terciaria conocida que fueron obtenidos por múltiples alineamientos. Empleando la secuencia primaria se obtuvieron perfiles de antigenicidad de las proteínas nativas y fueron analizados los perfiles de hidrofobicidad, polaridad, flexibilidad, accesibilidad tanto de las proteínas nativas como de las mutadas. Resultados. Las predicciones de estructura secundaria y terciariade las proteínas estudiadas muestran que en los tres casos, más del 65% son regiones en coil, 20-25% en hoja plegada y menos del 10% en alfa hélice. Los análisis de estructura primaria muestran que al menos uno de los perfiles estudiados, en cada mutación está alterado. Conclusiones. Los análisis comparativos de estructura sugieren que las mutaciones afectan la solubilidad de las proteínas mutadas y con ello su función como chaperonas moleculares

  6. Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, Hideki, E-mail: hkimura@u-fukui.ac.jp [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui (Japan); Mikami, Daisuke; Kamiyama, Kazuko [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Sugimoto, Hidehiro [Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui (Japan); Kasuno, Kenji; Takahashi, Naoki [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Yoshida, Haruyoshi [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Division of Nephrology, Obama Municipal Hospital, Obama, Fukui (Japan); Iwano, Masayuki [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan)

    2014-11-14

    Highlights: • TNF-α increased VEGF-C expression by enhancing phosphorylation of p38MAPK and HSP27. • Telmisartan decreased TNF-α-stimulated expression of VEGF-C. • Telmisartan suppressed TNF-α-induced phosphorylation of p38MAPK and HSP27. • Telmisartan activated endogenous PPAR-δ protein. • Telmisartan suppressed p38MAPK phosphorylation in a PPAR-δ-dependent manner. - Abstract: Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

  7. Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture of colon tumour cell spheroids with normal cells after incubation with rhTGF- beta1 and/or CPT-11.

    Science.gov (United States)

    Paduch, Roman; Jakubowicz-Gil, Joanna; Kandefer-Szerszen, Martyna

    2009-12-01

    We studied the expression of inducible heat shock protein (HSP27, HSP72) and multidrug-resistance protein (MRP) in co-cultures of human colon carcinoma cell spheroids obtained from different grades of tumour with normal human colon epithelium, myofibroblast and endothelial cell monolayers. We also measured the influence of recombinant human transforming growth factor beta1 (rhTGF-beta1) and camptothecin (CPT-11), added as single agents or in combination, on the levels of the HSPs, MRP, interleukin (IL)-6 and nitric oxide (NO). An immunoblotting analysis with densitometry showed that rhTGF-beta1 and/or CPT-11 increased HSP27, HSP72 and MRP expression in tumour cells and myofibroblasts, as well as in co-cultures compared with appropriate controls. By contrast, in colonic epithelium, inhibition of HSPs and MRP was comparable with that of the control. In endothelial cells, HSP72 was undetectable. Direct interaction of colon tumour spheroids with normal myofibroblasts caused a significant, tumour-grade dependent increase in IL-6 production. Production of IL-6 was significantly lowered by rhTGF-beta1 and/or CPT-11. Tumour cell spheroids cultivated alone produced larger amounts of NO than normal cells. In co-culture, the level of the radical decreased compared with the sum of NO produced by the monocultures of the two types of cells. rhTGF-beta1 and/or CPT-11 decreased NO production both in tumour and normal cell monocultures and their co-cultures. In conclusion, direct interactions between tumour and normal cells influence the expression of HSP27, HSP72 and MRP, and alter IL-6 and NO production. rhTGF-beta1 and/or CPT-11 may potentate resistance to chemotherapy by increasing HSP and MRP expression but, on the other hand, they may limit tumour cell spread by decreasing the level of some soluble mediators of inflammation (IL-6 and NO).

  8. Decoding Melanoma Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Damsky, William E. Jr. [Department of Dermatology, Yale School of Medicine, New Haven, Connecticut (United States); Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont (United States); Rosenbaum, Lara E.; Bosenberg, Marcus, E-mail: Marcus.Bosenberg@yale.edu [Department of Dermatology, Yale School of Medicine, New Haven, Connecticut (United States)

    2010-12-30

    Metastasis accounts for the vast majority of morbidity and mortality associated with melanoma. Evidence suggests melanoma has a predilection for metastasis to particular organs. Experimental analyses have begun to shed light on the mechanisms regulating melanoma metastasis and organ specificity, but these analyses are complicated by observations of metastatic dormancy and dissemination of melanocytes that are not yet fully malignant. Additionally, tumor extrinsic factors in the microenvironment, both at the site of the primary tumor and the site of metastasis, play important roles in mediating the metastatic process. As metastasis research moves forward, paradigms explaining melanoma metastasis as a step-wise process must also reflect the temporal complexity and heterogeneity in progression of this disease. Genetic drivers of melanoma as well as extrinsic regulators of disease spread, particularly those that mediate metastasis to specific organs, must also be incorporated into newer models of melanoma metastasis.

  9. Uveal melanoma: estimating prognosis.

    Science.gov (United States)

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-02-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately.

  10. Uveal melanoma: Estimating prognosis

    Directory of Open Access Journals (Sweden)

    Swathi Kaliki

    2015-01-01

    Full Text Available 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.

  11. Primary dermal melanoma: a West Australian cohort.

    Science.gov (United States)

    Teow, James; Chin, Olivia; Hanikeri, Mark; Wood, Benjamin A

    2015-09-01

    The objectives of this study were to identify a subgroup of patients with putative primary dermal melanoma after thorough multidisciplinary clinical and histological evaluation, and to describe the clinical, histological and selected molecular features of these lesions. The records of the Western Australian Melanoma Advisory Service were searched for potential cases of primary dermal melanoma. The clinical and histological features were reviewed, immunohistochemical assessment was performed and clinical outcomes recorded. Eighteen cases of putative primary dermal melanoma with available clinical data were identified. Two of 12 cases in which further histological sections could be obtained were excluded because of the presence of findings suggesting an epidermal origin on these further sections. In one additional case, such origin could not be histologically excluded. Median follow-up period for the remaining cases was 68 months. Confirmed primary dermal melanoma accounts for 0.87% of cases of melanoma referred to a subspecialist melanoma advisory service. These cases show significant histological overlap with dermal/subcutaneous metastases of melanoma, but display a relatively good prognosis, with a 5-year survival of 87.5%. Our results support the recognition of a distinct group of melanoma that mimics metastatic melanoma, but is associated with a relatively favourable outcome. The group of putative primary dermal melanoma is likely to be heterogenous, including cases of primary nodular melanoma in which epidermal connection has not been identified, metastatic melanoma with an occult primary lesion and true primary dermal melanoma. © 2015 Royal Australasian College of Surgeons.

  12. Decreased tumor-infiltrating lymphocytes in nodular melanomas compared with matched superficial spreading melanomas.

    Science.gov (United States)

    Lin, Richard L; Wang, Thomas J; Joyce, Cara J; Mihm, Martin C; Murphy, George F; Lian, Christine G; Lin, Jennifer Y

    2016-10-01

    Melanoma causes over 9000 deaths annually in the USA. Among its subtypes, nodular melanoma leads to a disproportionate number of fatalities compared with superficial spreading melanoma, the most common subtype. Recent breakthroughs in melanoma research have indicated a strong connection between melanoma virulence and the immune system. We hypothesize that the aggression of nodular melanoma may, in part, be because of decreased recognition by the immune system, as represented by a decreased presence of tumor-infiltrating lymphocytes (TILs), compared with its superficial spreading counterpart. Indeed, TILs on a primary melanoma have been used as a marker for immune response and have prognostic value for survival and sentinel lymph node status. After matching melanoma cases by age, sex, and Breslow thickness, we found significantly fewer TILs in nodular melanomas than in superficial spreading melanomas. This association was prominent in thin (≤2 mm) melanomas and was no longer significant in thick (>2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma.

  13. Thin melanoma.

    Science.gov (United States)

    Elder, David E

    2011-03-01

    The incidence of malignant melanoma is increasing and a preponderance of the melanomas diagnosed today are "thin in terms of Breslow criteria. Although thin melanomas, as a group, are associated with a very good prognosis, a subset of these tumors may metastasize and cause death. These cases can be identified by using prognostic models, including the "standard" American Joint Committee on Cancer criteria, and other attributes identified in follow-up studies. To review the history of concepts of prognostic modeling in melanoma, focusing on thin melanomas. Selected literature. About 40 years ago, it was realized that malignant melanoma, once almost uniformly fatal, could be divided into categories with better or worse prognosis through the use of prognostic models. The first simple models, Clark levels of invasion and Breslow thickness, are still in use. Thickness remains the single most useful variable. Breslow recognized that melanomas less than 0.76 mm in thickness were associated with a very good prognosis, with no metastases in his limited initial study. The American Joint Committee on Cancer selected a cutoff of 1.0 mm, which achieves a similar result, with stage modifiers, although some metastases and deaths do occur with stage I lesions. Clark demonstrated an almost equally good prognosis for his level II invasive melanomas and recognized that most of these lesions, although invasive, lacked the ability to form tumors or to undergo mitosis in the dermis and were therefore "nontumorigenic" and "nonmitogenic" and lacked competence for metastasis. Studies of these low-risk melanomas have led to the development of criteria for earlier diagnosis and a steady, but still inadequate, improvement in prognosis for melanoma overall. Multivariable models currently can identify groups of patients within the "thin melanoma" category whose prognosis varies, from a disease-free survival of close to 100% to about 70%. Prognosis declines more or less linearly with increasing

  14. Pregnancy and early-stage melanoma

    NARCIS (Netherlands)

    Daryanani, D; Plukker, JT; De Hullu, JA; Kuiper, H; Nap, RE; Hoekstra, HJ

    2003-01-01

    BACKGROUND. Cutaneous melanomas are aggressive tumors with an unpredictable biologic behavior. It has been suggested that women who present with melanoma during pregnancy have a worse prognosis due to more aggressive behavior of the melanoma. The objective of the current study was to evaluate the

  15. Ocular Melanoma

    Science.gov (United States)

    ... also occur on the conjunctiva . Because most eye melanomas form in the part of the eye you can’t see when looking in a mirror, they can be difficult to detect. Also, eye melanoma typically doesn’t cause early signs or symptoms . ...

  16. Malignant melanoma

    NARCIS (Netherlands)

    de Braud, Filippo; Khayat, David; Kroon, Bin B. R.; Valdagni, Riccardo; Bruzzi, Paolo; Cascinelli, Natale

    2003-01-01

    In the European Community cutaneous melanoma accounts for 1 and 1.8% of cancers occurring in men and women, respectively. The incidence rate is increasing faster than that of any other tumour. Sun exposure, patient's phenotype, family history, and history of a previous melanoma are the major risk

  17. Rapid externalization of 27-kDa heat shock protein (HSP27) and atypical cell death in neutrophils treated with the sphingolipid analog drug FTY720.

    Science.gov (United States)

    Skrzeczyńska-Moncznik, Joanna; Bzowska, Małgorzata; Nogieć, Anna; Sroka, Agnieszka; Zarębski, Mirosław; Vallières, Luc; Guzik, Krzysztof

    2015-10-01

    The sphingolipid analog fingolimod is known to induce apoptosis of tumor cells and lymphocytes. Its effect on neutrophils has not been investigated so far. Here, we describe a fingolimod-induced atypical cell death mechanism in human neutrophils, characterized by rapid translocation of heat shock protein 27 to the cell surface, extensive cell swelling and vacuolization, atypical chromatin staining and nuclear morphology, and phosphorylation of mixed lineage kinase domain-like protein. Fingolimod also induces typical apoptotic features, including rapid externalization of phosphatidylserine and activation of caspase-8. Fingolimod-induced neutrophil death is independent of sphingosine-1-phosphate receptors and positively regulated by protein phosphatase A. Externalization of phosphatidylserine and heat shock protein 27 can be partially inhibited by inhibitors of caspase-8 [Z-Ile-Glu(O-Me)-Thr-Asp(O-Me)-fluoromethyl ketone], receptor-interacting protein kinase 1 (necrostatin-1), receptor-interacting protein kinase 3 (necrosulfonamide), and heat shock protein 90 [geldanamycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin]. Furthermore, NADPH oxidase 1 inhibition with diphenyleneiodonium chloride protects neutrophils against fingolimod-mediated cell death. Overall, these observations suggest that fingolimod acts through a mechanism involving the necrosome signaling complex and the oxidative stress machinery. © Society for Leukocyte Biology.

  18. Chemoprevention of Melanoma

    Science.gov (United States)

    Madhunapantula, SubbaRao V.; Robertson, Gavin P.

    2013-01-01

    Despite advances in drug discovery programs and molecular approaches for identifying the drug targets, incidence and mortality rates due to melanoma continues to rise at an alarming rate. Existing preventive strategies generally involve mole screening followed by surgical removal of the benign nevi and abnormal moles. However, due to lack of effective programs for screening and disease recurrence after surgical resection there is a need for better chemopreventive agents. Although sunscreens have been used extensively for protecting from UV-induced skin cancer, results of correlative population based studies are controversial, requiring further authentication to conclusively confirm the chemoprotective efficacy of sunscreens. Certain studies suggest increased skin-cancer rates in sunscreen users. Therefore, effective chemopreventive agents for preventing melanoma are urgently required. This book-chapter, reviews the current understanding regarding melanoma chemoprevention and the various strategies used to accomplish this objective. PMID:22959032

  19. Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Eshini Perera

    2013-12-01

    Full Text Available Melanomas are a major cause of premature death from cancer. The gradual decrease in rates of morbidity and mortality has occurred as a result of public health campaigns and improved rates of early diagnosis. Survival of melanoma has increased to over 90%. Management of melanoma involves a number of components: excision, tumor staging, re-excision with negative margins, adjuvant therapies (chemo, radiation or surgery, treatment of stage IV disease, follow-up examination for metastasis, lifestyle modification and counseling. Sentinel lymph node status is an important prognostic factor for survival in patients with a melanoma >1 mm. However, sentinel lymph node biopsies have received partial support due to the limited data regarding the survival advantage of complete lymph node dissection when a micrometastasis is detected in the lymph nodes. Functional mutations in the mitogen-activated pathways are commonly detected in melanomas and these influence the growth control. Therapies that target these pathways are rapidly emerging, and are being shown to increase survival rates in patients. Access to these newer agents can be gained by participation in clinical trials after referral to a multidisciplinary team for staging and re-excision of the scar.

  20. Uveal Melanoma

    International Nuclear Information System (INIS)

    Papastefanou, V. P.; Cohen, V. M. L.; Cohen, V. 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

  1. Malignant Melanoma of the Foot

    Science.gov (United States)

    ... 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 ...

  2. Genomic characterisation of acral melanoma cell lines.

    Science.gov (United States)

    Furney, Simon J; Turajlic, Samra; Fenwick, Kerry; Lambros, Maryou B; MacKay, Alan; Ricken, Gerda; Mitsopoulos, Costas; Kozarewa, Iwanka; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J; Ashworth, Alan; Reis-Filho, Jorge S; Herlyn, Meenhard; Murata, Hiroshi; Marais, Richard

    2012-07-01

    Acral melanoma is a rare melanoma subtype with distinct epidemiological, clinical and genetic features. To determine if acral melanoma cell lines are representative of this melanoma subtype, six lines were analysed by whole-exome sequencing and array comparative genomic hybridisation. We demonstrate that the cell lines display a mutation rate that is comparable to that of published primary and metastatic acral melanomas and observe a mutational signature suggestive of UV-induced mutagenesis in two of the cell lines. Mutations were identified in oncogenes and tumour suppressors previously linked to melanoma including BRAF, NRAS, KIT, PTEN and TP53, in cancer genes not previously linked to melanoma and in genes linked to DNA repair such as BRCA1 and BRCA2. Our findings provide strong circumstantial evidence to suggest that acral melanoma cell lines and acral tumours share genetic features in common and that these cells are therefore valuable tools to investigate the biology of this aggressive melanoma subtype. Data are available at: http://rock.icr.ac.uk/collaborations/Furney_et_al_2012/. © 2012 John Wiley & Sons A/S.

  3. Choroidal melanoma

    International Nuclear Information System (INIS)

    Hernandez Quesada, Flora

    2013-01-01

    A useful and practical guide is developed to better track to the uveal melanoma, due to its highly malignant character. Melanoma of the uveal tract (choroid, iris, ciliary body) has been the intraocular tumor most frequent in adults. The biopsy has been inaccessible, due to its location; therefore, the diagnostic should be based on clinical examination and the correct utilization of the diagnostic procedures (ultrasound, fluorescent angiography, computed axial tomography and magnetic resonance). The cases are diagnosed in the histological examination of the operatory piece post-enucleation for other causes. Epidemiological research has been key to determine the associated factors and better to understand the mechanisms of onset of the disease. Anatomopathological studies of choroidal melanoma have permitted to know the natural history of the disease. The decrease of the visual acuity, pain or inflammation are presented as a defect in the visual field. Different techniques to diagnose the disease are explained. Ultrasound in mode A and B, computed axial tomography and magnetic resonance are the diagnostic method of election. Ultrasound has been the primary method of diagnostic, giving the size and vascularisation, useful in tracking, when they are treated in shape conservatively, showing changes in echogenicity and less vascularisation as good response to treatment. The treatments of choroidal melanoma are specified. The correct interpretation of the clinical symptoms and early utilization of diagnostic imaging methods, have permitted to establish the adequate therapeutic and to avoid local and distant metastasis. The uveal melanoma, depending on their size and location, traditionally has been treated by enucleation. Data from the literature and authors, have promoted the conservation of the ocular globe, depending on the size of the tumor. Transpupillary thermotherapy has been an available alternative for small tumors in Costa Rica and level of social security

  4. A new understanding in the epidemiology of melanoma

    OpenAIRE

    Erdei, Esther; Torres, Salina M

    2010-01-01

    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 progr...

  5. Nestin is expressed in HMB-45 negative melanoma cells in dermal parts of nodular melanoma.

    Science.gov (United States)

    Kanoh, Maho; Amoh, Yasuyuki; Tanabe, Kenichi; Maejima, Hideki; Takasu, Hiroshi; Katsuoka, Kensei

    2010-06-01

    Nestin, a marker of neural stem cells, is expressed in the stem cells of the mouse hair follicle. The nestin-expressing hair follicle stem cells can differentiate into neurons, glia, keratocytes, smooth muscle cells and melanocytes in vitro. These pluripotent nestin-expressing stem cells are keratin 15 (K15)-negative, suggesting that they are in a relatively undifferentiated state. Recent studies suggest that the epithelial stem cells are important in tumorigenesis, and nestin expression is thought to be important in tumorigenesis. In the present study, we examined the expression of the hair follicle and neural stem cell marker nestin, as well as S-100 and HMB-45, in melanoma. Nestin immunoreactivity was observed in the HMB-45-negative melanoma cells in all five cases of amelanotic nodular melanomas. Moreover, nestin immunoreactivity was observed in the dermal parts in seven of 10 cases of melanotic nodular melanomas. Especially, nestin immunoreactivity was observed in the HMB-45-negative melanoma cells in the dermal parts of all 10 cases of HMB-45-negative amelanotic and melanotic nodular melanomas. On the other hand, nestin expression was negative in 10 of 12 cases of superficial spreading melanoma. These results suggest that nestin is an important marker of HMB-45-negative melanoma cells in the dermal parts of patients with nodular melanoma.

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

    Science.gov (United States)

    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

  7. Cytotoxic T lymphocyte responses against melanocytes and melanoma

    Directory of Open Access Journals (Sweden)

    Schwartz Erich J

    2011-07-01

    Full Text Available Abstract Background Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs against melanoma commonly target melanoma-associated antigens (MAAs which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels. Methods To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines. Results CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR and immunohistochemistry. Conclusions Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.

  8. Skin cancer and melanoma

    International Nuclear Information System (INIS)

    Moylan, D.J.

    1991-01-01

    In this chapter, the author discusses various types of non-melanoma malignant skin cancer, as well as malignant melanoma. Non-melanoma skin cancer, such as basal cell and squamous cell carcinomas, occasionally metastasize, but only late in the course of the disease. On the other hand, even relatively small primary melanomas tend to disseminate to regional lymph nodes and to distant sites. The author presents various treatment plans, including radiation therapy. Cutaneous melanomas have been considered relatively radioresistant. This is the rationale for the use of large fraction radiation therapy in the treatment of melanomas with the fraction sizes varying from 4--8 Gy

  9. Malignant melanoma at a scientific laboratory

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. Treatment Option Overview (Melanoma)

    Science.gov (United States)

    ... Reporting & Auditing Grant Transfer Grant Closeout Contracts & Small Business Training Cancer Training at NCI (Intramural) Funding for ... the skin far away from where it first started. Recurrent Melanoma Recurrent melanoma is cancer that has ...

  11. General Information about Melanoma

    Science.gov (United States)

    ... Reporting & Auditing Grant Transfer Grant Closeout Contracts & Small Business Training Cancer Training at NCI (Intramural) Funding for ... the skin far away from where it first started. Recurrent Melanoma Recurrent melanoma is cancer that has ...

  12. Stages of Melanoma

    Science.gov (United States)

    ... Reporting & Auditing Grant Transfer Grant Closeout Contracts & Small Business Training Cancer Training at NCI (Intramural) Funding for ... the skin far away from where it first started. Recurrent Melanoma Recurrent melanoma is cancer that has ...

  13. Melanoma - neck (image)

    Science.gov (United States)

    This melanoma on the neck is variously colored with a very darkly pigmented area found centrally. It has irregular ... be larger than 0.5 cm. Prognosis in melanoma is best defined by its depth on resection.

  14. Primary ovarian malignant melanoma

    Directory of Open Access Journals (Sweden)

    Kostov Miloš

    2010-01-01

    Full Text Available Background. Primary ovarian malignant melanoma is extremely rare. It usually appears in the wall of a dermoid cyst or is associated with another teratomatous component. Metastatic primary malignant melanoma to ovary from a primary melanoma elsewhere is well known and has been often reported especially in autopsy studies. Case report. We presented a case of primary ovarian malignant melanoma in a 45- year old woman, with no evidence of extraovarian primary melanoma nor teratomatous component. The tumor was unilateral, macroscopically on section presented as solid mass, dark brown to black color. Microscopically, tumor cells showed positive immunohistochemical reaction for HMB-45, melan-A and S-100 protein, and negative immunoreactivity for estrogen and progesteron receptors. Conclusion. Differentiate metastatic melanoma from rare primary ovarian malignant melanoma, in some of cases may be a histopathological diagnostic problem. Histopathological diagnosis of primary ovarian malignant melanoma should be confirmed by immunohistochemical analyses and detailed clinical search for an occult primary tumor.

  15. Molecular Classification of Melanoma

    Science.gov (United States)

    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.

  16. Melanoma International Foundation

    Science.gov (United States)

    ... the state of Pennsylvania, certificate #29498 © 2013 Melanoma International Foundation. All Rights Reserved. Privacy Policy | Terms of Use Toll-free: 866-463-6663 International: 610-942-3432 Melanoma International Foundation 250 Mapleflower ...

  17. [Ocular melanomas : An update].

    Science.gov (United States)

    Kalirai, H; Müller, P L; Jaehne, D; Coupland, S E

    2017-11-01

    Melanoma is the most common type of primary cancer to affect the adult eye. Approximately 95% of ocular melanomas are intraocular and arise from the uvea (i. e. iris, ciliary body, and choroid), while the remaining 5% are located in the conjunctiva. Although both uveal and conjunctival melanomas are thought to derive from malignantly transformed melanocytes, uveal melanoma is clinically and biologically distinct from conjunctival melanoma, and indeed from its more common cutaneous counterpart. Intense efforts have been recently made to understand the molecular biology involved in the development of ocular melanomas, and in their progression. Molecular advances, particularly for uveal melanoma, have enhanced prognostication and the identification of rational therapeutic targets for disseminated disease. In this review, recent advances in the molecular characterisation of both uveal and conjunctival melanomas are discussed, and how these may be used to develop personalised therapeutic strategies.

  18. A new understanding in the epidemiology of melanoma.

    Science.gov (United States)

    Erdei, Esther; Torres, Salina M

    2010-11-01

    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.

  19. Drug effects on melanoma

    NARCIS (Netherlands)

    Koomen, Elsje Rosalie

    2010-01-01

    Cutaneous melanoma is the most aggressive form of skin cancer and its incidence among Caucasian populations has increased whereas mortality rates are stabilizing or decreasing. The total burden of melanoma is expected to be increasing. As effective treatment options for advanced melanoma are

  20. Burden of Melanoma

    NARCIS (Netherlands)

    C. Holterhues (Cynthia)

    2011-01-01

    markdownabstract__Abstract__ Melanoma is a type of skin cancer that arises from melanocytes. More than 95% of all melanomas occur in the skin, but rarely in the pigmented cells of the eye, meninges or mucosa. This thesis will only regard the invasive cutaneous malignant melanomas.

  1. Genetics of familial melanoma

    DEFF Research Database (Denmark)

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

    2015-01-01

    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...

  2. Cutaneous melanoma in women

    Directory of Open Access Journals (Sweden)

    Mi Ryung Roh, MD

    2017-03-01

    Conclusions: The published findings on gender disparities in melanoma have yielded many advances in our understanding of this disease. Biological, environmental, and behavioral factors may explain the observed gender difference in melanoma incidence and outcome. Further research will enable us to learn more about melanoma pathogenesis, with the goal of offering better treatments and preventative advice to our patients.

  3. Cutaneous melanoma in women

    Directory of Open Access Journals (Sweden)

    Mi Ryung Roh, MD

    2015-02-01

    Conclusions: The published findings on gender disparities in melanoma have yielded many advances in our understanding of this disease. Biological, environmental, and behavioral factors may explain the observed gender difference in melanoma incidence and outcome. Further research will enable us to learn more about melanoma pathogenesis, with the goal of offering better treatments and preventative advice to our patients.

  4. BAP1 PLAYS A SURVIVAL ROLE IN CUTANEOUS MELANOMA

    Science.gov (United States)

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

    2014-01-01

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

  5. Efficient adenovector CD40 ligand immunotherapy of canine malignant melanoma.

    Science.gov (United States)

    von Euler, Henrik; Sadeghi, Arian; Carlsson, Björn; Rivera, Patricio; Loskog, Angelica; Segall, Thomas; Korsgren, Olle; Tötterman, Thomas H

    2008-05-01

    Cutaneous canine melanomas are usually benign in contrast to human malignant melanoma. However, the canine oropharyngeal, uveal, and mucocutaneous neoplasms are aggressive and have metastatic potential. Surgery and to a lesser extent radiotherapy and chemotherapy are widely adopted treatments but are seldom curative in advanced stages. The similarities between human and canine melanoma make spontaneous canine melanoma an excellent disease model for exploring novel therapies. Herein, we report the first 2 adenovector CD40L immunogene (AdCD40L) treatments of aggressive canine malignant melanoma. Case no. 1 was an advanced stage III oral melanoma that was cured from malignant melanoma with 2 intratumor AdCD40L injections before cytoreductive surgery. After treatment, the tumor tissue was infiltrated with T lymphocytes and B lymphocytes suggesting immune activation. This dog survived 401 days after the first round of gene therapy and was free of melanoma at autopsy. Case no. 2 had a conjunctival malignant melanoma with a rapid progression. This case was treated with 6 AdCD40L injections over 60 days. One hundred and twenty days after start of gene therapy and 60 days after the last injection, the tumor had regressed dramatically, and the dog had a minimal tumor mass and no signs of progression or metastasis. Our results indicate that AdCD40L immunogene therapy is beneficial in canine malignant melanoma and could be considered for human malignant melanoma as well.

  6. Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations.

    Science.gov (United States)

    Goldstein, Alisa M; Landi, Maria Teresa; Tsang, Shirley; Fraser, Mary C; Munroe, David J; Tucker, Margaret A

    2005-09-01

    Major risk factors for melanoma include many nevi, especially dysplastic nevi, fair pigmentation, freckling, poor tanning ability, and germ line mutations in the CDKN2A, CDK4, or MC1R genes. We evaluated the relationship between MC1R and melanoma risk in CDKN2A melanoma-prone families with extensive clinical and epidemiologic data. We studied 395 subjects from 16 American CDKN2A families. Major melanoma risk factors were assessed by clinical examination or questionnaire; MC1R was sequenced. Odds ratios were estimated by unconditional and conditional logistic regression models. We examined the distribution of MC1R variants and median ages at melanoma diagnosis in multiple primary melanoma (MPM) and single primary melanoma (SPM) patients. Presence of multiple MC1R variants was significantly associated with melanoma, even after adjustment for major melanoma risk factors. All 40 MPM patients had at least one MC1R variant; 65% of MPM patients versus only 17% of SPM patients had at least two MC1R variants (P MC1R variants increased (P = 0.010 and P = 0.008, respectively). In contrast, no significant reduction in age at melanoma diagnosis was observed for SPM patients (P = 0.91). The current study suggests that the presence of multiple MC1R variants is associated with the development of multiple melanoma tumors in patients with CDKN2A mutations. Additional studies are needed to confirm these findings and to explore the mechanisms that may contribute to this relationship.

  7. Tumor progression in uveal melanoma

    NARCIS (Netherlands)

    C.M. Mooij (Cornelia)

    1995-01-01

    textabstractOphthalmic melanomas can be divided in extra-ocular (conjunctiva, caruncle) and intraocular uveal melanomas (iris, ciliary body and choroid). Uveal melanomas account for 95% of ocular melanomas, while only 5% are conjunctival in origin. The extra-ocular and intra-ocular melanomas differ

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

    Science.gov (United States)

    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

  9. PIM kinases as therapeutic targets against advanced melanoma

    Science.gov (United States)

    Shannan, Batool; Watters, Andrea; Chen, Quan; Mollin, Stefan; Dörr, Markus; Meggers, Eric; Xu, Xiaowei; Gimotty, Phyllis A.; Perego, Michela; Li, Ling; Benci, Joseph; Krepler, Clemens; Brafford, Patricia; Zhang, Jie; Wei, Zhi; Zhang, Gao; Liu, Qin; Yin, Xiangfan; Nathanson, Katherine L.; Herlyn, Meenhard; Vultur, Adina

    2016-01-01

    Therapeutic strategies for the treatment of metastatic melanoma show encouraging results in the clinic; however, not all patients respond equally and tumor resistance still poses a challenge. To identify novel therapeutic targets for melanoma, we screened a panel of structurally diverse organometallic inhibitors against human-derived normal and melanoma cells. We observed that a compound that targets PIM kinases (a family of Ser/Thr kinases) preferentially inhibited melanoma cell proliferation, invasion, and viability in adherent and three-dimensional (3D) melanoma models. Assessment of tumor tissue from melanoma patients showed that PIM kinases are expressed in pre- and post-treatment tumors, suggesting PIM kinases as promising targets in the clinic. Using knockdown studies, we showed that PIM1 contributes to melanoma cell proliferation and tumor growth in vivo; however, the presence of PIM2 and PIM3 could also influence the outcome. The inhibition of all PIM isoforms using SGI-1776 (a clinically-available PIM inhibitor) reduced melanoma proliferation and survival in preclinical models of melanoma. This was potentiated in the presence of the BRAF inhibitor PLX4720 and in the presence of PI3K inhibitors. Our findings suggest that PIM inhibitors provide promising additions to the targeted therapies available to melanoma patients. PMID:27448973

  10. Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy—From Animal Models to Clinical Trials

    Directory of Open Access Journals (Sweden)

    Martyna Śniegocka

    2018-04-01

    Full Text Available The focus of the present review is to investigate the role of melanin in the radioprotection of melanoma and attempts to sensitize tumors to radiation by inhibiting melanogenesis. Early studies showed radical scavenging, oxygen consumption and adsorption as mechanisms of melanin radioprotection. Experimental models of melanoma in hamsters and in gerbils are described as well as their use in biochemical and radiobiological studies, including a spontaneously metastasizing ocular model. Some results from in vitro studies on the inhibition of melanogenesis are presented as well as radio-chelation therapy in experimental and clinical settings. In contrast to cutaneous melanoma, uveal melanoma is very successfully treated with radiation, both using photon and proton beams. We point out that the presence or lack of melanin pigmentation should be considered, when choosing therapeutic options, and that both the experimental and clinical data suggest that melanin could be a target for radiosensitizing melanoma cells to increase efficacy of radiotherapy against melanoma.

  11. Hereditary Melanoma: Update on Syndromes and Management - Genetics of familial atypical multiple mole melanoma syndrome

    Science.gov (United States)

    Soura, E.; Eliades, P.; Shannon, K.; Stratigos, A.; Tsao, H.

    2015-01-01

    Malignant melanoma is considered the most lethal skin cancer if not detected and treated at its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (i.e. unilateral lineage, multi-generational, 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. Such patients have a high risk of developing multiple primary melanomas and internal organ malignancies especially pancreatic cancer; thus, a multidisciplinary approach is necessary in many cases. The value of dermoscopy 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. But, this must be performed with care and only by qualified individuals trained in cancer risk analysis. PMID:26892650

  12. Whole Body Melanoma Transcriptome Response in Medaka.

    Directory of Open Access Journals (Sweden)

    Manfred Schartl

    Full Text Available 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

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

    Science.gov (United States)

    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

  14. BAP1 has a survival role in cutaneous melanoma.

    Science.gov (United States)

    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.

  15. Primary malignant melanoma

    Directory of Open Access Journals (Sweden)

    A. Ferhat Mısır

    2016-04-01

    Full Text Available 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.

  16. CASE REPORT: NODULAR MELANOMA

    Directory of Open Access Journals (Sweden)

    Tina Zupančič

    2015-05-01

    Full Text Available Nodular melanoma is a rare type of cutaneous melanoma with an increased risk of death. It often mimics benign cutaneous tumors and inflammatory lesions. It has pronounced vertical growth phase and greater thickness at the time of diagnosis which caries ominous prognostic value. Nodular melanoma quickly develops metastases which are often present before the disease is clinically recognised. Here, we report a case of nodular melanoma clinically mimicking seborrheic keratosis. Therapy and 36 months follow-up after primal excision are also presented.

  17. Prognostic value of BRAF mutations in localized cutaneous melanoma.

    Science.gov (United States)

    Nagore, Eduardo; Requena, Celia; Traves, Víctor; Guillen, Carlos; Hayward, Nicholas K; Whiteman, David C; Hacker, Elke

    2014-05-01

    BRAF mutations are frequent in melanoma but their prognostic significance remains unclear. We sought to further evaluate the prognostic value of BRAF mutations in localized cutaneous melanoma. We undertook an observational retrospective study of 147 patients with localized invasive (stages I and II) cutaneous melanomas to determine the prognostic value of BRAF mutation status. After a median follow-up of 48 months, patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype (hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after adjustment for Breslow thickness, tumor ulceration, location, age, sex, and tumor mitotic rate. The retrospective design and the small number of events are limitations. Our findings suggest that reappraisal of clinical treatment approaches for patients with localized melanoma harboring tumors with BRAF mutation might be warranted. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  18. Kinase gene fusions in defined subsets of melanoma.

    Science.gov (United States)

    Turner, Jacqueline; Couts, Kasey; Sheren, Jamie; Saichaemchan, Siriwimon; Ariyawutyakorn, Witthawat; Avolio, Izabela; Cabral, Ethan; Glogowska, Magdelena; Amato, Carol; Robinson, Steven; Hintzsche, Jennifer; Applegate, Allison; Seelenfreund, Eric; Gonzalez, Rita; Wells, Keith; Bagby, Stacey; Tentler, John; Tan, Aik-Choon; Wisell, Joshua; Varella-Garcia, Marileila; Robinson, William

    2017-01-01

    Genomic rearrangements resulting in activating kinase fusions have been increasingly described in a number of cancers including malignant melanoma, but their frequency in specific melanoma subtypes has not been reported. We used break-apart fluorescence in situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1. Of these, three were confirmed by Immunohistochemistry (IHC) or sequencing and one was found to be an ARMC10-BRAF fusion that has not been previously reported in melanoma. These fusions occurred in different subtypes of melanoma but all in tumors lacking known driver mutations. Our data suggest gene fusions are more common than previously thought and should be further explored particularly in melanomas lacking known driver mutations. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Phytochemicals for the Management of Melanoma.

    Science.gov (United States)

    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.

  20. Staging of cutaneous melanoma

    NARCIS (Netherlands)

    P. Mohr (P.); A.M.M. Eggermont (Alexander); A. Hauschild (Axel); A. Buzaid (A.)

    2009-01-01

    textabstractThe American Joint Committee on Cancer (AJCC) staging of cutaneous melanoma is a continuously evolving system. The identification of increasingly more accurate prognostic factors has led to major changes in melanoma staging over the years, and the current system described in this review

  1. Canine oral melanoma.

    Science.gov (United States)

    Bergman, Philip J

    2007-05-01

    Melanoma is the most common oral malignancy in the dog. Oral and/or mucosal melanoma has been routinely considered an extremely malignant tumor with a high degree of local invasiveness and high metastatic propensity. Primary tumor size has been found to be extremely prognostic. The World Health Organization staging scheme for dogs with oral melanoma is based on size, with stage I = or = 4cm tumor and/or lymph node metastasis, and stage IV = distant metastasis. Median survival times for dogs with oral melanoma treated with surgery are approximately 17 to 18, 5 to 6, and 3 months with stage I, II, and III disease, respectively. Significant negative prognostic factors include stage, size, evidence of metastasis, and a variety of histologic criteria. Standardized treatments such as surgery, coarse-fractionation radiation therapy, and chemotherapy have afforded minimal to modest stage-dependent clinical benefits and death is usually due to systemic metastasis. Numerous immunotherapeutic strategies have been employed to date with limited clinical efficacy; however, the use of xenogeneic DNA vaccines may represent a leap forward in clinical efficacy. Oral melanoma is a spontaneous syngeneic cancer occurring in outbred, immunocompetent dogs and appears to be a more clinically faithful therapeutic model for human melanoma; further use of canine melanoma as a therapeutic model for human melanoma is strongly encouraged. In addition, the development of an expanded but clinically relevant staging system incorporating the aforementioned prognostic factors is also strongly encouraged.

  2. Bronchial malignant melanoma.

    Science.gov (United States)

    Weshler, Z; Sulkes, A; Kopolovitch, J; Leviatan, A; Shifrin, E

    1980-01-01

    We describe a case of malignant melanoma presenting initially as an endobronchial lesion located in the left main bronchus causing total atelectasis. This resolved with radiation therapy. Widespread metastases developed shortly thereafter. The differential diagnosis of primary and metastatic bronchial malignant melanoma is discussed. Other isolated case reports are reviewed.

  3. Melanoma do aparelho ungueal Nail apparatus melanoma

    Directory of Open Access Journals (Sweden)

    Ignez Regina dos Santos Muri Mendonça

    2004-10-01

    Full Text Available O melanoma do aparelho ungueal é apresentação relativamente rara dessa neoplasia, muitas vezes diagnosticada como nevo juncional, hematoma subungueal ou mesmo onicomicose. Esse fato leva a um atraso no diagnóstico e, conseqüentemente, na instituição da terapêutica específica, contribuindo para agravar o prognóstico de uma doença que por si só já é muito agressiva. Os autores relatam um caso de melanoma no primeiro quirodáctilo esquerdo de uma paciente negra com evolução de um ano, ressaltando a importância de avaliar certos critérios clínicos para obter o diagnóstico em fases mais precoces da doença.Nail apparatus melanoma is a rare presentation of melanoma and may be misdiagnosed as junctional nevus, subungual hematoma or onychomycosis. This fact often leads initially to inappropriate treatment and significant delays in appropriately managing such an aggressive disease. The authors report a case of melanoma on the left thumb of a black patient evolving for a year. Emphasis was placed on the importance of assessing certain clinical characteristics in order to reach an early diagnosis.

  4. Oral malignant melanoma: a rare case with unusual clinical ...

    African Journals Online (AJOL)

    Primary Oral malignant melanoma is a rare tumor with an indigent prognosis. This is a case report of 47-year-old Sudanese female diagnosed as Oral malignant melanoma of the mandible with an unusual pattern of growth and clinical presentation. Furthermore, a possibility of intraosseous origin is suggested. Pan African ...

  5. Hemosideric heterochromia iridum in malignant melanoma of the choroid.

    Science.gov (United States)

    Awan, K J

    1975-08-01

    A case is reported in which hyperchromic heterochromia iridum developed due to blood staining of an eye with malignant melanoma of the choroid in which massive hemorrhage developed. It is suggested that a possibility of the malignant melanoma of the choroid be kept in mind where hemosiderin deposits are suspected to be the cause of heterochromia but no intraocular iron foreign body is present.

  6. Melanoma during pregnancy

    DEFF Research Database (Denmark)

    de Haan, Jorine; Lok, Christianne A; de Groot, Christianne J M

    2017-01-01

    The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome......, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during...... pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed...

  7. The clinical and dermoscopic features of extremity melanomas

    Directory of Open Access Journals (Sweden)

    Fatma Pelin Cengiz

    2015-03-01

    Full Text Available Objectives: Dermoscopy is a noninvasive tool that helps to differentiate structures which can not be seen by naked eye. Dermoscopic and clinical features of malignant melanomas on the extremities are not well described in the literature. Therefore, in this study we aim to determine dermoscopic and clinical characteristics of melanoma on the extremities. Materials and Methods: 40 patients with melanoma on the extremities were included in this study. Their dermoscopic and clinical images, histopathological and clinical data were assessed. The relations between Breslow thickness and dermoscopic characteristics were evaluated. Results: The most frequent localization for women was lower extremities, whereas it was upper extremities for men. The most common subtype of melanoma was superficial spreading melanoma on the extremities. The mean age of patients with extremity melanoma was 56,21 ± 15,20 in men, as well as the mean age of patients with extremity melanoma was 53,09 ± 13,96 in women. The most common dermoscopic feature for extremity melanoma was irregular dots (85%. There were positive correlations between Breslow thickness and diameter, 3 or more colors in lesion, blue-white veil and lineer white streaks, respectively (p< 0.005, r= +0.462 (p< 0.001, r= +0.550 (p< 0.001, r= +0.606 (p< 0.001, r= +0.662. Conclusions: To our knowledge, this is the first study investigating dermoscopic and clinical features in patients with extremity melanomas. We should suggest that melanomas on the lower extremities are more common in women than men and the patients with lower extremity melanomas were younger than the patients with upper extremity melanomas and there are associations between Breslow thickness and some dermoscopic characteristics.

  8. Cutaneous manifestations associated with melanoma.

    Science.gov (United States)

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

    2016-06-01

    Melanoma is a malignancy most commonly arising from the skin; therefore, primary melanoma characteristics are usually the first cutaneous manifestations of melanoma. Cutaneous metastases, which can occur locally or diffusely, are important to detect in a timely manner as treatments for advanced melanoma that impact survival are now available. Melanoma can be associated with local or diffuse pigmentation changes, including depigmentation associated with the leukodermas and hyperpigmentation associated with diffuse melanosis cutis. The leukodermas occur frequently, illustrate the immunogenic nature of melanoma, and may impact prognosis. Paraneoplastic syndromes in association with melanoma are rare, though can occur. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Characterization of melanoma associated spongiform scleropathy

    DEFF Research Database (Denmark)

    Alyahya, Ghassan Ayish Jabur; Heegaard, Steffen; Prause, J.U.

    2002-01-01

    ophthalmology, melanoma associated spongiform scleropathy (MASS), MASS, malignant uveal melanoma, sclera, ciliary body, choroid, histopathology......ophthalmology, melanoma associated spongiform scleropathy (MASS), MASS, malignant uveal melanoma, sclera, ciliary body, choroid, histopathology...

  10. Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners

    NARCIS (Netherlands)

    Teulings, H. E.; Overkamp, M.; Ceylan, E.; Nieuweboer-Krobotova, L.; Bos, J. D.; Nijsten, T.; Wolkerstorfer, A. W.; Luiten, R. M.; van der Veen, J. P. W.

    2013-01-01

    Vitiligo is a common skin disease characterized by autoimmune melanocyte destruction. Recent genetic studies suggest a lower susceptibility to melanoma in patients with vitiligo; however, lifetime melanoma prevalence in patients with vitiligo has not previously been studied. Nonmelanoma skin cancer

  11. Management of Melanoma Families

    Directory of Open Access Journals (Sweden)

    Wilma Bergman

    2010-04-01

    Full Text Available In this review we have aimed to focus on the clinical management of familial melanoma patients and their relatives. Along this line three major topics will be discussed: (1 management/screening of familial melanoma families: what is advised and what is the evidence thereof; (2 variability of families worldwide with regard to clinical phenotype, including cancer spectrum and likelihood of finding germline mutations and (3 background information for clinicians on the molecular biology of familial melanoma and recent developments in this field.

  12. Increased HOX C13 expression in metastatic melanoma progression.

    Science.gov (United States)

    Cantile, Monica; Scognamiglio, Giosuè; Anniciello, Annamaria; Farina, Marisa; Gentilcore, Giusy; Santonastaso, Clemente; Fulciniti, Franco; Cillo, Clemente; Franco, Renato; Ascierto, Paolo A; Botti, Gerardo

    2012-05-14

    The process of malignant transformation, progression and metastasis of melanoma is not completely understood. Recently, the microarray technology has been used to survey transcriptional differences that might provide insight into the metastatic process, but the validation of changing gene expression during metastatic transition period is poorly investigated. A large body of literature has been produced on the role of the HOX genes network in tumour evolution, suggesting the involvement of HOX genes in several types of human cancers. Deregulated paralogous group 13 HOX genes expression has been detected in melanoma, cervical cancer and odonthogenic tumors. Among these, Hox C13 is also involved in the expression control of the human keratin genes hHa5 and hHa2, and recently it was identified as a member of human DNA replication complexes. In this study, to investigate HOX C13 expression in melanoma progression, we have compared its expression pattern between naevi, primary melanoma and metastasis. In addition HOXC13 profile pattern of expression has been evaluated in melanoma cell lines. Our results show the strong and progressive HOX C13 overexpression in metastatic melanoma tissues and cytological samples compared to nevi and primary melanoma tissues and cells. The data presentated in the paper suggest a possible role of HOX C13 in metastatic melanoma switch.

  13. Increased HOX C13 expression in metastatic melanoma progression

    Directory of Open Access Journals (Sweden)

    Cantile Monica

    2012-05-01

    Full Text Available Abstract Background The process of malignant transformation, progression and metastasis of melanoma is not completely understood. Recently, the microarray technology has been used to survey transcriptional differences that might provide insight into the metastatic process, but the validation of changing gene expression during metastatic transition period is poorly investigated. A large body of literature has been produced on the role of the HOX genes network in tumour evolution, suggesting the involvement of HOX genes in several types of human cancers. Deregulated paralogous group 13 HOX genes expression has been detected in melanoma, cervical cancer and odonthogenic tumors. Among these, Hox C13 is also involved in the expression control of the human keratin genes hHa5 and hHa2, and recently it was identified as a member of human DNA replication complexes. Methods In this study, to investigate HOX C13 expression in melanoma progression, we have compared its expression pattern between naevi, primary melanoma and metastasis. In addition HOXC13 profile pattern of expression has been evaluated in melanoma cell lines. Results Our results show the strong and progressive HOX C13 overexpression in metastatic melanoma tissues and cytological samples compared to nevi and primary melanoma tissues and cells. Conclusions The data presentated in the paper suggest a possible role of HOX C13 in metastatic melanoma switch.

  14. Associations between childhood height and morphologically different variants of melanoma in adulthood.

    Science.gov (United States)

    Meyle, Kathrine Damm; Gamborg, Michael; Hölmich, Lisbet Rosenkrantz; Baker, Jennifer Lyn

    2016-11-01

    Melanoma subtypes have different aetiological characteristics. Child height is positively associated with adult melanoma; however, a clarification of associations with specific melanoma variants is necessary for an improved understanding of risk factors underlying the histologic entities. This study investigated associations between childhood height and future development of cutaneous melanoma variants. A cohort study of 316,193 individuals from the Copenhagen School Health Records Register, with measured heights at ages 7-13 years who were born from 1930 to 1989. Melanoma cases were identified via linkage to the national Danish Cancer Registry and subdivided into subtypes. Cox proportional hazards regressions were performed. A total of 2223 cases of melanoma distributed as 60% superficial spreading melanoma (SSM), 27.5% melanoma not otherwise specified (NOS), 8.5% nodular melanoma (NM), and 2% lentigo maligna melanoma (LMM). The remaining rare melanoma forms were not analysed. Childhood height was positively and significantly associated with SSM, melanoma NOS, and NM, but not LMM, in adulthood. Per height z-score at age 13 years, the hazard ratios were 1.20 (95% confidence intervals [CI]: 1.13-1.27) for SSM, 1.19 (95% CI: 1.09-1.29) for melanoma NOS, and 1.21 (95% CI: 1.04-1.41) for NM. Further, growth patterns were linked to the melanoma variants with persistently tall children having an increased risk of developing SSM, melanoma NOS, or NM. Childhood height is positively associated with the majority of the melanoma variants. These results suggest that the underlying processes contributing to childhood height and growth patterns interconnect early-life events with the predisposition to melanomagenesis in adulthood. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. RSK1 activation promotes invasion in nodular melanoma.

    Science.gov (United States)

    Salhi, Amel; Farhadian, Joshua A; Giles, Keith M; Vega-Saenz de Miera, Eleazar; Silva, Ines P; Bourque, Caitlin; Yeh, Karen; Chhangawala, Sagar; Wang, Jinhua; Ye, Fei; Zhang, David Y; Hernando-Monge, Eva; Houvras, Yariv; Osman, Iman

    2015-03-01

    The two major melanoma histologic subtypes, superficial spreading and nodular melanomas, differ in their speed of dermal invasion but converge biologically once they invade and metastasize. Herein, we tested the hypothesis that distinct molecular alterations arising in primary melanoma cells might persist as these tumors progress to invasion and metastasis. Ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) was significantly hyperactivated in human melanoma lines and metastatic tissues derived from nodular compared with superficial spreading melanoma. RSK1 was constitutively phosphorylated at Ser-380 in nodular but not superficial spreading melanoma and did not directly correlate with BRAF or MEK activation. Nodular melanoma cells were more sensitive to RSK1 inhibition using siRNA and the pharmacological inhibitor BI-D1870 compared with superficial spreading cells. Gene expression microarray analyses revealed that RSK1 orchestrated a program of gene expression that promoted cell motility and invasion. Differential overexpression of the prometastatic matrix metalloproteinase 8 and tissue inhibitor of metalloproteinases 1 in metastatic nodular compared with metastatic superficial spreading melanoma was observed. Finally, using an in vivo zebrafish model, constitutive RSK1 activation increased melanoma invasion. Together, these data reveal a novel role for activated RSK1 in the progression of nodular melanoma and suggest that melanoma originating from different histologic subtypes may be biologically distinct and that these differences are maintained as the tumors invade and metastasize. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    2017-06-05

    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

  17. The Danish Melanoma Database

    DEFF Research Database (Denmark)

    Hölmich, Lisbet Rosenkrantz; Klausen, Siri; Spaun, Eva

    2016-01-01

    AIM OF DATABASE: The aim of the database is to monitor and improve the treatment and survival of melanoma patients. STUDY POPULATION: All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive......-node-metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a), results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence......, nature, and treatment hereof is registered. In case of death, the cause and date are included. Currently, all data are entered manually; however, data catchment from the existing registries is planned to be included shortly. DESCRIPTIVE DATA: The DMD is an old research database, but new as a clinical...

  18. Proteomics in uveal melanoma.

    LENUS (Irish Health Repository)

    Ramasamy, Pathma

    2014-01-01

    Uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence of 5-7 per million per year. It is associated with the development of metastasis in about 50% of cases, and 40% of patients with uveal melanoma die of metastatic disease despite successful treatment of the primary tumour. The survival rates at 5, 10 and 15 years are 65%, 50% and 45% respectively. Unlike progress made in many other areas of cancer, uveal melanoma is still poorly understood and survival rates have remained similar over the past 25 years. Recently, advances made in molecular genetics have improved our understanding of this disease and stratification of patients into low risk and high risk for developing metastasis. However, only a limited number of studies have been performed using proteomic methods. This review will give an overview of various proteomic technologies currently employed in life sciences research, and discuss proteomic studies of uveal melanoma.

  19. Primary leptomeningeal melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Aichner, F.; Schuler, G.

    1982-11-01

    A case of primary leptomeningeal melanoma is presented in which the diagnosis was made by ultrastructural demonstration of melanoma cells from the cerebrospinal fluid (CSF) at a time when cranial computed tomography (CT) still gave negative results. Later CT examinations documented the emergence of a tumor mass of the left temporoparietal lobe. This case clearly illustrates the complementary role of these investigational procedures for the diagnosis of cerebrospinal melanoma: leptomeningeal involvement, characterized by two-dimensional diffuse spread of melanoma tissue (''leptomeningeal melanomatosis''), is invisible with CT, but easily recognisable by CSF cytology; in contrast, nodular parenchymal tumor deposits can be readily detected by CT. Identification of pigmented cells recovered from the CSF requires ultrastructural confirmation.

  20. Primary Anorectal Melanoma: An Update

    Directory of Open Access Journals (Sweden)

    P Carcoforo, M.T Raiji, G.M Palini, M Pedriali, U Maestroni, G Soliani, A Detroia, M.V Zanzi, A.L Manna, J.G Crompton, R.C Langan, A Stojadinovic, I Avital

    2012-01-01

    Full Text Available The anorectum is a rare anatomic location for primary melanoma. Mucosal melanoma is a distinct biological and clinical entity from the more common cutaneous melanoma. It portrays worse prognosis than cutaneous melanoma, with distant metastases being the overwhelming cause of morbidity and mortality. Surgery is the treatment of choice, but significant controversy exists over the extent of surgical resection. We present an update on the state of the art of anorectal mucosal melanoma. To illustrate the multimodality approach to anorectal melanoma, we present a typical patient.

  1. MelanomaDB: a Web Tool for Integrative Analysis of Melanoma Genomic Information to Identify Disease-Associated Molecular Pathways

    Directory of Open Access Journals (Sweden)

    Alexander Joseph Trevarton

    2013-07-01

    Full Text Available Despite on-going research, metastatic melanoma survival rates remain low and treatment options are limited. Researchers can now access a rapidly growing amount of molecular and clinical information about melanoma. This information is becoming difficult to assemble and interpret due to its dispersed nature, yet as it grows it becomes increasingly valuable for understanding melanoma. Integration of this information into a comprehensive resource to aid rational experimental design and patient stratification is needed. As an initial step in this direction, we have assembled a web-accessible melanoma database, MelanomaDB, which incorporates clinical and molecular data from publically available sources, which will be regularly updated as new information becomes available. This database allows complex links to be drawn between many different aspects of melanoma biology: genetic changes (e.g. mutations in individual melanomas revealed by DNA sequencing, associations between gene expression and patient survival, data concerning drug targets, biomarkers, druggability and clinical trials, as well as our own statistical analysis of relationships between molecular pathways and clinical parameters that have been produced using these data sets. The database is freely available at http://genesetdb.auckland.ac.nz/melanomadb/about.html . A subset of the information in the database can also be accessed through a freely available web application in the Illumina genomic cloud computing platform BaseSpace at http://www.biomatters.com/apps/melanoma-profiler-for-research . This illustrates dysregulation of specific signalling pathways, both across 310 exome-sequenced melanomas and in individual tumours and identifies novel features about the distribution of somatic variants in melanoma. We suggest that this database can provide a context in which to interpret the tumour molecular profiles of individual melanoma patients relative to biological information and available

  2. Genetics of Melanoma

    Directory of Open Access Journals (Sweden)

    Janet eWangari-Talbot

    2013-01-01

    Full Text Available Genomic variation is a trend observed in various human diseases including cancer. Genetic studies have set out to understand how and why these variations result in cancer, why some populations are predisposed to the disease, and also how genetics affect drug responses. The melanoma incidence has been increasing at an alarming rate worldwide. The burden posed by melanoma has made it a necessity to understand the fundamental signaling pathways involved in this deadly disease. Signaling cascades such as MAPK and PI3K/AKT have been shown to be crucial in the regulation of processes that are commonly dysregulated during cancer development such as aberrant proliferation, loss of cell cycle control, impaired apoptosis and altered drug metabolism. Understanding how these and other oncogenic pathways are regulated has been integral in our challenge to develop potent anti-melanoma drugs. With advances in technology and especially in next generation sequencing, we have been able to explore melanoma genomes and exomes leading to the identification of previously unknown genes with functions in melanomagenesis such as GRIN2A and PREX2. The therapeutic potential of these novel candidate genes is actively being pursued with some presenting as druggable targets while others serve as indicators of therapeutic responses. In addition, the analysis of the mutational signatures of melanoma tumors continues to cement the causative role of UV exposure in melanoma pathogenesis. It has become distinctly clear that melanomas from sun exposed skin areas have distinct mutational signatures including C to T transitions indicative of UV-induced damage. It is thus necessary to continue spreading awareness on how to decrease the risk factors of developing the disease while at the same time working for a cure. Given the large amount of information gained from these sequencing studies, it is likely that in the future, treatment of melanoma will follow a highly personalized route

  3. Perforating metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Takenobu Ohashi

    2015-01-01

    Full Text Available We describe a case of metastatic malignant melanoma on the thigh with comedo-like appearance, which histologically showed elimination of tumor cells. A 70 year-old man was diagnosed with a nodular type malignant melanoma involving the lower back with satellite lesions (stage IIIB, T4b N2c M0, Breslow’s tumor thickness; 10.3 mm, Clark’s level; IV.

  4. Disseminated malignant melanoma

    Directory of Open Access Journals (Sweden)

    Verma Kaushal

    1999-01-01

    Full Text Available A 25-year-old man had multiple asymptomatic, nodular lesions on the trunk, extremities and the face for 3 months. He also had left facial palsy with severe headache and vomiting. There were no other systemic or constitutional symptoms. Skin biopsy from a nodular lesion showed features of malignant melanoma, confirmed by Fontana Masson and S-100 protein staining. A diagnosis of disseminated malignant melanoma was made and the patient was treated symptomatically. The patient died in 4 months.

  5. Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod

    Directory of Open Access Journals (Sweden)

    Taku Fujimura

    2018-01-01

    Full Text Available Simultaneous or sequential, planned administration of ipilimumab could significantly enhance the antitumor effects of nivolumab in advanced melanoma patients. On the other hand, the efficacy of ipilimumab for nivolumab-resistant advanced melanoma is extremely poor. Therefore, additional supportive therapy for anti-PD-1 antibody therapy-resistant advanced melanoma has been widely investigated. In this report, we describe a case of multiple in-transit melanomas developing in a nivolumab-resistant patient successfully treated with ipilimumab in combination with imiquimod. Our present case suggested a possible therapy for nivolumab-resistant multiple in-transit melanomas using ipilimumab in combination with topical imiquimod.

  6. Primary dermal melanoma: distinct immunohistochemical findings and clinical outcome compared with nodular and metastatic melanoma.

    Science.gov (United States)

    Cassarino, David S; Cabral, Erik S; Kartha, Reena V; Swetter, Susan M

    2008-01-01

    To provide an updated and expanded analysis of clinical outcome and immunohistochemical (IHC) findings unique to primary dermal melanoma (PDM) that may be used to differentiate this entity from primary nodular melanoma (PNM) and cutaneous metastatic melanoma (MM). Cohort analysis and extensive IHC panel comparing PDM with PNM and cutaneous MM. Melanoma clinics and pathology departments of academic and VA medical centers. Thirteen patients with a solitary dermal or subcutaneous nodule of histologically proven melanoma, prospectively followed through April 30, 2007. Clinical, pathologic, and IHC assessment of patients diagnosed as having PDM. Long-term clinical outcome and determination of unique clinical and IHC features in the study cohort compared with other melanoma subtypes. Histologically, there was no evidence of an overlying in situ component, ulceration, or regression, and there was no associated nevus in any cases. Clinical history and findings from workup, including imaging studies, skin examination, and sentinel lymph node biopsy, were negative for evidence of melanoma elsewhere. The mean Breslow depth was 9.6 mm. Two patients developed satellite or in-transit recurrences, 1 developed pulmonary metastasis, and another died of liver metastases. Overall, the cohort showed a 92% melanoma-specific survival rate at a mean duration of follow-up of 44 months. The IHC findings showed that PDM exhibited lower levels of staining for the antigens p53 (P = .02), Ki-67 (Mib-1) (P = .002), cyclin D1 (P = .001), and podoplanin (recognized by D2-40 antibody) lymphovascular staining (P <.001) compared with MM and PNM. All other markers were comparable. Patients with PDM have remarkably prolonged survival compared with patients with MM or PNM of similar thickness. Preliminary results suggest that PDM may be characterized by lower levels of p53, Ki-67, cyclin D1, and D2-40 compared with histologically similar MM and PNM.

  7. Comparative analysis of methods of preinvasive melanoma diagnostics

    Directory of Open Access Journals (Sweden)

    Kozlov S.V.

    2013-03-01

    Full Text Available The article discusses one of the problems of oncology — skin melanoma. The research objective is to study and to compare diagnostic methods of preinvasive melanoma including fluorescence diagnosis, dermatoscopy and microwave radiometry. Materials and Methods: The survey has used dermatoscope of Heine Delta 20 Company, the unit RTM-01-RES and the instrument of fluorescent diagnostics «Spectrum-Cluster.» The results suggest the possibility of early detection of melanoma with the use of dermatoscopy. The method may be applied to radiometry screening study. Fluorescence diagnostics is effective for the differential diagnosis of melanoma and melanocytic nevi. In conclusion it has been proved the need for an integrated approach to the diagnostics of melanoma of skin, depending on the different clinical situations.

  8. Radioimmunoscintigraphy in ocular melanoma

    International Nuclear Information System (INIS)

    Kovacs, J.; Chatterton, B.E.; Muecke, J.; Penglis, S.

    1999-01-01

    Full text: Malignant choroidal melanoma is one of the most common primary intraocular neoplasms. Despite significant advances in indirect ophthalmology, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and fluoroescein angiography, choroidal melanomas may be difficult to distinguish from other malignant and non-malignant eye lesions. Radioimmunoscintigraphy (RIS) with 99 Tc m -labelled monoclonal antibody F(ab')2 fragments was performed on three patients (2 females, 1 male) who were suspected of having a choroidal melanoma. Patients were injected with 240-420 MBq Technemab-K-1 and scanned 6 and 22 h post-injection. Both planar and single photon emission tomographic (SPET) imaging were performed. RIS was faintly positive in one patient in whom the diagnosis of choroidal melanoma was confirmed by enucleation of the left eye. In the other two patients, immunoscintigraphy was negative. One patient had a benign choroidal haemangioma and the other an amelanotic melanoma. This was confirmed on clinical follow-up. These preliminary results indicate that this procedure may have utility for choroidal melanoma

  9. Selenium for the Prevention of Cutaneous Melanoma

    Directory of Open Access Journals (Sweden)

    Douglas Grossman

    2013-03-01

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

  10. Immunohistochemical Expression of MCAM/CD146 in Canine Melanoma.

    Science.gov (United States)

    Abou Asa, S

    2017-07-01

    MCAM/CD146 (melanoma cell adhesion molecule/CD146) is a transmembrane immunoglobulin superfamily cell adhesion molecule involved in transendothelial migration and signal transduction. It is expressed in melanoma, squamous cell carcinoma, prostatic, ovarian, cervical and endometrial cancers and promotes tumour growth, angiogenesis and metastasis. Melanoma is the most common malignant oral tumour of dogs and also arises in the skin, nail bed and footpad. The aim of this study was to investigate the immunohistochemical expression of MCAM/CD146 in 51 canine melanomas, including oral, cutaneous and ocular tumours. Seventeen of the 51 (33.3%) cases were negative, eight (15.7%) were weakly positive, seven (13.7%) were moderately positive and 19 (37.3%) were strongly positive. MCAM/CD146 was expressed by both oral and cutaneous melanomas; however, the intensity and the extent of the immunoreactivity was higher in oral (P = 0.009) than in cutaneous tumours (P = 0.058). Most ocular melanomas did not express MCAM/CD146 (P = 0.256). Expression of MCAM/CD146 by canine melanomas may suggest the molecule as a target for treatment, especially in oral melanomas. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. IRF4 rs12203592 functional variant and melanoma survival.

    Science.gov (United States)

    Potrony, Miriam; Rebollo-Morell, Aida; Giménez-Xavier, Pol; Zimmer, Lisa; Puig-Butille, Joan Anton; Tell-Marti, Gemma; Sucker, Antje; Badenas, Celia; Carrera, Cristina; Malvehy, Josep; Schadendorf, Dirk; Puig, Susana

    2017-04-15

    Inherited genetic factors may modulate clinical outcome in melanoma. Some low-to-medium risk genes in melanoma susceptibility play a role in melanoma outcome. Our aim was to assess the role of the functional IRF4 SNP rs12203592 in melanoma prognosis in two independent sets (Barcelona, N = 493 and Essen, N = 438). Genotype association analyses showed that the IRF4 rs12203592 T allele increased the risk of dying from melanoma in both sets (Barcelona: odds ratio [OR] = 6.53, 95% CI 1.38-30.87, Adj p = 0.032; Essen: OR = 1.68, 95% CI 1.04-2.72, Adj p = 0.035). Survival analyses only showed significance for the Barcelona set (hazard ratio = 4.58, 95% CI 1.11-18.92, Adj p = 0.036). This SNP was also associated with tumour localization, increasing the risk of developing melanoma in head or neck (OR = 1.79, 95% CI 1.07-2.98, Adj p = 0.032) and protecting from developing melanoma in the trunk (OR = 0.59, 95% CI 0.41-0.85, Adj p = 0.004). These findings suggest for the first time that IRF4 rs12203592 plays a role in the modulation of melanoma outcome and confirms its contribution to the localization of the primary tumour. © 2017 UICC.

  12. Mitochondrial respiration--an important therapeutic target in melanoma.

    Directory of Open Access Journals (Sweden)

    Michelle Barbi de Moura

    Full Text Available The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the disease and related to it, whether oxidative phosphorylation (OXPHOS has a prominent role in advanced melanoma. In this study we demonstrate that compared to melanocytes, metastatic melanoma cells have elevated levels of OXPHOS. Furthermore, treating metastatic melanoma cells with the drug, Elesclomol, which induces cancer cell apoptosis through oxidative stress, we document by way of stable isotope labeling with amino acids in cell culture (SILAC that proteins participating in OXPHOS are downregulated. We also provide evidence that melanoma cells with high levels of glycolysis are more resistant to Elesclomol. We further show that Elesclomol upregulates hypoxia inducible factor 1-α (HIF-1α, and that prolonged exposure of melanoma cells to this drug leads to selection of melanoma cells with high levels of glycolysis. Taken together, our findings suggest that molecular targeting of OXPHOS may have efficacy for advanced melanoma.

  13. Tissue-Based Microarray Expression of Genes Predictive of Metastasis in Uveal Melanoma and Differentially Expressed in Metastatic Uveal Melanoma

    Directory of Open Access Journals (Sweden)

    Hakan Demirci

    2013-01-01

    Full Text Available Purpose: To screen the microarray expression of CDH1, ECM1, EIF1B, FXR1, HTR2B, ID2, LMCD1, LTA4H, MTUS1, RAB31, ROBO1, and SATB1 genes which are predictive of primary uveal melanoma metastasis, and NFKB2, PTPN18, MTSS1, GADD45B, SNCG, HHIP, IL12B, CDK4, RPLP0, RPS17, RPS12 genes that are differentially expressed in metastatic uveal melanoma in normal whole human blood and tissues prone to metastatic involvement by uveal melanoma. Methods: We screened the GeneNote and GNF BioGPS databases for microarray analysis of genes predictive of primary uveal melanoma metastasis and those differentially expressed in metastatic uveal melanoma in normal whole blood, liver, lung and skin. Results: Microarray analysis showed expression of all 22 genes in normal whole blood, liver, lung and skin, which are the most common sites of metastases. In the GNF BioGPS database, data for expression of the HHIP gene in normal whole blood and skin was not complete. Conclusions: Microarray analysis of genes predicting systemic metastasis of uveal melanoma and genes differentially expressed in metastatic uveal melanoma may not be used as a biomarker for metastasis in whole blood, liver, lung, and skin. Their expression in tissues prone to metastasis may suggest that they play a role in tropism of uveal melanoma metastasis to these tissues.

  14. The Danish Melanoma Database

    Directory of Open Access Journals (Sweden)

    Hölmich Lr

    2016-10-01

    Full Text Available Lisbet Rosenkrantz Hölmich,1 Siri Klausen,2 Eva Spaun,3 Grethe Schmidt,4 Dorte Gad,5 Inge Marie Svane,6,7 Henrik Schmidt,8 Henrik Frank Lorentzen,9 Else Helene Ibfelt10 1Department of Plastic Surgery, 2Department of Pathology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, 3Institute of Pathology, Aarhus University Hospital, Aarhus, 4Department of Plastic and Reconstructive Surgery, Breast Surgery and Burns, Rigshospitalet – Glostrup, University of Copenhagen, Copenhagen, 5Department of Plastic Surgery, Odense University Hospital, Odense, 6Center for Cancer Immune Therapy, Department of Hematology, 7Department of Oncology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, 8Department of Oncology, 9Department of Dermatology, Aarhus University Hospital, Aarhus, 10Registry Support Centre (East – Epidemiology and Biostatistics, Research Centre for Prevention and Health, Glostrup – Rigshospitalet, University of Copenhagen, Glostrup, Denmark Aim of database: The aim of the database is to monitor and improve the treatment and survival of melanoma patients.Study population: All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD. In 2014, 2,525 patients with invasive melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register.Main variables: The main variables include demographic, clinical, and pathological characteristics, including Breslow’s tumor thickness, ± ulceration, mitoses, and tumor–node–metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a, results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence, nature, and treatment hereof is registered. In case of death, the cause and date

  15. Cytoplasmic vacuoles: clue in the fine-needle aspiration diagnosis of melanoma.

    Science.gov (United States)

    Chen, Liansong; Raza, Anwar S; Simental, Raul G; Iverson, Kiva T; Cobb, Camilla J

    2014-02-01

    For the fine-needle aspiration (FNA) diagnosis of melanoma recognition of characteristic morphologic features is key. In our practice we noted that cytoplasmic vacuoles in Romanowsky-stained FNA smears of melanoma appeared to be a frequent finding. To investigate this premise, we examined 36 consecutive melanoma FNA cases that had both adequate Papanicolaou-stained and Romanowsky-stained smears in an effort to determine the prevalence, and thereby, the potential diagnostic utility of cytoplasmic vacuoles in the diagnosis of melanoma compared to established cytomorphologic parameters of melanoma. We found pigment in 21 cases (58%) and plasmacytoid cells in 28 cases (78%), and in all 36 cases (100%) we found bi/multinucleation, intranuclear cytoplasmic inclusions and prominent nucleoli. Cytoplasmic vacuoles were present in 30 cases (83%) and were found in air-dried Romanowsky-stained smears only. These findings suggest that in FNA smears of melanoma cytoplasmic vacuoles in Romanowsky-stained smears have prevalence and potential diagnostic utility that are comparable to widely recognized cytomorphologic features of melanoma. Numerous articles have focused on the cytomorphologic criteria for the FNA diagnosis of melanoma, but few have noted the presence of cytoplasmic vacuoles in FNA smears of melanoma, and rare reports suggest this finding to be a useful clue to the FNA diagnosis of melanoma. This report appears to be the first to focus on the prevalence and potential diagnostic utility of cytoplasmic vacuoles in FNA samples of melanoma. Copyright © 2013 Society of Plastics Engineers.

  16. Cell proliferation and expression of connexins differ in melanotic and amelanotic canine oral melanomas.

    Science.gov (United States)

    Teixeira, Tarso Felipe; Gentile, Luciana Boffoni; da Silva, Tereza Cristina; Mennecier, Gregory; Chaible, Lucas Martins; Cogliati, Bruno; Roman, Marco Antonio Leon; Gioso, Marco Antonio; Dagli, Maria Lucia Zaidan

    2014-03-01

    Melanoma is a malignant neoplasm occurring in several animal species, and is the most frequently found tumor in the oral cavity in dogs. Melanomas are classified into two types: melanotic and amelanotic. Prior research suggests that human amelanotic melanomas are more aggressive than their melanotic counterparts. This study evaluates the behavior of canine melanotic and amelanotic oral cavity melanomas and quantifies cell proliferation and the expression of connexins. Twenty-five melanomas (16 melanotic and 9 amelanotic) were collected from dogs during clinical procedures at the Veterinary Hospital of the School of Veterinary Medicine and Animal Science of the University of São Paulo, Brazil. After diagnosis, dogs were followed until death or euthanasia. Histopathology confirmed the gross melanotic or amelanotic characteristics and tumors were classified according to the WHO. HMB45 or Melan A immunostainings were performed to confirm the diagnosis of amelanotic melanomas. Cell proliferation was quantified both by counting mitotic figures and PCNA positive nuclei. Expressions of connexins 26 and 43 were evaluated by immunohistochemistry, qRT-PCR and Western blot. Dogs bearing amelanotic melanomas presented a shorter lifespan in comparison to those with melanotic melanomas. Cell proliferation was significantly higher in amelanotic melanomas. Expressions of Connexins 26 and 43 were significantly reduced in amelanotic melanomas. The results presented here suggest that oral cavity melanotic and amelanotic melanomas differ regarding their behavior, cell proliferation and connexin expression in dogs, indicating a higher aggressiveness of amelanotic variants.

  17. Treatment Options by Stage (Melanoma)

    Science.gov (United States)

    ... Reporting & Auditing Grant Transfer Grant Closeout Contracts & Small Business Training Cancer Training at NCI (Intramural) Funding for ... the skin far away from where it first started. Recurrent Melanoma Recurrent melanoma is cancer that has ...

  18. Intracerebral metastases from ocular melanoma.

    OpenAIRE

    Jones, D. R.; Scobie, I. N.; Sarkies, N. J.

    1988-01-01

    A blind painful eye may harbour an unsuspected malignant melanoma. We report a case of ocular melanoma that presented with confusion owing to direct extension via the optic nerve into the anterior cranial fossa.

  19. TAPIOCA MELANOMA OF THE IRIS

    NARCIS (Netherlands)

    DEKEIZER, RJW; OOSTERHUIS, JA; HOUTMAN, WA; DEWOLFFROUENDAAL, D

    Clinical identification of tapioca melanoma of the iris is important because its medical treatment may differ from that of other malignant iris melanomas. The characteristic iris nodules must be differentiated from granulomatous uveitis, metastases, and Lisch nodules (neurofibromatosis). We will

  20. Advanced Melanoma Facebook Live Event

    Science.gov (United States)

    In case you missed it, watch this recent Facebook Live event about the current state of research and treatment for advanced stage melanoma. To learn more, see our evidence-based information about skin cancer, including melanoma.

  1. Characterization of long noncoding RNA and messenger RNA signatures in melanoma tumorigenesis and metastasis.

    Directory of Open Access Journals (Sweden)

    Siqi Wang

    Full Text Available The incidence of melanoma, the most aggressive and life-threatening form of skin cancer, has significantly risen over recent decades. Therefore, it is essential to identify the mechanisms that underlie melanoma tumorigenesis and metastasis and to explore novel and effective melanoma treatment strategies. Accumulating evidence s uggests that aberrantly expressed long noncoding RNAs (lncRNAs have vital functions in multiple cancers. However, lncRNA functions in melanoma tumorigenesis and metastasis remain unclear. In this study, we investigated lncRNA and messenger RNA (mRNA expression profiles in primary melanomas, metastatic melanomas and normal skin samples from the Gene Expression Omnibus database. We used GSE15605 as the training set (n = 74 and GSE7553 as the validation set (n = 58. In three comparisons (primary melanoma versus normal skin, metastatic melanoma versus normal skin, and metastatic melanoma versus primary melanoma, 178, 295 and 48 lncRNAs and 847, 1758, and 295 mRNAs were aberrantly expressed, respectively. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses to examine the differentially expressed mRNAs, and potential core lncRNAs were predicted by lncRNA-mRNA co-expression networks. Based on our results, 15 lncRNAs and 144 mRNAs were significantly associated with melanoma tumorigenesis and metastasis. A subsequent analysis suggested a critical role for a five-lncRNA signature during melanoma tumorigenesis and metastasis. Low expression of U47924.27 was significantly associated with decreased survival of patients with melanoma. To the best of our knowledge, this study is the first to explore the expression patterns of lncRNAs and mRNAs during melanoma tumorigenesis and metastasis by re-annotating microarray data from the Gene Expression Omnibus (GEO microarray dataset. These findings reveal potential roles for lncRNAs during melanoma tumorigenesis and metastasis and provide a rich candidate

  2. Cutaneous malignant melanoma in situ: A Danish cross-sectional study on patient and tumour characteristics in 144 cases

    Directory of Open Access Journals (Sweden)

    Anders Klit

    2015-12-01

    Conclusion: The anatomical distribution of MIS differed with patient age and tumour subtype. The anatomical distribution was different in comparison to invasive malignant melanomas, and MIS cases were generally older. This suggests a non-linear relation between malignant melanoma in situ and invasive malignant melanoma.

  3. ORAL AMELANOTIC MELANOMA FEATURE ARTICLE

    African Journals Online (AJOL)

    hard palate (more than 40%) and the gingiva2. Melanomas arise from the uninhibited proliferation ... Malignant melanomas of the mucosal regions of the head and neck are extremely rare neoplasms accounting for less than 1% of .... head and neck region reported that amelanotic melanomas had a 20% survival at 3 years, ...

  4. Genetic Abnormalities in Uveal Melanoma

    NARCIS (Netherlands)

    N.C. Naus (Nicole)

    2001-01-01

    textabstractMelanocytic tumours are believed to arise from the neural crest-derived melanocytes. Five to twelve percent of all melanomas are located in the eye, making it, after the skin, the second most common site of melanomas (Egan et al., 1988; Chang et al., 1998). Uveal melanoma is the most

  5. High nevus counts confer a favorable prognosis in melanoma patients.

    Science.gov (United States)

    Ribero, Simone; Davies, John R; Requena, Celia; Carrera, Cristina; Glass, Daniel; Rull, Ramon; Vidal-Sicart, Sergi; Vilalta, Antonio; Alos, Lucia; Soriano, Virtudes; Quaglino, Pietro; Traves, Victor; Newton-Bishop, Julia A; Nagore, Eduardo; Malvehy, Josep; Puig, Susana; Bataille, Veronique

    2015-10-01

    A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5- and 10-year melanoma-specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21-0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08-0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi. © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  6. Analysis of TSC1 mutation spectrum in mucosal melanoma.

    Science.gov (United States)

    Ma, Meng; Dai, Jie; Xu, Tianxiao; Yu, Sifan; Yu, Huan; Tang, Huan; Yan, Junya; Wu, Xiaowen; Yu, Jiayi; Chi, Zhihong; Si, Lu; Cui, Chuanliang; Sheng, Xinan; Kong, Yan; Guo, Jun

    2018-02-01

    Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma. We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1. The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007). Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.

  7. Targeted Therapy for Melanoma

    International Nuclear Information System (INIS)

    Quinn, Thomas; Moore, Herbert

    2016-01-01

    The research project, entitled ''Targeted Therapy for Melanoma,'' was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203 Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg 11 )CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212 Pb labeled DOTA-Re(Arg 11 )CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212 Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  8. Targeted Therapy for Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Quinn, Thomas [Alphamed, Jackson, TN (United States); Moore, Herbert [Alphamed, Jackson, TN (United States)

    2016-12-05

    The research project, entitled ”Targeted Therapy for Melanoma,” was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg11)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212Pb labeled DOTA-Re(Arg11)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  9. Melanoma survival is superior in females across all tumour stages but is influenced by age.

    Science.gov (United States)

    Khosrotehrani, Kiarash; Dasgupta, Paramita; Byrom, Lisa; Youlden, Danny R; Baade, Peter D; Green, Adele C

    2015-10-01

    Among patients with invasive melanoma, females are known to have higher survival than males globally. However, this survival advantage has not been explored in thin melanomas, the most common form of the disease. In addition, it is unclear if this advantage is true across all age groups. We aimed to compare melanoma survival between males and females by clinical stage and within age groups. Melanomas from 1995 to 2008 were extracted from the Queensland Cancer Registry and the Surveillance, Epidemiology, and End Results (SEER) Program, and melanoma-specific deaths were ascertained up to 2011. Flexible parametric survival models compared survival between groups. The Queensland cohort of 28,979 patients experienced 1712 melanoma deaths and the SEER cohort of 57,402 patients included 6929 melanoma deaths. Survival rates were in favour of females across nearly all tumour stages, including thin invasive tumours in both cohorts after adjusting for demographic and clinical factors [odds ratio (OR) death female:male for stage I melanoma = 0.64 in Queensland; and OR = 0.79 in the US, both P age categories. In particular, the survival advantage was inconsistent in females with stage I melanoma aged under 60. Females with melanoma have a survival advantage over males including in stage I melanomas. However, this advantage is dependent on age at diagnosis, suggesting an underlying biological mechanism influenced by age that exists from the very early stages of the disease.

  10. Circulating tumor cells in melanoma patients.

    Directory of Open Access Journals (Sweden)

    Gary A Clawson

    Full Text Available Circulating tumor cells (CTCs are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (∼400X from blood of melanoma patients using a simple centrifugation device (OncoQuick, and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001. There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001, and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (∼50% stained for both pan-cytokeratin (KRT markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14. Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs. The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids

  11. Melanoma de corpo ciliar e coróide: relato de caso Choroidal and ciliary body melanoma: case report

    Directory of Open Access Journals (Sweden)

    Aline Amaral Fulgêncio da Cunha

    2010-04-01

    Full Text Available Melanomas oculares correspondem a 5% de todos os melanomas e 85% deles têm origem no trato uveal. Melanoma uveal é o tumor maligno intraocular primário mais comum no adulto. Relatamos neste artigo um caso de melanoma uveal em paciente, sexo feminino, 31 anos, com quadro de fotopsia, hiperemia e baixa da acuidade visual no olho esquerdo com evolução de quatro meses. Apresentava ao exame oftalmológico acuidade visual menor que 20/400, grande massa tumoral na região nasal retroiriana, com deslocamento anterior do cristalino, estreitamento da câmara anterior e descolamento seroso da retina. A ecografia sugeriu tratar-se de grande massa tumoral suspeita de melanoma de coróide com invasão do corpo ciliar. A confirmação diagnóstica foi possível por meio do exame anatomopatológico.Ocular melanomas correspond to 5% of all melanomas and 85% of them have its origin in the uveal tract. Uveal melanoma is the most commom primary intraocular malignant tumor in the adult. In this article, a case of uveal melanoma in a 31 year-old female patient, with photopsia, hyperemia and low visual acuity in the left eye with evolution of 4 months is presented. In the ophthalmologic examination, visual acuity was lower than 20/400, a large tumoral mass was noted at the nasal region behind the iris with anterior lens displacement, anterior chamber narrowing and serous retinal detachment. The ocular echography suggested a large tumoral mass as a choroidal melanoma extending to the ciliary body. The confirmation diagnosis was possible through the histopathologic examination.

  12. The Immunology of Melanoma.

    Science.gov (United States)

    Ko, Jennifer S

    2017-09-01

    The relatively high DNA mutational burden in melanoma allows for the creation of potentially "foreign," immune-stimulating neoantigens, and leads to its exceptional immunogenicity. Brisk tumor-infiltrating lymphocytes, a marker of immune editing, confer improved overall survival in melanoma, possibly due to reduced sentinel lymph node spread. Meanwhile, T-cell-stimulating drugs, so-called T-cell checkpoint inhibitors, which reverse peripheral tolerance-dependent tumor escape, have demonstrated unparalleled clinical success in metastatic melanoma. Markers to predict response to immunotherapy are currently imperfect, and the subject of intense research, which will guide the future of ancillary pathologic testing in this setting. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Selective boron accumulation in human ocular melanoma by 10B1-para-boronophenylalanine administration for neutron capture therapy

    International Nuclear Information System (INIS)

    Wadabayashi, Nobutoshi; Ichihashi, Masamitsu; Honda, Chihiro; Mishima, Yutaka.

    1994-01-01

    Malignant melanoma occurs not only in the skin but also in ocular tissues. Ocular melanoma located superficially as in conjunctiva can be treated successfully by BNCT. In the present study, we investigated 10 B dynamics in ocular melanoma and the surrounding normal tissues, to evaluate the possibility of applying BNCT to ocular melanoma. In three ocular melanoma patients, 10 B concentration in melanoma after administration of 10 B-BPA by oral or drip infusion ranged from 10.4 to 21.5 ppm. The boron concentrations in lens and vitreous body were lower than blood level, whereas higher than blood in sclera and palpebral skin. These results suggest that we can treat such a superficial melanoma lesions as conjunctival melanoma by BNCT using 10 B 1 -BPA. (author)

  14. LFA-1 and ICAM-1 expression induced during melanoma-endothelial cell co-culture favors the transendothelial migration of melanoma cell lines in vitro

    International Nuclear Information System (INIS)

    Ghislin, Stephanie; Obino, Dorian; Middendorp, Sandrine; Boggetto, Nicole; Alcaide-Loridan, Catherine; Deshayes, Frederique

    2012-01-01

    Patients with metastatic melanoma have a poor median rate of survival. It is therefore necessary to increase our knowledge about melanoma cell dissemination which includes extravasation, where cancer cells cross the endothelial barrier. Extravasation is well understood during travelling of white blood cells, and involves integrins such as LFA-1 (composed of two chains, CD11a and CD18) expressed by T cells, while ICAM-1 is induced during inflammation by endothelial cells. Although melanoma cell lines cross endothelial cell barriers, they do not express LFA-1. We therefore hypothesized that melanoma-endothelial cell co-culture might induce the LFA-1/ICAM ligand/receptor couple during melanoma transmigration. A transwell approach has been used as well as blocking antibodies against CD11a, CD18 and ICAM-1. Data were analyzed with an epifluorescence microscope. Fluorescence intensity was quantified with the ImageJ software. We show here that HUVEC-conditioned medium induce cell-surface expression of LFA-1 on melanoma cell lines. Similarly melanoma-conditioned medium activates ICAM-1 expression in endothelial cells. Accordingly blocking antibodies of ICAM-1, CD11a or CD18 strongly decrease melanoma transmigration. We therefore demonstrate that melanoma cells can cross endothelial monolayers in vitro due to the induction of ICAM-1 and LFA-1 occurring during the co-culture of melanoma and endothelial cells. Our data further suggest a role of LFA-1 and ICAM-1 in the formation of melanoma cell clumps enhancing tumor cell transmigration. Melanoma-endothelial cell co-culture induces LFA-1 and ICAM-1 expression, thereby favoring in vitro melanoma trans-migration

  15. Satellite in transit metastases in rapidly fatal conjunctival melanoma: implications for angiotropism and extravascular migratory metastasis (description of a murine model for conjunctival melanoma).

    Science.gov (United States)

    Barnhill, Raymond L; Lemaitre, Stéphanie; Lévy-Gabrielle, Christine; Rodrigues, Manuel; Desjardins, Laurence; Dendale, Rémi; Vincent-Salomon, Anne; Roman-Roman, Sergio; Lugassy, Claire; Cassoux, Nathalie

    2016-02-01

    Little information is currently available concerning loco-regional metastases such as satellite and in transit metastases and their natural history in conjunctival melanoma as compared to cutaneous melanoma. Angiotropism, a marker of extravascular migration of melanoma cells along vascular channels, often appears responsible for microscopic satellite, satellite and in transit metastases development in cutaneous melanoma. In addition, diffuse tissue microscopic satellites are correlated with widespread melanoma dissemination and death. Herein we report rapid conjunctival melanoma progression and a fatal outcome in four of five patients following recurrence as satellite in transit metastases. Five patients aged 31, 60, 63, 56, and 67 years developed primary conjunctival melanoma, histologically characterised by tumour thicknesses of 4, 4, 1.1, 3, and 2 mm. Two or more conjunctival melanomas manifested ulceration, significant mitotic rates, necrosis, angiotropism, and intralesional transformation. The conjunctival melanoma recurred in a matter of months as one or more discrete satellite in transit lesions in the vicinity of the primary melanoma. Histological examination revealed well-defined micronodules containing atypical melanocytes in the subepithelial connective tissue stroma. All lesions were extravascular and most appeared angiotropic. Four of five patients subsequently developed parotid or other loco-regional nodal disease and rapidly ensuing widespread metastases and death. The time course from diagnosis to the demise of the patients averaged about 13 (range 7-20) months. Our findings suggest that satellite in transit metastases constitute an important new risk marker for possible rapid metastatic disease progression and death in patients with conjunctival melanoma. This finding appears to take on even greater significance if such lesions develop rapidly, i.e., in a matter of weeks or months following diagnosis of primary conjunctival melanoma, and if the

  16. LFA-1 and ICAM-1 expression induced during melanoma-endothelial cell co-culture favors the transendothelial migration of melanoma cell lines in vitro

    Directory of Open Access Journals (Sweden)

    Ghislin Stephanie

    2012-10-01

    Full Text Available Abstract Background Patients with metastatic melanoma have a poor median rate of survival. It is therefore necessary to increase our knowledge about melanoma cell dissemination which includes extravasation, where cancer cells cross the endothelial barrier. Extravasation is well understood during travelling of white blood cells, and involves integrins such as LFA-1 (composed of two chains, CD11a and CD18 expressed by T cells, while ICAM-1 is induced during inflammation by endothelial cells. Although melanoma cell lines cross endothelial cell barriers, they do not express LFA-1. We therefore hypothesized that melanoma-endothelial cell co-culture might induce the LFA-1/ICAM ligand/receptor couple during melanoma transmigration. Methods A transwell approach has been used as well as blocking antibodies against CD11a, CD18 and ICAM-1. Data were analyzed with an epifluorescence microscope. Fluorescence intensity was quantified with the ImageJ software. Results We show here that HUVEC-conditioned medium induce cell-surface expression of LFA-1 on melanoma cell lines. Similarly melanoma-conditioned medium activates ICAM-1 expression in endothelial cells. Accordingly blocking antibodies of ICAM-1, CD11a or CD18 strongly decrease melanoma transmigration. We therefore demonstrate that melanoma cells can cross endothelial monolayers in vitro due to the induction of ICAM-1 and LFA-1 occurring during the co-culture of melanoma and endothelial cells. Our data further suggest a role of LFA-1 and ICAM-1 in the formation of melanoma cell clumps enhancing tumor cell transmigration. Conclusion Melanoma-endothelial cell co-culture induces LFA-1 and ICAM-1 expression, thereby favoring in vitro melanoma trans-migration.

  17. Angiogenesis and Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Ribatti, Domenico, E-mail: ribatti@anatomia.uniba.it; Annese, Tiziana; Longo, Vito [Department of Human Anatomy and Histology, University of Bari Medical School, Piazza G. Cesare, 11, Policlinico 70124, Bari (Italy)

    2010-02-25

    Angiogenesis occurs in pathological conditions, such as tumors, where a specific critical point in tumor progression is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells, which are able to stimulate the growth of the host’s blood vessels. This article summarizes the literature concerning the relationship between angiogenesis and human melanoma progression. The recent applications of antiangiogenic agents which interfere with melanoma progression are also described.

  18. Regulatory properties of statins and rho gtpases prenylation inhibitiors to stimulate melanoma immunogenicity and promote anti-melanoma immune response.

    Science.gov (United States)

    Sarrabayrouse, Guillaume; Pich, Christine; Teiti, Iotefa; Tilkin-Mariame, Anne Françoise

    2017-02-15

    Melanoma is a highly lethal cutaneous tumor, killing affected patients through development of multiple poorly immunogenic metastases. Suboptimal activation of immune system by melanoma cells is often due to molecular modifications occurring during tumor progression that prevent efficient recognition of melanoma cells by immune effectors. Statins are HMG-CoA reductase inhibitors, which block the mevalonate synthesis pathway, used by millions of people as hypocholesterolemic agents in cardiovascular and cerebrovascular diseases. They are also known to inhibit Rho GTPase activation and Rho dependent signaling pathways. Rho GTPases are regarded as molecular switches that regulate a wide spectrum of cellular functions and their dysfunction has been characterized in various oncogenic process notably in melanoma progression. Moreover, these molecules can modulate the immune response. Since 10 years we have demonstrated that Statins and other Rho GTPases inhibitors are critical regulators of molecules involved in adaptive and innate anti-melanoma immune response. In this review we summarize our major observations demonstrating that these pharmacological agents stimulate melanoma immunogenicity and suggest a potential use of these molecules to promote anti-melanoma immune response. © 2016 UICC.

  19. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma

    Science.gov (United States)

    Frederick, Dennie Tompers; Piris, Adriano; Cogdill, Alexandria P.; Cooper, Zachary A.; Lezcano, Cecilia; Ferrone, Cristina R.; Mitra, Devarati; Boni, Andrea; Newton, Lindsay P.; Liu, Chengwen; Peng, Weiyi; Sullivan, Ryan J; Lawrence, Donald P.; Hodi, F. Stephen; Overwijk, Willem W.; Lizée, Gregory; Murphy, George F.; Hwu, Patrick; Flaherty, Keith T.; Fisher, David E.; Wargo, Jennifer A.

    2013-01-01

    Purpose To evaluate the effects BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. Experimental Design Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10-14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib), and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T cell markers, and immunomodulatory cytokines. Results Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines (IL-6 & IL-8) and an increase in markers of T cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 were increased on treatment. A decrease in melanoma antigen expression and CD8 T cell infiltrate was noted at time of progression on BRAF inhibitor alone, and was reversed with combined BRAF and MEK inhibition. Conclusions Together, this data suggests that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma. PMID:23307859

  20. Radiosensitivity of malignant melanomas. Part II. Clinical studies

    International Nuclear Information System (INIS)

    Trott, K.R.; von Lieven, H.; Kummermehr, J.; Skopal, D.; Lukacs, S.; Braun-Falco, O.; Kellerer, A.M.

    1981-01-01

    Forty-four lymph node or skin metastases of malignant melanomas received definite radiotherapy. Twenty were locally controlled for 2 or more years. Local control rate increased with dose. TCD-50 was about 1800 ret. The effectiveness of radiotherapy was more dependent on overall treatment time than on fraction size or number of fractions. Radiotherapy is suggested to decrease the high rate of locoregional failure of surgery of nodular melanomas in the foot and face

  1. Melanoma Risk Prediction Models

    Science.gov (United States)

    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.

  2. Congenital uveal melanoma?

    Science.gov (United States)

    Singh, Arun D; Schoenfield, Lynn A; Bastian, Boris C; Aziz, Hassan A; Marino, Meghan J; Biscotti, Charles V

    2016-01-01

    A 3-month-old infant with a white mother and Asian father presented with discoloration and prominence of the left eye since birth. Examination revealed a normal right eye. The left eye had hyperchromic heterochromia and an enlarged cornea (diameter, 13.0 mm) with intraocular pressure of 26 mm Hg. There were multiple areas of subconjunctival nodular pigmentation that extended posteriorly into the superior fornix. Fundus examination showed a large ciliochoroidal pigmented mass extending from 10:30 to 3:00 o'clock position involving the superior half of the choroid and adjacent ciliary body. The eye was enucleated, confirming the diagnosis of diffuse uveal melanoma with extraocular extension. Systemic surveillance (hepatic panel and ultrasonography of the liver) performed every 6 months for 5 years was has been negative for metastases. The tumor was investigated intensively for the panel of genes (BAP1, BRAF, NRAS12, NRAS61, GNAQ, Kit 9,11,13,17,18) implicated in pathogenesis of blue nevus, cutaneous melanoma, and mucosal melanomas with negative results. Moreover, germline BAP1 mutation could not be identified. This case possibly represents as yet unidentified uveal melanocytic proliferation rather than a true variant of uveal melanoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Interleukin-6 and melanoma

    DEFF Research Database (Denmark)

    Hoejberg, Lise; Bastholt, Lars; Schmidt, Henrik

    2012-01-01

    Interleukin-6 (IL-6) is a pleiotropic immunomodulatory cytokine produced by various types of cells, including melanoma cells. IL-6 plays a major role in the pathogenesis and development of malignancies. It promotes tumour growth by inhibition of apoptosis and induces tumour angiogenesis. IL-6...

  4. Coffee, tea, and melanoma risk among postmenopausal women.

    Science.gov (United States)

    Wu, Haotian; Reeves, Katherine W; Qian, Jing; Sturgeon, Susan R

    2015-07-01

    Laboratory research suggests that components in coffee and tea may have anticarcinogenic effects. Some epidemiologic studies have reported that women who consume coffee and tea have a lower risk for melanoma. We assessed coffee, tea, and melanoma risk prospectively in the Women's Health Initiative - Observational Study cohort of 66,484 postmenopausal women, followed for an average of 7.7 years. Coffee and tea intakes were measured through self-administered questionnaires at baseline and at year 3 of follow-up. Self-reported incident melanomas were adjudicated using medical records. Cox proportional hazard models were used to estimate risk, adjusting for covariates, with person-time accumulation until melanoma diagnosis (n=398), death, loss to follow-up, or through 2005. Daily coffee [hazard ratio (HR)=0.87, 95% confidence interval (CI) 0.68-1.12] and tea (HR=1.03, 95% CI 0.81-1.31) intakes were not significantly associated with melanoma risk compared with nondaily intake of each beverage. No significant trends were observed between melanoma risk and increasing intakes of coffee (P for trend=0.38) or tea (P for trend=0.22). Women who reported daily coffee intake at both baseline and year 3 had a significantly decreased risk compared with women who reported nondaily intake at both time points (HR=0.68, 95% CI 0.48-0.97). Consistent daily tea intake was not associated with decreased melanoma risk. Overall, there is no strong evidence that increasing coffee or tea consumption can lead to a lower melanoma risk. We observed a decrease in melanoma risk among long-term coffee drinkers, but the lack of consistency in the results by dose and type cautioned against overinterpretation of the results.

  5. CEACAM1 Promotes Melanoma Cell Growth through Sox-2

    Directory of Open Access Journals (Sweden)

    Rona Ortenberg

    2014-05-01

    Full Text Available The prognostic value of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1 in melanoma was demonstrated more than a decade ago as superior to Breslow score. We have previously shown that intercellular homophilic CEACAM1 interactions protect melanoma cells from lymphocyte-mediated elimination. Here, we study the direct effects of CEACAM1 on melanoma cell biology. By employing tissue microarrays and low-passage primary cultures of metastatic melanoma, we show that CEACAM1 expression gradually increases from nevi to metastatic specimens, with a strong dominance of the CEACAM1-Long tail splice variant. Using experimental systems of CEACAM1 knockdown and overexpression of selective variants or truncation mutants, we prove that only the full-length long tail variant enhances melanoma cell proliferation in vitro and in vivo. This effect is not reversed with a CEACAM1-blocking antibody, suggesting that it is not mediated by intercellular homophilic interactions. Downstream, CEACAM1-Long increases the expression of Sox-2, which we show to be responsible for the CEACAM1-mediated enhanced proliferation. Furthermore, analysis of the CEACAM1 promoter reveals two single-nucleotide polymorphisms (SNPs that significantly enhance the promoter's activity compared with the consensus nucleotides. Importantly, case-control genetic SNP analysis of 134 patients with melanoma and matched healthy donors show that patients with melanoma do not exhibit the Hardy-Weinberg balance and that homozygous SNP genotype enhances the hazard ratio to develop melanoma by 35%. These observations shed new mechanistic light on the role of CEACAM1 in melanoma, forming the basis for development of novel therapeutic and diagnostic technologies.

  6. Melanoma risk prediction models

    Directory of Open Access Journals (Sweden)

    Nikolić Jelena

    2014-01-01

    Full Text Available Background/Aim. The lack of effective therapy for advanced stages of melanoma emphasizes the importance of preventive measures and screenings of population at risk. Identifying individuals at high risk should allow targeted screenings and follow-up involving those who would benefit most. The aim of this study was to identify most significant factors for melanoma prediction in our population and to create prognostic models for identification and differentiation of individuals at risk. Methods. This case-control study included 697 participants (341 patients and 356 controls that underwent extensive interview and skin examination in order to check risk factors for melanoma. Pairwise univariate statistical comparison was used for the coarse selection of the most significant risk factors. These factors were fed into logistic regression (LR and alternating decision trees (ADT prognostic models that were assessed for their usefulness in identification of patients at risk to develop melanoma. Validation of the LR model was done by Hosmer and Lemeshow test, whereas the ADT was validated by 10-fold cross-validation. The achieved sensitivity, specificity, accuracy and AUC for both models were calculated. The melanoma risk score (MRS based on the outcome of the LR model was presented. Results. The LR model showed that the following risk factors were associated with melanoma: sunbeds (OR = 4.018; 95% CI 1.724- 9.366 for those that sometimes used sunbeds, solar damage of the skin (OR = 8.274; 95% CI 2.661-25.730 for those with severe solar damage, hair color (OR = 3.222; 95% CI 1.984-5.231 for light brown/blond hair, the number of common naevi (over 100 naevi had OR = 3.57; 95% CI 1.427-8.931, the number of dysplastic naevi (from 1 to 10 dysplastic naevi OR was 2.672; 95% CI 1.572-4.540; for more than 10 naevi OR was 6.487; 95%; CI 1.993-21.119, Fitzpatricks phototype and the presence of congenital naevi. Red hair, phototype I and large congenital naevi were

  7. RARE METASTASES OF MALIGNANT MELANOMA

    Directory of Open Access Journals (Sweden)

    Marija Trenkić-Božinović

    2014-09-01

    Full Text Available Melanomas are malignant neoplasms that originate from melanocytes. The most common are on the skin and mucous membranes. Choroidal melanomas are quite different from cutaneous melanomas with regard to presentation, metastases, and treatment. We report two cases of metastatic gastric malignant melanoma of the eye and skin, with reference to the literature. The first patient was a woman aged 23 years, who underwent gastrectomy 22 months after enucleation of the eye due to malignant choroid melanoma. The second patient was a man, 72 years old, who underwent surgery 28 months before because of malignant melanoma of the skin of the forehead. Paraffin sections, 4 μm thick were stained using a classic method, as well as immunohistochemical DAKO APAAP method, using a specific S - 100 antibody and Melan A antibodies. The stomach is considered a rare place for the development of metastases. Metastases in the stomach are often limited to the submucosal as well as the serousmuscular layer, as noted in one of our patients. Metastatic melanoma of the gastrointestinal tract should be suspected in any patient with a history of malignant melanoma and new gastrointestinal symptoms. Because of the similarity between certain common histopathological types of malignant melanoma, primarily achromatic, and types of primary cancers of the stomach, the following immunohistochemical studies are needed: Melan A and S - 100 protein ( markers of malignant melanoma , as well as mucins: MUC5AC, MUC2 and CDX2 ( markers of different types of primary gastric carcinoma.

  8. Communication about melanoma and risk reduction after melanoma diagnosis.

    Science.gov (United States)

    Rodríguez, Vivian M; Berwick, Marianne; Hay, Jennifer L

    2017-12-01

    Melanoma patients are advised to perform regular risk-reduction practices, including sun protection as well as skin self-examinations (SSEs) and physician-led examinations. Melanoma-specific communication regarding family risk and screening may promote such behaviors. To this end, associations between patients' melanoma-specific communication and risk reduction were examined. Melanoma patients (N = 169) drawn from a population-based cancer registry reported their current risk-reduction practices, perceived risk of future melanoma, and communication with physicians and relatives about melanoma risk and screening. Patients were, on average, 56 years old and 6.7 years' post diagnosis; 51% were male, 93% reported "fair/very fair" skin color, 75% completed at least some college, and 22% reported a family history of melanoma. Patients reported varying levels of regular (always/nearly always) sun protection: sunscreen use (79%), shade seeking (60%), hat use (54%), and long-sleeve shirt use (30%). Only 28% performed thorough SSE regularly, whereas 92% reported undergoing physician-led skin examinations within the past year. Participants who were female, younger, and had a higher perceived risk of future melanoma were more likely to report past communication. In adjusted analyses, communication remained uniquely associated with increased sunscreen use and SSE. Encouraging melanoma patients to have a more active role in discussions concerning melanoma risk and screening with relatives and physicians alike may be a useful strategy to promote 2 key risk-reduction practices post melanoma diagnosis and treatment. Future research is needed to identify additional strategies to improve comprehensive risk reduction in long-term melanoma patients. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

    Science.gov (United States)

    Castelli, Germana; Pelosi, Elvira

    2017-01-01

    Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID:29156643

  10. Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

    Directory of Open Access Journals (Sweden)

    Ugo Testa

    2017-11-01

    Full Text Available Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

  11. RAGE and S100 protein transcription levels are highly variable in human melanoma tumors and cells.

    Science.gov (United States)

    Leclerc, Estelle; Heizmann, Claus W; Vetter, Stefan W

    2009-01-01

    The Receptor for Advanced Glycation Endproducts (RAGE) has been suggested to play an important role in melanoma. Animal studies with anti-RAGE antibodies have shown that RAGE blockade leads to reduced melanoma tumor growth and metastasis formation. RAGE is a multiligand receptor and among its ligands are the Ca-binding S100 proteins. Certain S100 proteins are differentially expressed in melanoma. For example, S100B is currently used as a reliable prognostic biomarker in patients with malignant melanoma. We have surveyed 40 human melanoma tumor samples for the transcription of RAGE and five of its known S100 protein ligands. Compared to normal skin tissue, we found highly significant (p no significant difference in transcription of S100A6 and S100A10 was observed. RAGE showed slightly increased transcription in stage IV. Between individual tumor samples tremendous differences in transcription of the S100 proteins were observed, whereas RAGE expression showed relatively little variance. We also analyzed three well-characterized melanoma cell lines for S100 and RAGE expression. The S100 protein transcription profile showed clear differences between cultured melanoma cells and melanoma tumor tissue. Detailed profiling of S100 and RAGE transcription in melanoma tumors in combination with imunohisto-chemical and clinical data may lead to improved molecular diagnostic of melanoma and subsequently may facilitate improved treatment in the future.

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

    Science.gov (United States)

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

    2014-06-03

    We report the case of an 84-year-old woman who had a nodal recurrence of melanoma 45 years after the primary diagnosis of an extremity cutaneous melanoma. It is believed to be the longest disease-free latency period reported between primary melanoma diagnosis and recurrence to date. Late recurrences of melanoma are rare and recurrence after four decades extremely rare. This article suggests melanoma is a disease with a potentially lifelong risk of recurrence and thus clinicians and patients must be vigilant and aware of this risk, particularly if late recurrences are to be recognised early and management optimised. 2014 BMJ Publishing Group Ltd.

  13. CHOROIDAL MELANOMA IN A PATIENT WITH WAARDENBURG SYNDROME.

    Science.gov (United States)

    Itty, Sujit; Richter, Elizabeth R; McCannel, Tara A

    2015-01-01

    To report a case of choroidal malignant melanoma in a patient with Waardenburg syndrome and bilateral choroidal pigmentary abnormalities. Clinical examination and multimodal imaging of the case. A 45-year-old woman presented with asymptomatic flat choroidal pigmentation abnormalities in both eyes. A choroidal lesion was identified in the inferotemporal periphery of the left eye arising from an area of hyperpigmentation; ultrasonography findings were consistent with a choroidal melanoma. The patient endorsed a personal and family history of premature graying of hair and was identified to have dystopia canthorum consistent with the diagnosis of Waardenburg syndrome. The authors present the first reported case of concurrent Waardenburg syndrome and choroidal malignant melanoma. This cooccurrence may suggest that the relative hyperpigmented regions in affected fundi may be abnormal and should be monitored closely for the development of choroidal melanoma.

  14. Hyaluronan synthase 3 (HAS3) overexpression downregulates MV3 melanoma cell proliferation, migration and adhesion

    International Nuclear Information System (INIS)

    Takabe, Piia; Bart, Geneviève; Ropponen, Antti; Rilla, Kirsi; Tammi, Markku; Tammi, Raija; Pasonen-Seppänen, Sanna

    2015-01-01

    Malignant skin melanoma is one of the most deadly human cancers. Extracellular matrix (ECM) influences the growth of malignant tumors by modulating tumor cells adhesion and migration. Hyaluronan is an essential component of the ECM, and its amount is altered in many tumors, suggesting an important role for hyaluronan in tumorigenesis. Nonetheless its role in melanomagenesis is not understood. In this study we produced a MV3 melanoma cell line with inducible expression of the hyaluronan synthase 3 (HAS3) and studied its effect on the behavior of the melanoma cells. HAS3 overexpression expanded the cell surface hyaluronan coat and decreased melanoma cell adhesion, migration and proliferation by cell cycle arrest at G1/G0. Melanoma cell migration was restored by removal of cell surface hyaluronan by Streptomyces hyaluronidase and by receptor blocking with hyaluronan oligosaccharides, while the effect on cell proliferation was receptor independent. Overexpression of HAS3 decreased ERK1/2 phosphorylation suggesting that inhibition of MAP-kinase signaling was responsible for these suppressive effects on the malignant phenotype of MV3 melanoma cells. - Highlights: • Inducible HAS3-MV3 melanoma cell line was generated using Lentiviral transduction. • HAS3 overexpression inhibits MV3 cell migration via hyaluronan–receptor interaction. • HAS3 overexpression decreases MV3 melanoma cell proliferation and adhesion. • ERK1/2 phosphorylation is downregulated by 50% in HAS3 overexpressing cells. • The results suggest that hyaluronan has anti-cancer like effects in melanoma

  15. Melanoma Epidemiology and Public Health

    Science.gov (United States)

    Berwick, Marianne; Erdei, Esther; Hay, Jennifer

    2013-01-01

    Melanoma has presented a conundrum to physicians and prevention researchers. We should be able to reduce incidence and mortality rather easily because evolving melanoma lesions are observable on the surface of the skin. However, melanoma has not proved tractable. The incidence and mortality have risen in all developed countries during the past 50 years. However, mortality appears to be abating among younger cohorts even though the reason for this is not clear. PMID:19254665

  16. Melanoma and immunotherapy bridge 2015

    OpenAIRE

    Nanda, Vashisht G. Y.; Peng, Weiyi; Hwu, Patrick; Davies, Michael A.; Ciliberto, Gennaro; Fattore, Luigi; Malpicci, Debora; Aurisicchio, Luigi; Ascierto, Paolo Antonio; Croce, Carlo M.; Mancini, Rita; Spranger, Stefani; Gajewski, Thomas F.; Wang, Yangyang; Ferrone, Soldano

    2016-01-01

    Table of contents MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancin...

  17. Rho kinase inhibitors block melanoma cell migration and inhibit metastasis.

    Science.gov (United States)

    Sadok, Amine; McCarthy, Afshan; Caldwell, John; Collins, Ian; Garrett, Michelle D; Yeo, Maggie; Hooper, Steven; Sahai, Erik; Kuemper, Sandra; Mardakheh, Faraz K; Marshall, Christopher J

    2015-06-01

    There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both "amoeboid-like" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis. ©2015 American Association for Cancer Research.

  18. Intraocular malignant melanoma of the choroid presenting as orbital cellulitis.

    Science.gov (United States)

    Nair, Akshay Gopinathan; Kaliki, Swathi; Ali, Mohammed Javed; Naik, Milind N; Vemuganti, Geeta K

    2014-06-01

    We report a case of choroidal melanoma with features suggestive of orbital cellulitis. A 24-year-old Asian Indian male presented with a 20-day history of sudden loss of vision in the right eye. Edematous eyelids with complete mechanical ptosis, complete ophthalmoplegia, gross proptosis accompanied by massive chemosis, and prolapse of the inferior forniceal conjunctiva were noted. He denied perception of light in the right eye. The left eye was unremarkable. B-scan ultrasonography of the right eye showed a large dome-shaped mass filling the posterior segment suggestive of choroidal melanoma. Computed tomography confirmed those findings and showed no extraocular tumor extension. The patient was conservatively treated with systemic steroids following which the inflammation subsided. He underwent enucleation of the right eye and a diagnosis of spindle A cell choroidal melanoma was confirmed by histopathological examination. Although rare, orbital cellulitis is one of the presenting features of choroidal melanoma. Uveal melanoma-associated orbital cellulitis can be well controlled with systemic steroids, does not always indicate extraocular tumor extension, and can occur in spindle A cell melanomas.

  19. Gamma knife radiosurgery for uveal melanoma ineligible for brachytherapy by the Collaborative Ocular Melanoma Study criteria

    Directory of Open Access Journals (Sweden)

    Nicola G Ghazi

    2008-09-01

    Full Text Available Nicola G Ghazi1, Christopher S Ketcherside1, Jason Sheehan2, Brian P Conway11Department of Ophthalmology and 2Neurosurgery, University of Virginia Health System, Charlottesville, VA, USAPurpose: To report outcomes of Gamma Knife radiosurgery (GKRS in treating uveal melanoma lesions ineligible for standard brachytherapy.Methods: A retrospective interventional case series of uveal melanoma patients treated with GKRS between 1996 and 2004 was performed. The main outcome measures were local tumor control, metastasis, and death.Results: Four patients with uveal melanoma treated with GKS were identified. Three tumors involved the ciliary body and one was macular with its border within 2 mm of the optic disc. Adequate globe stabilization was achieved by retrobulbar anesthesia in all cases. Pretreatment mean visual acuity was 20/30. Tumor volume as determined by magnetic resonance imaging ranged from 0.05 to 0.30 cc. Ultrasonographic greatest tumor diameter and height ranged from 11 to 18 mm (mean 14.5 mm and 2.9 to 4.5 mm (mean 3.6 mm, respectively. The peripheral dose varied from 16.5 to 30 Gray. Local tumor control was achieved in all cases over a follow up period of 6 to 96 months. Mean final visual acuity was 20/50. One eye was enucleated for neovascular glaucoma and one patient died from liver and lung metastasis.Conclusions: GKRS for uveal melanoma appears to be safe and effective. The metastasis and mortality rates appear to be comparable to those following brachytherapy and enucleation. Moreover, local tumor control and enucleation rates are similar to those following brachytherapy. The findings in this small series suggest a role for GKRS in the treatment of selected cases of uveal melanomas.Keywords: gamma knife radiosurgery, radiation therapy, uveal melanoma

  20. Orbital melanoma masquerading as a "Galloping haemangioma".

    Science.gov (United States)

    Lorenzano, Daniele; Miszkiel, Katherine; Rose, Geoffrey E

    2017-04-01

    We describe a 32-year-old pregnant woman who was referred to our clinic after 6 weeks of observation elsewhere with a rapidly expanding orbital mass, proptosed globe and slowly decreasing of vision in her left eye. To our examination the patient presented with congested optic disc fine macular striae and some slight choroidal elevation without any retinal pigmentation. An MRI scan without contrast was performed, suggesting the signal charactheristics of an orbital mass consistent with a cellular lesion such as a cavernous hemangioma or a solitary fibrous tumour. Despite the benign-looking imaging, the fast-growing pattern of the lesion suggested a more sinister picture. A fine needle aspiration of the orbital mass was carried out, revealing the presence of an amelanotic melanoma. This case highlights the importance of considering the presence of a melanoma when there is a clear history of a rapid lesion progression.

  1. Nodular amelanotic melanoma

    Directory of Open Access Journals (Sweden)

    Nalamwar Rashmi

    2010-01-01

    Full Text Available We report a case of 65-year-old male patient who presented with multiple erythematous papules coalescing to form a nodular mass over posterior aspect of right thigh of six months duration. His general and systemic examinations were within normal range except for right inguinal lymphadenopathy. Biopsy from the lesion was done, which showed diffuse infiltrate of nests of atypical melanocytes extending upto reticular dermis. Malignant cells were positive for S100 and human melanin black 45(HMB 45. Hence, a diagnosis of amelanotic melanoma (AM - Clarke level IV and TNM stage III was reached. MRI of involved leg showed fungating soft tissue mass in the posterolateral aspect of right thigh and metastatic right inguinal adenopathy. Fine needle aspiration cytology (FNAC from the right inguinal nodes confirmed metastasis of melanoma. The patient was referred to oncosurgery department for further management.

  2. Pathology and genomics of pediatric melanoma: A critical reexamination and new insights.

    Science.gov (United States)

    Bahrami, Armita; Barnhill, Raymond L

    2018-02-01

    The clinicopathologic features of pediatric melanoma are distinct from those of the adult counterpart. For example, most childhood melanomas exhibit a uniquely favorable biologic behavior, save for those arising in large/giant congenital nevi. Recent studies suggest that the characteristically favorable biologic behavior of childhood melanoma may be related to extreme telomere shortening and dysfunction in the cancer cells. Herein, we review the genomic profiles that have been defined for the different subtypes of pediatric melanoma and particularly emphasize the potential prognostic value of telomerase reverse transcriptase alterations for these tumors. © 2017 Wiley Periodicals, Inc.

  3. Dermoscopy of difficult-to-diagnose Melanomas

    Directory of Open Access Journals (Sweden)

    Papageorgiou Chrysoula

    2016-09-01

    Full Text Available Dermoscopy is a non-invasive procedure that allows the evaluation of cutaneous lesions, and is considered to be a useful tool that improves the diagnostic accuracy of melanoma. Many dermoscopic criteria of melanoma have been established and several algorithms have been created for melanoma detection. However, the recognition of some melanomas remains challenging. Melanomas on specific body sites, melanomas in patients with multiple atypical moles, and nodular melanomas represent the most difficult-to-recognize melanoma subtypes, since they typically lack the “classic” melanoma-specific criteria. This paper provides an update on dermoscopy of difficult-to-diagnose melanomas by summarizing the newest data. Lastly, we highlight the importance of digital dermoscopy in the follow-up of melanocytic lesions for the detection of incipient melanomas while maintaining a low excision rate.

  4. Antiestrogen therapy for breast cancer modifies the risk of subsequent cutaneous melanoma.

    Science.gov (United States)

    Huber, Caroline; Bouchardy, Christine; Schaffar, Robin; Neyroud-Caspar, Isabelle; Vlastos, Georges; Le Gal, Frédérique-Anne; Rapiti, Elisabetta; Benhamou, Simone

    2012-01-01

    Increased risk of secondary melanoma after breast cancer has been reported. Several lines of evidence suggest that elevated estrogen levels may be implicated in melanoma etiology. Accordingly, use of antiestrogens should be associated with decreased risk of melanoma. We compared melanoma incidence among a cohort of breast cancer patients with and without antiestrogen therapy, with data from the Geneva Cancer Registry. The cohort consisted of 7,360 women diagnosed with breast cancer between 1980 and 2005. About 54% of these patients received antiestrogens. All women were followed until December 2008. We compared cutaneous melanoma incidence rates among patients with and without antiestrogens with those expected in the general population by age and period standardized incidence ratios (SIR). A total of 34 women developed a melanoma during the follow-up period. Compared with the general population, the risk of melanoma was higher for patients who did not receive antiestrogens (SIR: 1.60, 95% CI: 1.08-2.12, P = 0.02). On the contrary, the risk was close to 1 (SIR: 0.98, 95% CI: 0.40-1.56, P = 0.57) for patients who received antiestrogen therapy. This study suggests that antiestrogen therapy modifies the risk of melanoma after breast cancer. Although our results are in agreement with the hypothesis that estrogens could play a role in melanoma occurrence, they need to be replicated in a larger study with data on potential confounders. . ©2011 AACR

  5. Circulating melanoma cells and survival in metastatic melanoma

    NARCIS (Netherlands)

    Rao, C.; Bui, T.; Connelly, M.; Doyle, G.; Karydis, I.; Middleton, M. R.; Clack, G.; Malone, M.; Coumans, F. A. W.; Terstappen, L. W. M. M.

    2011-01-01

    A validated assay for the enumeration of circulating melanoma cells (CMCs) may facilitate the development of more effective therapies for metastatic melanoma patients. In this study CD146(+) cells were immunomagnetically enriched from 7.5 ml of blood. Isolated cells were fluorescently stained with

  6. Analysis of losses of heterozygosity of the candidate tumour suppressor gene DMBT1 in melanoma resection specimens

    DEFF Research Database (Denmark)

    Deichmann, M; Mollenhauer, J; Helmke, B

    2002-01-01

    Deleted in malignant brain tumours 1 (DMBT1), a candidate tumour suppressor gene located on chromosome 10q25.3-q26.1, has recently been identified and found to be deleted in several different types of human tumours. In melanomas, the chromosomal region 10q22-qter is commonly affected by losses......, hence we screened primary melanoma samples for losses of heterozygosity (LOH), and acquired melanocytic naevi and melanomas for transcription of DMBT1 and protein expression. Of 38 informative melanomas, 1 nodular melanoma and 2 subcutaneous metastases showed LOH of both microsatellites flanking...... the gene, suggesting loss of 1 DMBT1 allele. Three further melanomas showed LOH at 1 informative locus but were heterozygous for the second marker. Applying reverse-transcription polymerase chain reaction (RT-PCR), DMBT1 transcription was not found in melanomas. However, DMBT1 transcription was also absent...

  7. Analysis of losses of heterozygosity of the candidate tumour suppressor gene DMBT1 in melanoma resection specimens

    DEFF Research Database (Denmark)

    Deichmann, M; Mollenhauer, J; Helmke, B

    2002-01-01

    , hence we screened primary melanoma samples for losses of heterozygosity (LOH), and acquired melanocytic naevi and melanomas for transcription of DMBT1 and protein expression. Of 38 informative melanomas, 1 nodular melanoma and 2 subcutaneous metastases showed LOH of both microsatellites flanking......Deleted in malignant brain tumours 1 (DMBT1), a candidate tumour suppressor gene located on chromosome 10q25.3-q26.1, has recently been identified and found to be deleted in several different types of human tumours. In melanomas, the chromosomal region 10q22-qter is commonly affected by losses...... the gene, suggesting loss of 1 DMBT1 allele. Three further melanomas showed LOH at 1 informative locus but were heterozygous for the second marker. Applying reverse-transcription polymerase chain reaction (RT-PCR), DMBT1 transcription was not found in melanomas. However, DMBT1 transcription was also absent...

  8. Cancer stem cell as therapeutic target for melanoma treatment.

    Science.gov (United States)

    Alamodi, Abdulhadi A; Eshaq, Abdulaziz M; Hassan, Sofie-Yasmin; Al Hmada, Youssef; El Jamal, Siraj M; Fothan, Ahmed M; Arain, Omair M; Hassan, Sarah-Lilly; Haikel, Youssef; Megahed, Mosaad; Hassan, Mohamed

    2016-12-01

    Human malignant melanoma is a highly aggressive skin tumor that is characterized by its extraordinary heterogeneity, propensity for dissemination to distant organs and resistance to cytotoxic agents. Although chemo- and immune-based therapies have been evaluated in clinical trials, most of these therapeutics do not show significant benefit for patients with advanced disease. Treatment failure in melanoma patients is attributed mainly to the development of tumor heterogeneity resulting from the formation of genetically divergent subpopulations. These subpopulations are composed of cancer stem-like cells (CSCs) as a small fraction and non-cancer stem cells that form the majority of the tumor mass. In recent years, CSCs gained more attention and suggested as valuable experimental model system for tumor study. In melanoma, intratumoral heterogeneity, progression and drug resistance result from the unique characteristics of melanoma stem cells (MSCs). These MSCs are characterized by their distinct protein signature and tumor growth-driving pathways, whose activation is mediated by driver mutation-dependent signal. The molecular features of MSCs are either in a causal or consequential relationship to melanoma progression, drug resistance and relapse. Here, we review the current scientific evidence that supports CSC hypothesis and the validity of MSCs-dependent pathways and their key molecules as potential therapeutic target for melanoma treatment.

  9. CHOROIDAL MELANOMA IN PHAKOMATOSIS PIGMENTOVASCULARIS WITH KLIPPEL-TRENAUNAY SYNDROME.

    Science.gov (United States)

    Shields, Carol L; Di Nicola, Maura; Pellegrini, Marco; Shields, Jerry A

    2017-09-20

    To describe the relationship of choroidal melanoma with phakomatosis pigmentovascularis in patients with Klippel-Trenaunay syndrome. Retrospective review of 5 patients. In all 5 cases, the patient was white and the cutaneous port-wine stain was congenital. The port-wine stain involved the chin (n = 1), jawline (n = 2), lower cheek (n = 1), thorax (n = 5), abdomen (n = 4), upper (n = 4), and lower (n = 3) limb(s). The ocular melanocytosis involved the sclera (n = 5), iris (n = 2) and choroid (n = 4). At diagnosis of choroidal melanoma, mean patient age was 57 years (median 61, range 17-83 years). The melanoma demonstrated mean basal diameter of 11.6 mm (median 12, range 5-16 mm) and mean thickness of 5.7 mm (median 6.1, range 2-9), revealing intrinsic tumor pigment and subretinal fluid in all cases. Melanoma management included plaque radiotherapy (n = 3), thermotherapy (n = 1), or enucleation (n = 1). At mean follow-up of 4 years, one patient demonstrated melanoma-related metastasis with death. Phakomatosis pigmentovascularis represents coexistence of Klippel-Trenaunay syndrome (or Sturge-Weber syndrome) and oculo(dermal) melanocytosis, promoting risk for life-threatening uveal melanoma. The authors suggest that all patients with Klippel-Trenaunay syndrome be evaluated for phakomatosis pigmentovascularis and affected patients have dilated fundus examination once or twice a year.

  10. UVA radiation augments cytotoxic activity of psoralens in melanoma cells.

    Science.gov (United States)

    Wrześniok, Dorota; Beberok, Artur; Rok, Jakub; Delijewski, Marcin; Hechmann, Anna; Oprzondek, Martyna; Rzepka, Zuzanna; Bacler-Żbikowska, Barbara; Buszman, Ewa

    2017-07-01

    Melanoma is an aggressive form of skin cancer. The aim of the study was to evaluate the influence of UVA radiation and psoralens: 5-methoxypsoralen (5-MOP) or 8-methoxypsoralen (8-MOP) on melanoma cells viability. The amelanotic C32 and melanotic COLO829 human melanoma cell lines were exposed to increasing concentrations of psoralens (0.1-100 μM) in the presence or absence of UVA radiation. Cell viability was evaluated by the WST-1 assay. We demonstrated that 8-MOP, in contrast to 5-MOP, has no cytotoxic effect on both melanoma cell lines. Simultaneous exposure of cells to 8-MOP and UVA radiation caused significant cytotoxic response in C32 cells where the EC 50 value was estimated to be 131.0 μM (UVA dose: 1.3 J/cm 2 ) and 105.3 μM (UVA dose: 2.6 J/cm 2 ). The cytotoxicity of 5-MOP on both C32 and COLO829 cells was significantly augmented by UVA radiation - the EC 50 was estimated to be 22.7 or 7.9 μM (UVA dose: 1.3 J/cm 2 ) and 24.2 or 7.0 μM (UVA dose: 2.6 J/cm 2 ), respectively. The demonstrated high cytotoxic response after simultaneous exposure of melanoma cells to psoralens and UVA radiation in vitro suggests the usefulness of PUVA therapy to treat melanoma in vivo.

  11. Melanoma NOS1 expression promotes dysfunctional IFN signaling.

    Science.gov (United States)

    Liu, Qiuzhen; Tomei, Sara; Ascierto, Maria Libera; De Giorgi, Valeria; Bedognetti, Davide; Dai, Cuilian; Uccellini, Lorenzo; Spivey, Tara; Pos, Zoltan; Thomas, Jaime; Reinboth, Jennifer; Murtas, Daniela; Zhang, Qianbing; Chouchane, Lotfi; Weiss, Geoffrey R; Slingluff, Craig L; Lee, Peter P; Rosenberg, Steven A; Alter, Harvey; Yao, Kaitai; Wang, Ena; Marincola, Francesco M

    2014-05-01

    In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells.

  12. Migration and melanoma incidence rates among Washington state counties.

    Science.gov (United States)

    Chan, Victor; Thompson, Ian; Whitney, David; Switzer, Michael; Anderson, Amy D; Smits, Shelly

    2013-08-01

    The purpose of this study was to look for a possible explanation for the variation in the incidence rate of melanoma among counties in Washington state. We used data from the Washington State Cancer Registry (WSCR), the Cancer Center at PeaceHealth St. Joseph Hospital in Whatcom County, and the Surveillance, Epidemiology, and End Results registry to get information on melanoma incidence. Demographic and migration records were obtained from the US Census Bureau, the Washington State Department of Licensing (DOL), and the US Internal Revenue Service (IRS). A number of different analytic techniques were used to address our research question, including a multiple regression analysis, time trend comparisons, and an analysis of birthplace data of melanoma patients in Whatcom county. We found a significant association between migration rate from the Southwest (SW) USA and melanoma incidence (PWhatcom county, almost half of all residents were born outside of Washington state, but they accounted for about 70% of all melanoma cases. Our analyses suggest that migration from the SW is an important factor in explaining the variation in melanoma rate among counties in Washington.

  13. STAT3 targeting by polyphenols: Novel therapeutic strategy for melanoma.

    Science.gov (United States)

    Momtaz, Saeideh; Niaz, Kamal; Maqbool, Faheem; Abdollahi, Mohammad; Rastrelli, Luca; Nabavi, Seyed Mohammad

    2017-05-06

    Melanoma or malignant melanocytes appear with the low incidence rate, but very high mortality rate worldwide. Epidemiological studies suggest that polyphenolic compounds contribute for prevention or treatment of several cancers particularly melanoma. Such findings motivate to dig out novel therapeutic strategies against melanoma, including research toward the development of new chemotherapeutic and biologic agents that can target the tumor cells by different mechanisms. Recently, it has been found that signal transducer and activator of transcription 3 (STAT3) is activated in many cancer cases surprisingly. Different evidences supply the aspect that STAT3 activation plays a vital role in the metastasis, including proliferation of cells, survival, invasion, migration, and angiogenesis. This significant feature plays a vital role in various cellular processes, such as cell proliferation and survival. Here, we reviewed the mechanisms of the STAT3 pathway regulation and their role in promoting melanoma. Also, we have evaluated the emerging data on polyphenols (PPs) specifically their contribution in melanoma therapies with an emphasis on their regulatory/inhibitory actions in relation to STAT3 pathway and current progress in the development of phytochemical therapeutic techniques. An understanding of targeting STAT3 by PPs brings an opportunity to melanoma therapy. © 2016 BioFactors, 43(3):347-370, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

  14. Using risk factors for detection and prognostication of uveal melanoma

    Science.gov (United States)

    Rishi, Pukhraj; Koundanya, Vikram V; Shields, Carol L

    2015-01-01

    The early detection of malignancy, particularly uveal melanoma, is crucial in protecting visual acuity, salvaging the eye, and preventing metastasis. Risk factors for early detection of uveal melanoma have been clearly delineated in the literature and allow identification of melanoma when it is tiny and simulates a nevus. These factors include thickness >2 mm, presence of subretinal fluid (SRF), symptoms, the orange pigment, margin near optic disc, acoustic hollowness, surrounding halo, and absence of drusen. The importance of early detection is realized when one considers melanoma thickness, as each millimeter increase in melanoma thickness imparts 5% increased risk for metastatic disease. Newer imaging modalities like enhanced depth imaging optical coherence tomography and fundus autoflouroscence facilitate in detection of SRF and orange pigment. Additional molecular biomarkers and cytological features have been identified which can predict the clinical behavior of a small melanocytic lesion. Features that suggest a poor prognosis include higher blood levels of tyrosinase m-RNA, vascular endothelial growth factor, insulin-like growth factor; monosomy 3 and gains in chromosome 8. Management of uveal melanoma includes enucleation (for large), local eye wall resection, brachytherapy, charged particle irradiation, and thermotherapy (for small to medium tumors). Although the role of a good clinical evaluation cannot be underestimated, it is advisable to evaluate the various radiological, molecular, and cytological features, to enhance the accuracy of early diagnosis and improved prognosis. PMID:25827540

  15. Using risk factors for detection and prognostication of uveal melanoma

    Directory of Open Access Journals (Sweden)

    Pukhraj Rishi

    2015-01-01

    Full Text Available The early detection of malignancy, particularly uveal melanoma, is crucial in protecting visual acuity, salvaging the eye, and preventing metastasis. Risk factors for early detection of uveal melanoma have been clearly delineated in the literature and allow identification of melanoma when it is tiny and simulates a nevus. These factors include thickness >2 mm, presence of subretinal fluid (SRF, symptoms, the orange pigment, margin near optic disc, acoustic hollowness, surrounding halo, and absence of drusen. The importance of early detection is realized when one considers melanoma thickness, as each millimeter increase in melanoma thickness imparts 5% increased risk for metastatic disease. Newer imaging modalities like enhanced depth imaging optical coherence tomography and fundus autoflouroscence facilitate in detection of SRF and orange pigment. Additional molecular biomarkers and cytological features have been identified which can predict the clinical behavior of a small melanocytic lesion. Features that suggest a poor prognosis include higher blood levels of tyrosinase m-RNA, vascular endothelial growth factor, insulin-like growth factor; monosomy 3 and gains in chromosome 8. Management of uveal melanoma includes enucleation (for large, local eye wall resection, brachytherapy, charged particle irradiation, and thermotherapy (for small to medium tumors. Although the role of a good clinical evaluation cannot be underestimated, it is advisable to evaluate the various radiological, molecular, and cytological features, to enhance the accuracy of early diagnosis and improved prognosis.

  16. Historical, clinical, and dermoscopic characteristics of thin nodular melanoma.

    Science.gov (United States)

    Kalkhoran, Sara; Milne, Olivia; Zalaudek, Iris; Puig, Susana; Malvehy, Josep; Kelly, John W; Marghoob, Ashfaq A

    2010-03-01

    Nodular melanoma (NM), representing 15% to 30% of all melanomas, constitutes nearly half of all melanomas thicker than 2 mm. Nodular melanoma frequently lacks clinical features seen in other melanoma subtypes and has a faster growth rate. We reviewed a series of cases of NM that was less than 1.3 mm thick to identify historical, clinical, and dermoscopic factors that may facilitate earlier diagnosis of NM, with the hope of reducing its associated morbidity and mortality. The thin NM lesions we analyzed had a rather subtle clinical appearance, often lacking the ABCD (asymmetry, border irregularity, color variegation, and diameter greater than 6 mm) criteria. On dermoscopy, most lesions had a homogeneous disorganized asymmetric pattern or a featureless pattern with atypical vessels. Although many dermoscopic features seen in other melanoma subtypes were frequently absent, some features such as a blue-white veil, structureless areas, and atypical vascular structures were often identified. The often unremarkable clinical presentation of NM necessitates physicians and patients to be wary of new or changing lesions. Dermoscopy may help increase suspicion in early NM because dermoscopic features are typically more suggestive of malignancy than clinical ones. We hope that secondary prevention efforts combined with prompt dermatologic consultations will allow for the timely diagnosis and management of NM.

  17. The DEAD/DEAH box helicase, DDX11, is essential for the survival of advanced melanomas

    Directory of Open Access Journals (Sweden)

    Bhattacharya Chitralekha

    2012-11-01

    segregation defects, telomere shortening, and massive melanoma cell apoptosis. These findings suggest that DDX11 could be an important candidate for molecular targeted therapy for advanced melanoma.

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

    International Nuclear Information System (INIS)

    Ungerer, Christopher; Doberstein, Kai; Buerger, Claudia; Hardt, Katja; Boehncke, Wolf-Henning; Boehm, Beate; Pfeilschifter, Josef; Dummer, Reinhard; Mihic-Probst, Daniela; Gutwein, Paul

    2010-01-01

    Research highlights: → Strong ADAM15 expression is found in normal melanocytes. → ADAM15 expression is significantly downregulated in patients with melanoma metastasis. → TGF-β can downregulate ADAM15 expression in melanoma cells. → Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. → 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-γ and TGF-β 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Ungerer, Christopher; Doberstein, Kai [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany); Buerger, Claudia; Hardt, Katja; Boehncke, Wolf-Henning [Department of Dermatology, Clinic of the Goethe-University, Theodor-Stern-Kai, Frankfurt (Germany); Boehm, Beate [Division of Rheumatology, Goethe University, Frankfurt am Main (Germany); Pfeilschifter, Josef [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany); Dummer, Reinhard [Department of Pathology, Institute of Surgical Pathology, University Hospital, Zurich (Switzerland); Mihic-Probst, Daniela [Department of Dermatology, University Hospital Zurich (Switzerland); Gutwein, Paul, E-mail: p.gutwein@med.uni-frankfurt.de [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany)

    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.

  20. Pediatric Melanoma and Drug Development

    Directory of Open Access Journals (Sweden)

    Klaus Rose

    2018-03-01

    Full Text Available Importance—Pediatric melanoma occurs, albeit rarely. Should patients be treated by today’s medical standards, or be subjected to medically unnecessary clinical studies? Observations—We identified international, industry-sponsored pediatric melanoma studies triggered by regulatory demands in www.clinicaltrials.gov and further pediatric melanoma studies demanded by European Union pediatric investigation plans. We retrieved related regulatory documents from the internet. We analyzed these studies for rationale and medical beneficence on the basis of physiology, pediatric clinical pharmacology and rationale. Regulatory authorities define children by chronological age, not physiologically. Newborns’ organs are immature but they develop and mature rapidly. Separate proof of efficacy in underage patients is justified formally/regulatorily but lacks medical sense. Children—especially post-puberty—and adults vis-a-vis medications are physiologically very similar. Two adolescent melanoma studies were terminated in 2016 because of waning recruitment, while five studies in pediatric melanoma and other solid tumors, triggered by European Union pediatric investigation plans, continue recruiting worldwide. Conclusions and Relevance—Regulatory-demanded pediatric melanoma studies are medically superfluous. Melanoma patients of all ages should be treated with effective combination treatment. Babies need special attention. Children need dose-finding and pharmacokinetic studies but adolescents metabolize and respond to drugs similarly to adults. Institutional Review Boards/ethics committees should suspend ongoing questionable pediatric melanoma studies and reject newly submitted questionable studies.

  1. Histopathological findings concerning ocular melanomas.

    Science.gov (United States)

    Costache, Mariana; Pătraşcu, Oana Maria; Dumitru, Adrian; Costache, Diana; Voinea, Liliana Mary; Simionescu, Olga; Sajin, Maria

    2014-01-01

    Ocular melanoma is rare in clinical practice. In this study, we present three cases of ocular melanoma surgically removed in the Department of Ophthalmology of the Emergency University Hospital of Bucharest, Romania, and diagnosed in the Department of Pathology of the same hospital using conventional histopathological techniques and immunohistochemical tests.

  2. Angiogenic profile of uveal melanoma.

    NARCIS (Netherlands)

    Notting, I.C.; Missotten, G.S.; Sijmons, B.; Boonman, Z.F.; Keunen, J.E.E.; Pluijm, G. van der

    2006-01-01

    Uveal melanoma develops in one of the most capillary-rich tissues of the body and is disseminated hematogenously. Knowledge of the nature and the spatiotemporal expression of angiogenic factors in uveal melanoma is essential to the development of new treatment strategies, especially with regard to

  3. Ultraviolet exposure of melanoma cells induces fibroblast activation protein-α in fibroblasts: Implications for melanoma invasion.

    Science.gov (United States)

    Wäster, Petra; Rosdahl, Inger; Gilmore, Brendan F; Seifert, Oliver

    2011-07-01

    Fibroblast activation protein-α (FAP-α) promotes tumor growth and cell invasiveness through extracellular matrix degradation. How ultraviolet radiation (UVR), the major risk factor for malignant melanoma, influences the expression of FAP-α is unknown. We examined the effect of UVR on FAP-α expression in melanocytes, keratinocytes and fibroblasts from the skin and in melanoma cells. UVR induces upregulation of FAP-α in fibroblasts, melanocytes and primary melanoma cells (PM) whereas keratinocytes and metastatic melanoma cells remained FAP-α negative. UVA and UVB stimulated FAP-α-driven migration and invasion in fibroblasts, melanocytes and PM. In co-culture systems UVR of melanocytes, PM and cells from regional metastases upregulated FAP-α in fibroblasts but only supernatants from non-irradiated PM were able to induce FAP-α in fibroblasts. Further, UV-radiated melanocytes and PM significantly increased FAP-α expression in fibroblasts through secretory crosstalk via Wnt5a, PDGF-BB and TGF-β1. Moreover, UV radiated melanocytes and PM increased collagen I invasion and migration of fibroblasts. The FAP-α/DPPIV inhibitor Gly-ProP(OPh)2 significantly decreased this response implicating FAP-α/DPPIV as an important protein complex in cell migration and invasion. These experiments suggest a functional association between UVR and FAP-α expression in fibroblasts, melanocytes and melanoma cells implicating that UVR of malignant melanoma converts fibroblasts into FAP-α expressing and ECM degrading fibroblasts thus facilitating invasion and migration. The secretory crosstalk between melanoma and tumor surrounding fibroblasts is mediated via PDGF-BB, TGF-β1 and Wnt5a and these factors should be evaluated as targets to reduce FAP-α activity and prevent early melanoma dissemination.

  4. Preclinical study of selective thermal neutron capture treatment of pigs having spontaneous melanoma using melanin productive activity

    International Nuclear Information System (INIS)

    Miyashita, Ichiro; Sawaya, Hiroshi; Nomura, Toyoichiro

    1980-01-01

    Four pigs having spontaneous melanoma were irradiated with 0.5 - 2 x 10 13 n/cm 2 of thermal neutron under remote anesthesia. Compounds of 10 B used in this experiment were 10 B 12 -chlorpromazine ( 10 B 12 -CPZ), 10 B-dopa, and 10 B 1 -para-boronophenylalanine ( 10 B 1 -BPA), and they were injected into melanoma or regions around melanoma. After irradiation of thermal neutron, melanoma tended to reduce in four pigs, and melanoma cells in white fur and hair bulb disappeared in 3 of 4 pigs. Hematological examinations and blood chemistry tests did not show any changes in blood findings both before and after the irradiation, and white blood cell counts were within a normal range. Dermatitis following the irradiation disappeared one week later. Histological changes one month after the irradiation indicated that many melanophages feeding melanosome replaced melanoma cells, which suggested disintegration of melanoma cells. Marked effectiveness of this treatment was recognized in each pig. 10 B-BPA.HCI was injected into one pig twice, and its accumulation in melanoma and normal regions around melanoma was expressed as boron concentrations. As a result, the accumulation in melanoma (6.6 μg/g wet tissue) was 3.1 times as much as that in normal regions around melanoma (2.1 μg/g wet tissue). (Tsunoda, M.)

  5. Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid.

    Science.gov (United States)

    Passeron, Thierry; Valencia, Julio C; Namiki, Takeshi; Vieira, Wilfred D; Passeron, Hélène; Miyamura, Yoshinori; Hearing, Vincent J

    2009-04-01

    Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.

  6. Clinical characteristics and management of melanoma families

    NARCIS (Netherlands)

    Rhee, Jasper Immanuel van der

    2013-01-01

    Being a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first part of the thesis clinical and histological characteristics of melanoma (patients) from families with

  7. Utility of chest X-ray and abdominal ultrasound for stage III cutaneous malignant melanoma

    DEFF Research Database (Denmark)

    Breitenbauch, M. T. W.; Holm, J.; Rødgaard, J. C.

    2015-01-01

    Background: Current Danish Melanoma Guidelines suggest that stage III cutaneous malignant melanoma receive chest X-ray and abdominal ultrasound to exclude lung and liver metastases. The aim of this study was to examine the sensitivity, specificity, and negative predictive value of chest X-ray and...

  8. Iodine-125 radiation of posterior uveal melanoma

    International Nuclear Information System (INIS)

    Packer, S.

    1987-01-01

    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

  9. Iodine-125 radiation of posterior uveal melanoma

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. Comparative Aspects of Canine Melanoma

    Directory of Open Access Journals (Sweden)

    Adriana Tomoko Nishiya

    2016-02-01

    Full Text Available Melanomas are malignant neoplasms originating from melanocytes. They occur in most animal species, but the dog is considered the best animal model for the disease. Melanomas in dogs are most frequently found in the buccal cavity, but the skin, eyes, and digits are other common locations for these neoplasms. The aim of this review is to report etiological, epidemiological, pathological, and molecular aspects of melanomas in dogs. Furthermore, the particular biological behaviors of these tumors in the different body locations are shown. Insights into the therapeutic approaches are described. Surgery, chemotherapy, radiotherapy, immunotherapy, and the outcomes after these treatments are presented. New therapeutic perspectives are also depicted. All efforts are geared toward better characterization and control of malignant melanomas in dogs, for the benefit of these companion animals, and also in an attempt to benefit the treatment of human melanomas.

  11. Impact of MAPK Pathway Activation in BRAFV600 Melanoma on T Cell and Dendritic Cell Function

    Directory of Open Access Journals (Sweden)

    Patrick A. Ott

    2013-10-01

    Full Text Available Constitutive upregulation of the MAPK pathway by a BRAFV600 mutation occurs in about half of melanomas. This leads to increased oncogenic properties such as tumor cell invasion, metastatic potential, and resistance to apoptosis. Blockade of the MAPK pathway with highly specific kinase inhibitors induces unprecedented tumor response rates in patients with advanced BRAFV600 mutant melanoma. Immune checkpoint blockade with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 and programed death-1/PD-L1 has also demonstrated striking anti-tumor activity in patients with advanced melanoma. Tumor responses are likely limited by multiple additional layers of immune suppression in the tumor microenvironment. There is emerging preclinical and clinical evidence suggesting that MAPK inhibition has a beneficial effect on the immunosuppressive tumor microenvironment, providing a strong rationale for combined immunotherapy and MAPK pathway inhibition in melanoma. The T cell response has been the main focus in the studies reported to date. Since dendritic cells (DCs are important in the induction of tumor-specific T cell responses, the impact of MAPK pathway activation in melanoma on DC function is critical for the melanoma directed immune response. BRAFV600E melanoma cells modulate DCs through the MAPK pathway because its blockade in melanoma cells can reverse suppression of DC function. As both MEK/BRAF inhibition and immune checkpoint blockade have recently taken center stage in the treatment of melanoma, a deeper understanding of how MAPK pathway inhibition affects the tumor immune response is needed.

  12. Effects of Wnt-10b on proliferation and differentiation of murine melanoma cells

    International Nuclear Information System (INIS)

    Misu, Masayasu; Ouji, Yukiteru; Kawai, Norikazu; Nishimura, Fumihiko; Nakamura-Uchiyama, Fukumi; Yoshikawa, Masahide

    2015-01-01

    In spite of the strong expression of Wnt-10b in melanomas, its role in melanoma cells has not been elucidated. In the present study, the biological effects of Wnt-10b on murine B16F10 (B16) melanoma cells were investigated using conditioned medium from Wnt-10b-producing COS cells (Wnt-CM). After 2 days of culture in the presence of Wnt-CM, proliferation of B16 melanoma cells was inhibited, whereas tyrosinase activity was increased. An in vitro wound healing assay demonstrated that migration of melanoma cells to the wound area was inhibited with the addition of Wnt-CM. Furthermore, evaluation of cellular senescence revealed prominent induction of SA-β-gal-positive senescent cells in cultures with Wnt-CM. Finally, the growth of B16 melanoma cell aggregates in collagen 3D-gel cultures was markedly suppressed in the presence of Wnt-CM. These results suggest that Wnt-10b represses tumor cell properties, such as proliferation and migration of B16 melanoma cells, driving them toward a more differentiated state along a melanocyte lineage. - Highlights: • Wnt-10b inhibited proliferation and migration of melanoma cells. • Wnt-10b induced tyrosinase activity and senescence of melanoma cells. • Wnt-10b suppressed growth of cell aggregates in collagen 3D-gel cultures. • Wnt-10b represses tumor cell properties, driving them toward a more differentiated state along a melanocyte lineage

  13. Effects of Wnt-10b on proliferation and differentiation of murine melanoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Misu, Masayasu [Department of Pathogen, Infection and Immunity, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ouji, Yukiteru, E-mail: oujix@naramed-u.ac.jp [Department of Pathogen, Infection and Immunity, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Kawai, Norikazu [Department of Pathogen, Infection and Immunity, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Nishimura, Fumihiko [Department of Neurosurgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Nakamura-Uchiyama, Fukumi [Department of Pathogen, Infection and Immunity, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Yoshikawa, Masahide, E-mail: myoshika@naramed-u.ac.jp [Department of Pathogen, Infection and Immunity, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan)

    2015-08-07

    In spite of the strong expression of Wnt-10b in melanomas, its role in melanoma cells has not been elucidated. In the present study, the biological effects of Wnt-10b on murine B16F10 (B16) melanoma cells were investigated using conditioned medium from Wnt-10b-producing COS cells (Wnt-CM). After 2 days of culture in the presence of Wnt-CM, proliferation of B16 melanoma cells was inhibited, whereas tyrosinase activity was increased. An in vitro wound healing assay demonstrated that migration of melanoma cells to the wound area was inhibited with the addition of Wnt-CM. Furthermore, evaluation of cellular senescence revealed prominent induction of SA-β-gal-positive senescent cells in cultures with Wnt-CM. Finally, the growth of B16 melanoma cell aggregates in collagen 3D-gel cultures was markedly suppressed in the presence of Wnt-CM. These results suggest that Wnt-10b represses tumor cell properties, such as proliferation and migration of B16 melanoma cells, driving them toward a more differentiated state along a melanocyte lineage. - Highlights: • Wnt-10b inhibited proliferation and migration of melanoma cells. • Wnt-10b induced tyrosinase activity and senescence of melanoma cells. • Wnt-10b suppressed growth of cell aggregates in collagen 3D-gel cultures. • Wnt-10b represses tumor cell properties, driving them toward a more differentiated state along a melanocyte lineage.

  14. Intracranial Tumor Cell Migration and the Development of Multiple Brain Metastases in Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Trude G. Simonsen

    2016-06-01

    Full Text Available INTRODUCTION: A majority of patients with melanoma brain metastases develop multiple lesions, and these patients show particularly poor prognosis. To develop improved treatment strategies, detailed insights into the biology of melanoma brain metastases, and particularly the development of multiple lesions, are needed. The purpose of this preclinical investigation was to study melanoma cell migration within the brain after cell injection into a well-defined intracerebral site. METHODS: A-07, D-12, R-18, and U-25 human melanoma cells transfected with green fluorescent protein were injected stereotactically into the right cerebral hemisphere of nude mice. Moribund mice were killed and autopsied, and the brain was evaluated by fluorescence imaging or histological examination. RESULTS: Intracerebral inoculation of melanoma cells produced multiple lesions involving all regions of the brain, suggesting that the cells were able to migrate over substantial distances within the brain. Multiple modes of transport were identified, and all transport modes were observed in all four melanoma lines. Thus, the melanoma cells were passively transported via the flow of cerebrospinal fluid in the meninges and ventricles, they migrated actively along leptomeningeal and brain parenchymal blood vessels, and they migrated actively along the surfaces separating different brain compartments. CONCLUSION: Migration of melanoma cells after initial arrest, extravasation, and growth at a single location within the brain may contribute significantly to the development of multiple melanoma brain metastases.

  15. Role of epithelial-mesenchymal transition involved molecules in the progression of cutaneous melanoma.

    Science.gov (United States)

    Murtas, Daniela; Maxia, Cristina; Diana, Andrea; Pilloni, Luca; Corda, Claudia; Minerba, Luigi; Tomei, Sara; Piras, Franca; Ferreli, Caterina; Perra, Maria Teresa

    2017-12-01

    Epithelial-mesenchymal transition (EMT) has been suggested to have a driving role in the acquisition of a metastatic potential by melanoma cells. Important hallmarks of EMT include both E-cadherin downregulation and increased expression of N-cadherin. This switch in distinct classes of adhesion molecules leads melanoma cells to lose contact with adjacent keratinocytes and interact instead with stromal fibroblasts and endothelial cells, thus promoting dermal and vascular melanoma invasion. Consequently, tumor cells migrate to distant host tissues and establish metastases. A key regulator in the induction of EMT in melanoma is the Notch1 signaling pathway that, when activated, is prompt to upregulate N-cadherin expression. By means of this strategy, melanoma cells gain enhanced survival, proliferation and invasion properties, driving the tumor toward a more aggressive phenotype. On the basis of these statements, the present study aimed to investigate the possible association between N-cadherin and Notch1 presence in primary cutaneous melanomas and lymph node metastases. Our results from immunohistochemical analysis confirmed a positive correlation between N-cadherin and Notch1 presence in the same tumor samples. Moreover, this study highlighted that a concomitant high expression of N-cadherin and Notch1, both in primary lesions and in lymph node metastases, predicts an adverse clinical outcome in melanoma patients. Therefore, N-cadherin and Notch1 co-presence can be monitored as a predictive factor in early- and advanced-stage melanomas and open additional therapeutic targets for the restraint of melanoma metastasis.

  16. Pentoxifylline Inhibits WNT Signalling in β-Cateninhigh Patient-Derived Melanoma Cell Populations.

    Directory of Open Access Journals (Sweden)

    Beata Talar

    Full Text Available The heterogeneity of melanoma needs to be addressed and combination therapies seem to be necessary to overcome intrinsic and acquired resistance to newly developed immunotherapies and targeted therapies. Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized. Using patient-derived melanoma cell populations, we investigated the influence of pentoxifylline on melanoma cells with either high or low expression of β-catenin.Our results indicate that pentoxifylline inhibits the activity of the canonical WNT pathway in melanoma cell populations with high basal activity of this signalling. This is supported by lowered overall activity of transcription factors TCF/LEF and reduced nuclear localisation of active β-catenin. Moreover, treatment of β-cateninhigh melanoma cell populations with pentoxifylline induces downregulation of genes that are targets of the WNT/β-catenin pathway including connective tissue growth factor (CTGF and microphthalmia-associated transcription factor (MITF-M, a melanocyte- and melanoma cell-specific regulator.These results suggest that pentoxifylline, a drug approved by the FDA in the treatment of peripheral arterial disease, might be tested in a subset of melanoma patients with elevated activity of β-catenin. This pharmaceutical might be tested as an adjuvant drug in combination therapies when the response to immunotherapy is prevented by high activity of the WNT/β-catenin pathway.

  17. Association between dermoscopic and reflectance confocal microscopy features of cutaneous melanoma with BRAF mutational status.

    Science.gov (United States)

    Bombonato, C; Ribero, S; Pozzobon, F C; Puig-Butille, J A; Badenas, C; Carrera, C; Malvehy, J; Moscarella, E; Lallas, A; Piana, S; Puig, S; Argenziano, G; Longo, C

    2017-04-01

    Melanomas harbouring common genetic mutations might share certain morphological features detectable with dermoscopy and reflectance confocal microscopy. BRAF mutational status is crucial for the management of metastatic melanoma. To correlate the dermoscopic characteristics of primary cutaneous melanomas with BRAF mutational status. Furthermore, a subset of tumours has also been analysed for the presence of possible confocal features that might be linked with BRAF status. Retrospectively acquired dermoscopic and confocal images of patients with melanoma in tertiary referral academic centres: Skin Cancer Unit in Reggio Emilia and at the Melanoma Unit in Barcelona. Kruskal-Wallis test, logistic regressions, univariate and multivariate analyses have been performed to find dermoscopic and confocal features significantly correlated with BRAF mutational status. Dermoscopically, the presence of irregular peripheral streaks and ulceration were positive predictors of BRAF-mutated melanomas with a statistically significance value, while dotted vessels were more represented in wild-type melanomas. None of the evaluated reflectance confocal microscopy features were correlated with genetic profiling. Ulceration and irregular peripheral streaks represent dermoscopic feature indicative for BRAF-mutated melanoma, while dotted vessels are suggestive for wild-type melanoma. © 2016 European Academy of Dermatology and Venereology.

  18. Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer.

    Science.gov (United States)

    McEwan, Conor; Nesbitt, Heather; Nicholas, Dean; Kavanagh, Oisin N; McKenna, Kevin; Loan, Philip; Jack, Iain G; McHale, Anthony P; Callan, John F

    2016-07-01

    Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions. Copyright © 2016. Published by Elsevier Ltd.

  19. Positron emission tomography scanning in malignant melanoma.

    Science.gov (United States)

    Tyler, D S; Onaitis, M; Kherani, A; Hata, A; Nicholson, E; Keogan, M; Fisher, S; Coleman, E; Seigler, H F

    2000-09-01

    metastatic disease. These findings led to a change in the planned clinical management in patients after 16 of the 106 PET scans (15.1%). FDG PET scanning can be helpful in managing patients with Stage III melanoma in whom further surgery is contemplated. Although false-positive areas are not uncommon, PET scans did change the management of patients 15% of the time. PET's inability to identify microscopic disease suggests that it is of limited use in evaluating patients with Stage I-II disease.

  20. Interactive Tailored Website to Promote Sun Protection and Skin Self-Check Behaviors in Patients With Stage 0-III Melanoma

    Science.gov (United States)

    2017-11-15

    Stage 0 Skin Melanoma; Stage I Skin Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage II Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma

  1. Histological Types of Polypoid Cutaneous Melanoma II

    OpenAIRE

    Knežević, Fabijan; Duančić, Vjekoslav; Šitić, Sanda; Horvat-Knežević, Anica; Benković, Vesna; Ramić, Snježana; Kostović, Krešimir; Ramljak, Vesna; Velemir Vrdoljak, Danko; Stanec, Mladen; Božović, Angelina

    2007-01-01

    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 a...

  2. Brachytherapy of choroidal melanomas

    International Nuclear Information System (INIS)

    Brady, L.W.; Hernandez, J.C.

    1992-01-01

    In a compilation of nine reported series consisting of 2,024 enucleations, the five- and ten-year survivals following surgery were 63% and 43%, respectively. The 25-year survival has been reported to be 40%. In 1974 at Wills Eye Hospital and Hahnemann University, the cobalt-60 plaques technique was introduced. During the following years, other radioactive isotopes were introduced including irridium-192, iodine-125, ruthenium-106/rhodium-106 and more recently palladium-103. At the present time, iodine-125 is the most widely used radionuclide. Until now, 302 patients treated with plaque brachytherapy showed an actuarial survival of 77% and 67.8% at five and eight years, respectively. There was no significant survival difference when compared with a similar group of patients undergoing enucleation. Other retrospective studies show similar excellent results. In spite of these convincing results, the decision making process in management melanoma remains unsettled primarily due to the absence of prospective randomized trials. Because of this, the Collaborative Ocular Melanoma Study was initiated. From the standpoint of toxicity, the data are available on ocular radiation toxicity. In an analysis of 77 patients from the Wills Eye Hospital with pretreatment visual acuities of 20/25 or better, it was noted that 90% of patients who had received less than 500 Gy to the fovea retained visual acuity of 20/200 or better while only 52% of patients receiving more than 5,000 Gy to the fovea had vision of 20/200 or better. A serious late effect of radioactivity plaque treatment is scleral necrosis which may require repair or enucleation even in the absence of tumor progression. Enucleation may be necessary in approximately 10% of patients. We conclude that malignant melanoma of the uvea can be safely treated with radioactive plaques. (orig./MG) [de

  3. Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    2016-10-01

    Full Text Available Cutaneous melanoma is an aggressive tumor with its incidence increasing faster than any other cancer in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies.Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ER and ERβ that exert opposite effects on cancer growth: ER is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant estrogen receptor in melanoma and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation. However, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention

  4. Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

    Science.gov (United States)

    Marzagalli, Monica; Montagnani Marelli, Marina; Casati, Lavinia; Fontana, Fabrizio; Moretti, Roberta Manuela; Limonta, Patrizia

    2016-01-01

    Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to

  5. Preventing Melanoma PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    2015-06-02

    This 60 second public service announcement is based on the June 2015 CDC Vital Signs report. Skin cancer is the most common form of cancer in the U.S. In 2011, there were more than 65,000 cases of melanoma, the most deadly form of skin cancer. Learn how everyone can help prevent skin cancer.  Created: 6/2/2015 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 6/2/2015.

  6. Treatment of cutaneous melanoma: current approaches and future prospects

    Directory of Open Access Journals (Sweden)

    Alain P Algazi

    2010-08-01

    Full Text Available Alain P Algazi1, Christopher W Soon2, Adil I Daud11Department of Medicine, Division of Hematology and Oncology, 2Department of Dermatology, University of California, San Francisco San Francisco, CA, USAAbstract: Melanoma is the most aggressive and deadly type of skin cancer. Surgical resection with or without lymph node sampling is the standard of care for primary cutaneous melanoma. Adjuvant therapy decisions may be informed by careful consideration of prognostic factors. High-dose adjuvant interferon alpha-2b increases disease-free survival and may modestly improve overall survival. Less toxic alternatives for adjuvant therapy are currently under study. External beam radiation therapy is an option for nodal beds where the risk of local recurrence is very high. In-transit melanoma metastases may be treated locally with surgery, immunotherapy, radiation, or heated limb perfusion. For metastatic melanoma, the options include chemotherapy or immunotherapy; targeted anti-BRAF and anti-KIT therapy is under active investigation. Standard chemotherapy yields objective tumor responses in approximately 10%–20% of patients, and sustained remissions are uncommon. Immunotherapy with high-dose interleukin-2 yields objective tumor responses in a minority of patients; however, some of these responses may be durable. Identification of activating mutations of BRAF, NRAS, c-KIT, and GNAQ in distinct clinical subtypes of melanoma suggest that these are molecularly distinct. Emerging data from clinical trials suggest that substantial improvements in the standard of care for melanoma may be possible.Keywords: melanoma, resection, immune modulation, small molecule kinase inhibitors, chemotherapy, clinical trials

  7. Dermoscopy of melanoma and non-melanoma skin cancer.

    Science.gov (United States)

    Babino, G; Lallas, A; Longo, C; Moscarella, E; Alfano, R; Argenziano, G

    2015-10-01

    Skin cancer is a major health problem because of its high incidence in white populations, as well as its related potential morbidity and mortality. Dermoscopy is a noninvasive tool that allows the identification of specific morphological features in different skin tumors, improving significantly the early diagnosis of melanoma and non-melanoma skin cancer (NMSC). This tool has also gained increased interest in the management of NMSC therapy and in the post-treatment follow-up. In this article, we provide a review of the dermoscopic patterns and criteria for the diagnosis of melanoma and NMSC described until now in the literature.

  8. Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma.

    Science.gov (United States)

    Yang, H; Kircher, D A; Kim, K H; Grossmann, A H; VanBrocklin, M W; Holmen, S L; Robinson, J P

    2017-07-06

    The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAF V600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes causing complete tumor regression, the majority of melanomas eventually become resistant. Mitogen-activated protein kinase kinase (MEK) mutations are found in primary melanomas and frequently reported in BRAF melanomas that develop resistance to targeted therapy; however, melanoma is a molecularly heterogeneous cancer, and which mutations are drivers and which are passengers remains to be determined. In this study, we demonstrate that in BRAF V600E melanoma cell lines, activating MEK mutations drive resistance and contribute to suboptimal growth of melanoma cells following the withdrawal of BRAF inhibition. In this manner, the cells are drug-addicted, suggesting that melanoma cells evolve a 'just right' level of mitogen-activated protein kinase signaling and the additive effects of MEK and BRAF mutations are counterproductive. We also used a novel mouse model of melanoma to demonstrate that several of these MEK mutants promote the development, growth and maintenance of melanoma in vivo in the context of Cdkn2a and Pten loss. By utilizing a genetic approach to control mutant MEK expression in vivo, we were able to induce tumor regression and significantly increase survival; however, after a long latency, all tumors subsequently became resistant. These data suggest that resistance to BRAF or MEK inhibitors is probably inevitable, and novel therapeutic approaches are needed to target dormant tumors.

  9. Melanoma detection using a mobile phone app

    Science.gov (United States)

    Diniz, Luciano E.; Ennser, K.

    2016-03-01

    Mobile phones have had their processing power greatly increased since their invention a few decades ago. As a direct result of Moore's Law, this improvement has made available several applications that were impossible before. The aim of this project is to develop a mobile phone app, integrated with its camera coupled to an amplifying lens, to help distinguish melanoma. The proposed device has the capability of processing skin mole images and suggesting, using a score system, if it is a case of melanoma or not. This score system is based on the ABCDE signs of melanoma, and takes into account the area, the perimeter and the colors present in the nevus. It was calibrated and tested using images from the PH2 Dermoscopic Image Database from Pedro Hispano Hospital. The results show that the system created can be useful, with an accuracy of up to 100% for malign cases and 80% for benign cases (including common and atypical moles), when used in the test group.

  10. Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression.

    Science.gov (United States)

    Mustafi, Sushmita; Sant, David W; Liu, Zhao-Jun; Wang, Gaofeng

    2017-06-16

    Pharmacological levels of ascorbate have long been suggested as a potential treatment of cancer. However, we observed that EC50 of ascorbate was at a similar level for cultured healthy melanocytes and melanoma cells, suggesting a limit of pharmacological ascorbate in treating cancer. Loss of 5-hydroxymethylcytosine (5 hmC) is an epigenetic hallmark of cancer and ascorbate promotes 5 hmC generation by serving as a cofactor for TET methylcytosine dioxygenases. Our previous work demonstrated that ascorbate treatment at physiological level (100 μM) increased 5 hmC content in melanoma cells toward the level of healthy melanocytes. Here we show that 100 µM of ascorbate induced apoptosis in A2058 melanoma cells. RNA-seq analysis revealed that expression of the Clusterin (CLU) gene, which is related to apoptosis, was downregulated by ascorbate. The suppression of CLU was verified at transcript level in different melanoma cell lines, and at protein level in A2058 cells. The anti-apoptotic cytoplasmic CLU was decreased, while the pro-apoptotic nuclear CLU was largely maintained, after ascorbate treatment. These changes in CLU subcellular localization were also associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, this study establishes an impending therapeutic role of physiological ascorbate to potentiate apoptosis in melanoma.

  11. Melanoma Surveillance in the US: The Economic Burden of Melanoma

    Centers for Disease Control (CDC) Podcasts

    2011-10-19

    This podcast accompanies the publication of a series of articles on melanoma surveillance in the United States, available in the November supplement edition of the Journal of the American Academy of Dermatology. Dr. Gery Guy, from the CDC’s Division of Cancer Prevention and Control, discusses the economic burden of melanoma.  Created: 10/19/2011 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 10/19/2011.

  12. miR-193b Regulates Mcl-1 in Melanoma.

    Science.gov (United States)

    Chen, Jiamin; Zhang, Xiao; Lentz, Cindy; Abi-Daoud, Marie; Paré, Geneviève C; Yang, Xiaolong; Feilotter, Harriet E; Tron, Victor A

    2011-11-01

    MicroRNAs play important roles in gene regulation, and their expression is frequently dysregulated in cancer cells. In a previous study, we reported that miR-193b represses cell proliferation and regulates cyclin D1 in melanoma cells, suggesting that miR-193b could act as a tumor suppressor. Herein, we demonstrate that miR-193b also down-regulates myeloid cell leukemia sequence 1 (Mcl-1) in melanoma cells. MicroRNA microarray profiling revealed that miR-193b is expressed at a significantly lower level in malignant melanoma than in benign nevi. Consistent with this, Mcl-1 is detected at a higher level in malignant melanoma than in benign nevi. In a survey of melanoma samples, the level of Mcl-1 is inversely correlated with the level of miR-193b. Overexpression of miR-193b in melanoma cells represses Mcl-1 expression. Previous studies showed that Mcl-1 knockdown cells are hypersensitive to ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w. Similarly, overexpression of miR-193b restores ABT-737 sensitivity to ABT-737-resistant cells. Furthermore, the effect of miR-193b on the expression of Mcl-1 seems to be mediated by direct interaction between miR-193b and seed and seedless pairing sequences in the 3' untranslated region of Mcl-1 mRNA. Thus, this study provides evidence that miR-193b directly regulates Mcl-1 and that down-regulation of miR-193b in vivo could be an early event in melanoma progression. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  13. Superficial melanomas of oral mucous membranes.

    Science.gov (United States)

    Regezi, J A; Hayward, J R; Pickens, T N

    1978-05-01

    In accordance with microscopic and clinical criteria established for superficial melanomas of the skin (superficial spreading melanoma, lentigo maligna melanoma, acral-lentiginous melanoma), three oral lesions have been evaluated. The literature on oral melanomas has also been reviewed, with special attention given to those cases that had pre-existing melanosis. One patient with a diagnosis of superficial spreading melanoma eventually died of his untreated lesion 11 years after its first appearance. Two patients had lesions diagnosed as acral-lentiginous melanoma (a group which also includes volar and subungual melanomas) that exhibited aggressive, recurrent behavior. These lesions had microsocpic features similar to lentigo maligna melanoma but did not behave in a manner consistent with that diagnosis. Electron microscopic study of one acral-lentiginous melanoma demonstrated malenosomes and premelanosomes that were like those seen in normal melanocytes and nevus cells. The superficial or radial growth phase of many oral melanomas has apparently gone unrecognized. Melanosis has been reported to be a common feature of invasive oral melanomas but has not generally been related to the natural history of these lesions. Oral lesions with a prolonged intra-epithelial or radial growth phase would be expected to have a better prognosis than nodular melanomas, but meaningful survival data are not available because of the infrequency with which oral melanomas have been subclassified.

  14. Melanoma of the skin in the Danish Cancer Registry and the Danish Melanoma Database

    DEFF Research Database (Denmark)

    Pedersen, Sidsel Arnspang; Schmidt, Sigrun Alba Johannesdottir; Klausen, Siri

    2018-01-01

    BACKGROUND: The nationwide Danish Cancer Registry and the Danish Melanoma Database both record data on melanoma for purposes of monitoring, quality assurance and research. However, the data quality of the Cancer Registry and the Melanoma Database has not been formally evaluated. METHODS: We...... estimated the positive predictive value (PPV) of melanoma diagnosis for random samples of 200 patients from the Cancer Registry (n=200) and the Melanoma Database (n=200) during 2004-2014, using the Danish Pathology Registry as 'gold-standard' reference. We further validated tumor characteristics...... in the Cancer Registry and the Melanoma Database. Additionally, we estimated the PPV of in situ melanoma diagnoses in the Melanoma Database, and the sensitivity of melanoma diagnoses in 2004-2014. RESULTS: The PPVs of melanoma in the Cancer Registry and the Melanoma Database were 97% (95% CI, 94-99) and 100...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    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...

  16. Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival

    Directory of Open Access Journals (Sweden)

    Slipicevic Ana

    2012-02-01

    Full Text Available Abstract Background/aims Breast cancer metastasis suppressor 1 (BRMS1 blocks metastasis in melanoma xenografts; however, its usefulness as a biomarker in human melanomas has not been widely studied. The goal was to measure BRMS1 expression in benign nevi, primary and metastatic melanomas and evaluate its impact on disease progression and prognosis. Methods Paraffin-embedded tissue from 155 primary melanomas, 69 metastases and 15 nevi was examined for BRMS1 expression using immunohistochemistry. siRNA mediated BRMS1 down-regulation was used to study impact on invasion and migration in melanoma cell lines. Results A significantly higher percentage of nevi (87%, compared to primary melanomas (20% and metastases (48%, expressed BRMS1 in the nucelus (p Waf1/Cip1 (p = 0.009. Cytoplasmic score index was inversely associated with nuclear p-Akt (p = 0.013 and positively associated with cytoplasmic p-ERK1/2 expression (p = 0.033. Nuclear BRMS1 expression in ≥ 10% of primary melanoma cells was associated with thicker tumors (p = 0.016 and decreased relapse-free period (p = 0.043. Nuclear BRMS1 was associated with expression of fatty acid binding protein 7 (FABP7; p = 0.011, a marker of invasion in melanomas. In line with this, repression of BRMS1 expression reduced the ability of melanoma cells to migrate and invade in vitro. Conclusion Our data suggest that BRMS1 is localized in cytoplasm and nucleus of melanocytic cells and that cellular localization determines its in vivo effect. We hypothesize that cytoplasmic BRMS1 restricts melanoma progression while nuclear BRMS1 possibly promotes melanoma cell invasion. Please see related article: http://www.biomedcentral.com/1741-7015/10/19

  17. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Directory of Open Access Journals (Sweden)

    Amy E Gilbert

    Full Text Available Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10 to primary and metastatic melanoma cells compared to healthy volunteers (n = 10 (P<0.0001. Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21 (P<0.0001. Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800 compared to 2% of cultures from healthy controls (n = 600 produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  18. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Science.gov (United States)

    Gilbert, Amy E; Karagiannis, Panagiotis; Dodev, Tihomir; Koers, Alexander; Lacy, Katie; Josephs, Debra H; Takhar, Pooja; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Acland, Katharine M; Rudman, Sarah M; Beavil, Rebecca L; Blower, Philip J; Beavil, Andrew J; Gould, Hannah J; Spicer, James; Nestle, Frank O; Karagiannis, Sophia N

    2011-04-29

    Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  19. Epigenetic regulation of the transcription factor Foxa2 directs differential elafin expression in melanocytes and melanoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Kyung Sook [Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806 (Korea, Republic of); Jo, Ji Yoon; Kim, Su Jin [Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Lee, Yangsoon [Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806 (Korea, Republic of); Bae, Jong Hwan [NeoPharm Co. Ltd., Daejeon 305-510 (Korea, Republic of); Chung, Young-Hwa [Department of Cogno-Mechatronics Engineering, BK21 Nanofusion Technology Team, Pusan National University, Busan 609-736 (Korea, Republic of); Koh, Sang Seok, E-mail: sskoh@kribb.re.kr [Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of)

    2011-04-29

    Highlights: {yields} Elafin expression is epigenetically silenced in human melanoma cells. {yields} Foxa2 expression in melanoma cells is silenced by promoter hypermethylation. {yields} Foxa2 directs activation of the elafin promoter in vivo. {yields} Foxa2 expression induces apoptosis of melanoma cells via elafin re-expression. -- Abstract: Elafin, a serine protease inhibitor, induces the intrinsic apoptotic pathway in human melanoma cells, where its expression is transcriptionally silenced. However, it remains unknown how the elafin gene is repressed in melanoma cells. We here demonstrate that elafin expression is modulated via epigenetically regulated expression of the transcription factor Foxa2. Treatment of melanoma cells with a DNA methyltransferase inhibitor induced elafin expression, which was specifically responsible for reduced proliferation and increased apoptosis. Suppression of Foxa2 transcription, mediated by DNA hypermethylation in its promoter region, was released in melanoma cells upon treatment with the demethylating agent. Luciferase reporter assays indicated that the Foxa2 binding site in the elafin promoter was critical for the activation of the promoter. Chromatin immunoprecipitation assays further showed that Foxa2 bound to the elafin promoter in vivo. Analyses of melanoma cells with varied levels of Foxa2 revealed a correlated expression between Foxa2 and elafin and the ability of Foxa2 to induce apoptosis. Our results collectively suggest that, in melanoma cells, Foxa2 expression is silenced and therefore elafin is maintained unexpressed to facilitate cell proliferation in the disease melanoma.

  20. Podoplanin Expression in Canine Melanoma.

    Science.gov (United States)

    Ogasawara, Satoshi; Honma, Ryusuke; Kaneko, Mika K; Fujii, Yuki; Kagawa, Yumiko; Konnai, Satoru; Kato, Yukinari

    2016-12-01

    A type I transmembrane protein, podoplanin (PDPN), is expressed in several normal cells such as lymphatic endothelial cells or pulmonary type I alveolar cells. We recently demonstrated that anticanine PDPN monoclonal antibody (mAb), PMab-38, recognizes canine PDPN of squamous cell carcinomas, but does not react with lymphatic endothelial cells. Herein, we investigated whether PMab-38 reacts with canine melanoma. PMab-38 reacted with 90% of melanoma cells (9/10 cases) using immunohistochemistry. Of interest, PMab-38 stained the lymphatic endothelial cells and cancer-associated fibroblasts in melanoma tissues, although it did not stain any lymphatic endothelial cells in normal tissues. PMab-38 could be useful for uncovering the function of PDPN in canine melanomas.

  1. Podoplanin Expression in Canine Melanoma

    OpenAIRE

    Ogasawara, Satoshi; Honma, Ryusuke; Kaneko, Mika K.; Fujii, Yuki; Kagawa, Yumiko; Konnai, Satoru; Kato, Yukinari

    2016-01-01

    A type I transmembrane protein, podoplanin (PDPN), is expressed in several normal cells such as lymphatic endothelial cells or pulmonary type I alveolar cells. We recently demonstrated that anticanine PDPN monoclonal antibody (mAb), PMab-38, recognizes canine PDPN of squamous cell carcinomas, but does not react with lymphatic endothelial cells. Herein, we investigated whether PMab-38 reacts with canine melanoma. PMab-38 reacted with 90% of melanoma cells (9/10 cases) using immunohistochemistr...

  2. Case studies of skin melanoma

    Directory of Open Access Journals (Sweden)

    A. V. Kozlova

    2015-01-01

    Full Text Available Skin melanoma is a malignant tumor originating in the cells of the melanocytic system, which is characterized by an aggressive clinical course, significant metastatic potential and unfavorable prognosis. These features of the tumor stipulate the need to improve measures to optimize early diagnosis of tumors. The article presents cases of pigmented skin melanoma to demonstrate the variability of clinical manifestations of this tumor requiring dermatologist skills in the differential diagnostics of neoplasms.

  3. [Choroidal melanoma - evolution and prognosis].

    Science.gov (United States)

    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.

  4. Umbilicus reconstruction after melanoma excision

    Directory of Open Access Journals (Sweden)

    Miguel Costa-Silva

    2017-01-01

    Full Text Available An 81-year-old woman was admitted with a nodular cutaneous melanoma of the abdominal wall involving the umbilicus. After performing wide excision with 2 cm margin of the melanoma, umbilical reconstruction and defect closure were planned. After careful consideration, we decided to use an island pedicle flap which allowed closure of the defect and reconstruction of the umbilicus.

  5. Routine X-ray of the chest is not justified in staging of cutaneous melanoma patients

    DEFF Research Database (Denmark)

    Gjorup, Caroline Asirvatham; Hendel, Helle Westergren; Pilegaard, Rita Kaae

    2016-01-01

    INTRODUCTION: The incidence of cutaneous melanoma is increasing in Denmark and worldwide. However, the prevalence of distant metastases at the time of diagnosis has decreased to 1%. We therefore questioned the value of routine preoperative chest X-ray (CXR) for staging asymptomatic melanoma...... patients and hypothesised that routine CXR is not justified. METHODS: A retrospective study was conducted on patients undergoing wide local excision and sentinel lymph node biopsy for cutaneous melanoma in the period from 2010 to 2014. RESULTS: A total of 603 patients were included. The mean time of follow...... value was 8%, and the negative predictive value was 100%. CONCLUSION: Our results suggest that CXR cannot be justified in the initial staging of cutaneous melanoma patients. The guideline for the treatment of melanoma in Denmark is under revision: The use of CXR has been omitted. FUNDING: This study...

  6. Combined endovascular and surgical treatment of melanoma of the nasal cavity: a case report; Melanoma de fosas nasales. Tratamiento combinado endovascular y quirurgico. A proposito de un caso

    Energy Technology Data Exchange (ETDEWEB)

    Romero, A.; Delgado, F.; Ramos, M.; Bravo, F. [Hospital Universitario Reina Sofia. Cordoba (Spain)

    2000-07-01

    Melanoma of the nasal cavity is a rare tumor with a worse prognosis than cutaneous melanoma. It usually presents as nasal obstruction and/or epistaxis. The observation of a pigmented mass in the nasal cavity is highly suggestive of this lesion. Computed tomography shows a mass with nonspecific features. In magnetic resonance studies, it has a characteristics signal consisting of hyperintensity of T1-weighted images and hypointensity on T2-weighted images, depending on the amount of melanin. The treatment of choice is surgical resection. We present a case of melanoma of the nasal cavity in which endovascular embolization of the tumor was performed prior to surgical treatment. (Author) 11 refs.

  7. Chromosome 7 Aneusomy. A Marker for Metastatic Melanoma?

    Directory of Open Access Journals (Sweden)

    Martin Udart

    2001-01-01

    Full Text Available Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR play an important role in a variety of malignant neoplasias, making the search for aberrations in the relevant chromosomes an important issue. Differential expression of the EGFR gene was investigated by reverse transcriptase (RT-PCR on tissue samples of normal skin, nevi, primary melanomas, and melanoma metastases. The EGFR gene is located on chromosome 7p12.3-p12.1. To determine the number of chromosomes 7 in cell nuclei of the mentioned tissue samples we performed fluorescence in situ hybridization (FISH on touch preparations, using a DNA probe that hybridizes specifically to the centromeric region of chromosome 7. Additionally, chromosome 7 number in interphase nuclei was determined in short-term primary cell cultures of nevi, primary melanomas, and metastases. The highest EGFR gene expression frequency was found in melanoma metastases. By FISH we detected the highest fraction of cell nuclei with more than two chromosomes 7 in the group of metastases. Our results suggest that overexpression of the EGFR gene might play an important role in metastasis of malignant melanoma. This is well reflected by polysomy 7, possibly accounting for an increased EGFRgene copy number.

  8. Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression.

    Science.gov (United States)

    Fiziev, Petko; Akdemir, Kadir C; Miller, John P; Keung, Emily Z; Samant, Neha S; Sharma, Sneha; Natale, Christopher A; Terranova, Christopher J; Maitituoheti, Mayinuer; Amin, Samirkumar B; Martinez-Ledesma, Emmanuel; Dhamdhere, Mayura; Axelrad, Jacob B; Shah, Amiksha; Cheng, Christine S; Mahadeshwar, Harshad; Seth, Sahil; Barton, Michelle C; Protopopov, Alexei; Tsai, Kenneth Y; Davies, Michael A; Garcia, Benjamin A; Amit, Ido; Chin, Lynda; Ernst, Jason; Rai, Kunal

    2017-04-25

    The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. SHP2 phosphatase as a novel therapeutic target for melanoma treatment.

    Science.gov (United States)

    Zhang, Ruo-Yu; Yu, Zhi-Hong; Zeng, Lifan; Zhang, Sheng; Bai, Yunpeng; Miao, Jinmin; Chen, Lan; Xie, Jingwu; Zhang, Zhong-Yin

    2016-11-08

    Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.

  10. Long Noncoding RNA HOTAIR Is Associated with Motility, Invasion, and Metastatic Potential of Metastatic Melanoma

    Directory of Open Access Journals (Sweden)

    Lihua Tang

    2013-01-01

    Full Text Available Metastatic melanoma, the primary cause of skin cancer-related death, warrants new therapeutic approaches that target the regulatory machinery at molecular level. While long noncoding RNAs (lncRNAs are dysregulated in a number of cancer types, limited data are available on the expression and function of lncRNAs in melanoma metastasis. The primary objective of this study was to investigate the role of 6 metastasis-related lncRNAs in pairs of primary melanoma and matched lymph node metastatic tissues. Among the tested lncRNAs, HOTAIR was the most highly expressed in lymph node metastasis. The role of HOTAIR in melanoma cell motility and invasion was further evaluated by knocking down HOTAIR with siRNAs. Knockdown of HOTAIR resulted in the reduction of motility and invasion of human melanoma cell line A375, as assessed by wound healing assay and Matrigel-based invasion assay. siHOTAIR also suppressed the degradation of gelatin matrix, suggesting that HOTAIR promotes gelatinase activity. Together, our study shows that HOTAIR is overexpressed in metastatic tissue, which is associated with the ability of HOTAIR to promote melanoma cell motility and invasion. These data indicate that lncRNAs may be involved in the metastasis of melanoma and provide support for further evaluation of lncRNAs in melanoma.

  11. Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

    International Nuclear Information System (INIS)

    Androlewicz, M.J.; Straus, D.S.; Brandenburg, D.F.

    1989-01-01

    Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe 125 I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37 degree C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation

  12. AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress.

    Science.gov (United States)

    Kfoury, Alain; Armaro, Marzia; Collodet, Caterina; Sordet-Dessimoz, Jessica; Giner, Maria Pilar; Christen, Stefan; Moco, Sofia; Leleu, Marion; de Leval, Laurence; Koch, Ute; Trumpp, Andreas; Sakamoto, Kei; Beermann, Friedrich; Radtke, Freddy

    2018-03-01

    Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the Nras Q61K INK4a -/- mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance, and metastasis. c-Myc-expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c-Myc-positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc-expressing melanoma cells, while AMPK activation protected against cell death of c-Myc-depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early-stage human melanoma samples revealed an inverse correlation between C-MYC and patient survival, suggesting that C-MYC expression levels could serve as a prognostic marker for early-stage disease. © 2018 The Authors.

  13. A series of melanomas smaller than 4 mm and implications for the ABCDE rule.

    Science.gov (United States)

    Goldsmith, S M; Solomon, A R

    2007-08-01

    Although multiple studies have reported that a significant number of melanomas have diameters of less than or equal to 6 mm at the time of diagnosis, there has been only one series evaluating the proportion of melanomas less than 4 mm in diameter. The objective of this study was to determine the proportion of melanomas, in a single-practitioner, general dermatology practice, with clinical diameters less than 4 mm. Information regarding each new diagnosis of melanoma had been recorded during the study period of 2000-2004. Patient records and pathology reports were examined from these patients. Thirteen (13.7%) of the 95 melanomas had diameters less than 4 mm at the time of presentation, including five invasive and eight in situ melanomas. The defining clinical characteristic of these lesions was intensity of pigment. Three of these 13 melanomas, including one invasive and two in situ lesions, showed features of regression. The findings of this study support those authors who have suggested elimination of the 6-mm diameter criterion in the ABCDE rule. In addition, this study provides further evidence that dark colour as a diagnostic criterion for melanoma should be given more emphasis. The substitution of 'D' to represent dark instead of diameter is worthy of consideration to enhance the value of the ABCDE mnemonic.

  14. Expression of IL-27 by tumor cells in invasive cutaneous and metastatic melanomas [corrected]..

    Directory of Open Access Journals (Sweden)

    Julie Gonin

    Full Text Available Interleukin (IL-27 is a cytokine of the IL-12 family that displays either immunostimulatory or immunosuppressive functions depending on the context. In various murine tumor models including melanoma models, ectopic expression of IL-27 has been shown to play an anti-tumoral role and to favor tumor regression. In this study, we investigated whether IL-27 might play a role in the development of melanoma in humans. We analyzed the in situ expression of IL-27 in melanocytic lesions (n = 82 representative of different stages of tumor progression. IL-27 expression was not observed in nevus (n = 8 nor in in situ melanoma (n = 9, but was detected in 28/46 (61% cases of invasive cutaneous melanoma, notably in advanced stages (19/23 cases of stages 3 and 4. In most cases, the main source of IL-27 was tumor cells. Of note, when IL-27 was detected in primary cutaneous melanomas, its expression was maintained in metastatic lesions. These in situ data suggested that the immunosuppressive functions of IL-27 may dominate in human melanoma. Consistent with this hypothesis, we found that IL-27 could induce suppressive molecules such as PD-L1, and to a lesser extent IL-10, in melanoma cells, and that the in situ expression of IL-27 in melanoma correlated with those of PD-L1 and IL-10.

  15. CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity.

    Directory of Open Access Journals (Sweden)

    Molly H Jenkins

    Full Text Available Patients with early stage, radial growth phase (RGP melanoma have a 97% survival rate; however, when the melanoma progresses to the invasive vertical growth phase (VGP, survival rates decrease to 15%. The targets of many clinical trials are the known genetic and molecular mechanisms involved in melanoma progression, with the most common oncogenic mutation being the BRAFV600E. However, less than half of melanomas harbor this mutation, and consequently, do not respond to the current BRAF targeted treatments. It is therefore critical to elucidate alternative mechanisms regulating melanoma progression. Increased expression of the chemokine receptor, CXCR3, on melanoma cells is correlated with increased metastasis and poor patient outcomes, suggesting a role for CXCR3 in the RGP to VGP transition. We found that endogenous CXCR3 can be induced in two RGP cell lines, BOWES (BRAFWT and WM35 (BRAFV600E, with in vitro environmental stress and nutrient deprivation. Signaling via induced endogenous CXCR3 is linked with IL-8 expression in BOWES cells. Ectopic overexpression of CXCR3 in BOWES cells leads to increased ligand-mediated phERK, cellular migration, and IL-8 expression in vitro, and to increased tumorigenesis and lymph node metastasis in vivo. Our results demonstrate that, in BRAFWT melanomas, CXCR3 signaling mediates significant increases in IL-8 expression, suggesting that CXCR3 expression and signaling may represent a transformative event that drives the progression of BRAFWT melanomas.Expression of CXCR3 on BRAFWT melanoma cells may be a mediator of melanoma progression.

  16. Chondrosarcomatous Differentiation in a Large Malignant Melanoma of the Scalp

    Directory of Open Access Journals (Sweden)

    Colin S. Alderson

    2016-01-01

    Full Text Available Background. Divergent differentiation in malignant melanoma is a rare phenomenon, which can lead to delayed diagnosis or misdiagnosis, impacting upon patient treatment and outcome, as well as the understanding of tumour behaviour. Case. We present the case of a large long-standing tumour on the scalp of a 72-year-old female patient, which when excised and examined histologically was revealed to be a nodular malignant melanoma displaying chondrosarcomatous differentiation. Foci suggestive of lentigo maligna were also present. Rapid metastatic spread of the tumour was observed shortly after the primary resection. Discussion. To our knowledge, this is the first reported case in the literature of chondrosarcomatous differentiation in a lentigo maligna melanoma. The clinical and histopathological details and images of this case are presented alongside a discussion regarding such tumours and patterns of similar tumour behaviour.

  17. Melanoma screening: Informing public health policy with quantitative modelling.

    Directory of Open Access Journals (Sweden)

    Stephen Gilmore

    1982 has resulted in greater diagnostic incidence and reduced mortality, but the reduced mortality carried a significant cost per life saved. I implement the model out to 2028 and demonstrate that the enhanced secondary prevention that began in 1982 becomes increasingly cost-effective over the period 2013-2028. On the other hand, I show that reductions in mortality achieved by significantly enhancing secondary prevention beyond 2013 levels are comparable with those achieved by only modest improvements in late-stage disease survival. Given the ballooning costs of increased melanoma surveillance, I suggest the process of public health policy decision-making-particularly with respect to the public funding of melanoma screening and discretionary mole removal-would be better served by incorporating the results of quantitative modelling.

  18. Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression.

    Science.gov (United States)

    da Silva, Wanessa Cardoso; Oshiro, Telma Miyuki; de Sá, Daniel Coelho; Franco, Dilcilea D G S; Festa Neto, Cyro; Pontillo, Alessandra

    2016-10-01

    Sporadic melanoma malignancy is correlated with constitutive secretion of IL-1β in transformed melanocytes suggesting the involvement of inflammasome in melanoma. Common variants in inflammasome genes are known to affect IL-1β expression. To investigate the contribution of inflammasome genetics in melanoma development and progression and to identify a potential prognostic marker, the distribution of selected inflammasome SNPs was analysed in a Brazilian case/control cohort of sporadic malignant melanoma (SMM) and then the expression of inflammasome components was evaluated in melanoma biopsies. Allele and gene-specific Taqman assays were implied for genotyping of case/control DNA samples and for relative expression analysis in skin biopsies respectively. CARD8 rs6509365 was found to be significantly more common in healthy volunteers than in SMM patients suggesting a protection effect of this variant towards melanoma development. Accordingly, CARD8 expression was found to be reduced in nevus compared to melanoma biopsies. Upon stratification, NLRP1 rs11651270 and CARD8 rs2043211 were found associated with nodular melanoma; IL1B rs1143643 to a lower value of Breslow index; IL18 rs5744256 to melanoma development in sun sensitive individuals. As expected, IL1B expression was up-regulated in tumour biopsies especially in metastatic samples, whereas IL18 was down-regulated compared to nevus. Our results demonstrated for the first time the contribution of inflammasome genes CARD8, IL1B and IL18 in SMM. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Ubiquitination in melanoma pathogenesis and treatment.

    Science.gov (United States)

    Ma, Jinyuan; Guo, Weinan; Li, Chunying

    2017-06-01

    Melanoma is one of the most aggressive skin cancers with fiercely increasing incidence and mortality. Since the progressive understanding of the mutational landscape and immunologic pathogenic factors in melanoma, the targeted therapy and immunotherapy have been recently established and gained unprecedented improvements for melanoma treatment. However, the prognosis of melanoma patients remains unoptimistic mainly due to the resistance and nonresponse to current available drugs. Ubiquitination is a posttranslational modification which plays crucial roles in diverse cellular biological activities and participates in the pathogenesis of various cancers, including melanoma. Through the regulation of multiple tumor promoters and suppressors, ubiquitination is emerging as the key contributor and therefore a potential therapeutic target for melanoma. Herein, we summarize the current understanding of ubiquitination in melanoma, from mechanistic insights to clinical progress, and discuss the prospect of ubiquitination modification in melanoma treatment. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  20. The role of nitric oxide in melanoma.

    Science.gov (United States)

    Yarlagadda, Keerthi; Hassani, John; Foote, Isaac P; Markowitz, Joseph

    2017-12-01

    Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Tool to Distinguish Moles from Melanoma

    Science.gov (United States)

    “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.

  2. Coffee, tea and melanoma risk : findings from the European Prospective Investigation into Cancer and Nutrition

    NARCIS (Netherlands)

    Caini, Saverio; Masala, Giovanna; Saieva, Calogero; Kvaskoff, Marina; Savoye, Isabelle; Sacerdote, Carlotta; Hemmingsson, Oskar; Hammer Bech, Bodil; Overvad, Kim; Tjønneland, Anne; Petersen, Kristina E N; Mancini, Francesca Romana; Boutron-Ruault, Marie Christine; Cervenka, Iris; Kaaks, Rudolf; Kühn, Tilman; Boeing, Heiner; Floegel, Anna; Trichopoulou, Antonia; Valanou, Elisavet; Kritikou, Maria; Tagliabue, Giovanna; Panico, Salvatore; Tumino, Rosario; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.; Veierød, Marit B.; Ghiasvand, Reza; Lukic, Marko; Quirós, José Ramón; Chirlaque, Maria Dolores; Ardanaz, Eva; Salamanca Fernández, Elena; Larrañaga, Nerea; Zamora-Ros, Raul; Maria Nilsson, Lena; Ljuslinder, Ingrid; Jirström, Karin; Sonestedt, Emily; Key, Timothy J.; Wareham, Nick; Khaw, Kay Tee; Gunter, Marc; Huybrechts, Inge; Murphy, Neil; Tsilidis, Konstantinos K.; Weiderpass, Elisabete; Palli, Domenico

    2017-01-01

    In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption

  3. Large melanoma metastases to the gastrointestinal tract.

    OpenAIRE

    Silverman, J M; Hamlin, J A

    1989-01-01

    It is well known that malignant melanoma can metastasize widely. Although these metastases in the gastrointestinal tract usually appear as small 'bull's-eye' or 'target' lesions, there are a few reports of relatively large melanoma metastases. We report five cases of large melanoma lesions metastatic to the alimentary canal. We also emphasise the consideration of a thorough gastrointestinal tract evaluation in patients with malignant melanoma especially if they are symptomatic.

  4. Unusual presentations of melanoma: melanoma of unknown primary site, melanoma arising in childhood, and melanoma arising in the eye and on mucosal surfaces.

    Science.gov (United States)

    Sondak, Vernon K; Messina, Jane L

    2014-10-01

    Most melanomas present as primary tumors on the skin surface in adults; however, melanomas also arise in the eye and on the mucosal surfaces or present as apparently metastatic disease without any known history of a cutaneous primary. Melanoma is also being diagnosed during childhood more frequently than ever. Surgeons need to be aware of and understand these unusual presentations of melanoma to optimally manage their patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Hypnosis, suggestion, and suggestibility: an integrative model.

    Science.gov (United States)

    Lynn, Steven Jay; Laurence, Jean-Roch; Kirsch, Irving

    2015-01-01

    This article elucidates an integrative model of hypnosis that integrates social, cultural, cognitive, and neurophysiological variables at play both in and out of hypnosis and considers their dynamic interaction as determinants of the multifaceted experience of hypnosis. The roles of these variables are examined in the induction and suggestion stages of hypnosis, including how they are related to the experience of involuntariness, one of the hallmarks of hypnosis. It is suggested that studies of the modification of hypnotic suggestibility; cognitive flexibility; response sets and expectancies; the default-mode network; and the search for the neurophysiological correlates of hypnosis, more broadly, in conjunction with research on social psychological variables, hold much promise to further understanding of hypnosis.

  6. Clinicopathological and molecular aspects of cutaneous Melanoma

    NARCIS (Netherlands)

    Bogenrieder, T.

    2009-01-01

    Clinicopathological and molecular aspects of cutaneous melanoma. Melanoma arises form the transformation of neural crest-derived melanocytes, the pigment cells of the skin, which reside in the basal layer of the epidermis. Melanoma is the deadliest form of skin cancer and one of the most aggressive

  7. Genetic prognostic factors in uveal melanoma

    NARCIS (Netherlands)

    Maat, Willem

    2012-01-01

    Uveal melanoma (UM) is the most common malignancy of the eye in adults and it is the second most common form of melanoma after cutaneous melanoma (CM). The identification of patients who have a high risk of developing metastases would allow the possibility of providing adjuvant therapies to prevent

  8. Melanoma continues to rise throughout the world

    African Journals Online (AJOL)

    Review Article: Melanoma continues to rise throughout the world. 530 ... of melanoma. The radiation in the ultraviolet B range is said to be the critical component. Generally, worldwide, the incidence of melanoma in white people4,5 correlates inversely with .... lymphocytes, mitotic rate, regression, angiolymphatic invasion ...

  9. Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma.

    Directory of Open Access Journals (Sweden)

    Yuchun Luo

    Full Text Available Developing analytical methodologies to identify biomarkers in easily accessible body fluids is highly valuable for the early diagnosis and management of cancer patients. Peripheral whole blood is a "nucleic acid-rich" and "inflammatory cell-rich" information reservoir and represents systemic processes altered by the presence of cancer cells.We conducted transcriptome profiling of whole blood cells from melanoma patients. To overcome challenges associated with blood-based transcriptome analysis, we used a PAXgene™ tube and NuGEN Ovation™ globin reduction system. The combined use of these systems in microarray resulted in the identification of 78 unique genes differentially expressed in the blood of melanoma patients. Of these, 68 genes were further analyzed by quantitative reverse transcriptase PCR using blood samples from 45 newly diagnosed melanoma patients (stage I to IV and 50 healthy control individuals. Thirty-nine genes were verified to be differentially expressed in blood samples from melanoma patients. A stepwise logit analysis selected eighteen 2-gene signatures that distinguish melanoma from healthy controls. Of these, a 2-gene signature consisting of PLEK2 and C1QB led to the best result that correctly classified 93.3% melanoma patients and 90% healthy controls. Both genes were upregulated in blood samples of melanoma patients from all stages. Further analysis using blood fractionation showed that CD45(- and CD45(+ populations were responsible for the altered expression levels of PLEK2 and C1QB, respectively.The current study provides the first analysis of whole blood-based transcriptome biomarkers for malignant melanoma. The expression of PLEK2, the strongest gene to classify melanoma patients, in CD45(- subsets illustrates the importance of analyzing whole blood cells for biomarker studies. The study suggests that transcriptome profiling of blood cells could be used for both early detection of melanoma and monitoring of patients

  10. Personal History of Prostate Cancer and Increased Risk of Incident Melanoma in the United States

    Science.gov (United States)

    Li, Wen-Qing; Qureshi, Abrar A.; Ma, Jing; Goldstein, Alisa M.; Giovannucci, Edward L.; Stampfer, Meir J.; Han, Jiali

    2013-01-01

    Purpose Steroid hormones, particularly androgens, play a major role in prostatic carcinogenesis. Personal history of severe acne, a surrogate for higher androgen activity, has been associated with an increased risk of prostate cancer (PCa), and one recent study indicated that severe teenage acne was a novel risk factor for melanoma. These findings suggest a possible relationship between PCa and risk of melanoma. We prospectively evaluated this association among US men. Methods A total of 42,372 participants in the Health Professionals' Follow-Up Study (HPFS; 1986 to 2010) were included. Biennially self-reported PCa diagnosis was confirmed using pathology reports. Diagnosis of melanoma and nonmelanoma skin cancer (NMSC) was self-reported biennially, and diagnosis of melanoma was pathologically confirmed. We sought to confirm the association in 18,603 participants from the Physicians' Health Study (PHS; 1982 to 1998). Results We identified 539 melanomas in the HPFS. Personal history of PCa was associated with an increased risk of melanoma (multivariate-adjusted hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54). Although we also detected a marginally increased risk of NMSC associated with PCa (HR, 1.08; 95% CI, 0.995 to 1.16), the difference in the magnitude of the association between melanoma and NMSC was significant (P for heterogeneity = .002). We did not find an altered risk of melanoma associated with personal history of other cancers. The association between PCa and risk of incident melanoma was confirmed in the PHS (HR, 2.17; 95% CI, 1.12 to 4.21). Conclusion Personal history of PCa is associated with an increased risk of melanoma, which may not be entirely a result of greater medical scrutiny. PMID:24190118

  11. Differential PAX3 functions in normal skin melanocytes and melanoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Medic, Sandra [School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, WA (Australia); Rizos, Helen [Westmead Institute for Cancer Research and Melanoma Institute of Australia, University of Sydney at Westmead Millennium Institute, Westmead, NSW (Australia); Ziman, Mel, E-mail: m.ziman@ecu.edu.au [School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, WA (Australia); School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA (Australia)

    2011-08-12

    Highlights: {yields} PAX3 retains embryonic roles in adult melanocytes and melanoma cells. {yields} Promotes 'stem' cell-like phenotype via NES and SOX9 in both cells types. {yields} Regulates melanoma and melanocyte migration through MCAM and CSPG4. {yields} PAX3 regulates melanoma but not melanocyte proliferation via TPD52. {yields} Regulates melanoma cell (but not melanocyte) survival via BCL2L1 and PTEN. -- Abstract: The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as 'stem' cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated 'stem' cell like phenotype, PAX3 may contribute to melanoma development and progression.

  12. Decreased expression of hyaluronan synthase 1 and 2 associates with poor prognosis in cutaneous melanoma.

    Science.gov (United States)

    Poukka, Mari; Bykachev, Andrey; Siiskonen, Hanna; Tyynelä-Korhonen, Kristiina; Auvinen, Päivi; Pasonen-Seppänen, Sanna; Sironen, Reijo

    2016-05-16

    Hyaluronan is a large extracellular matrix molecule involved in several biological processes such as proliferation, migration and invasion. In many cancers, hyaluronan synthesis is altered, which implicates disease progression and metastatic potential. We have previously shown that synthesis of hyaluronan and expression of its synthases 1-2 (HAS1-2) decrease in cutaneous melanoma, compared to benign melanocytic lesions. In the present study, we compared immunohistological staining results of HAS1 and HAS2 with clinical and histopathological parameters to investigate whether HAS1 or HAS2 has prognostic value in cutaneous melanoma. The specimens consisted of 129 tissue samples including superficial (Breslow ≤ 1 mm) and deep (Breslow > 4 mm) melanomas and lymph node metastases. The differences in immunostainings were analysed with non-parametric Mann-Whitney U test. Associations between immunohistological staining results and clinical parameters were determined with the χ(2) test. Survival between patient groups was compared by the Kaplan-Meier method using log rank test and Cox's regression model was used for multivariate analyses. The expression of HAS1 and HAS2 was decreased in deep melanomas and metastases compared to superficial melanomas. Decreased immunostaining of HAS2 in melanoma cells was significantly associated with several known unfavourable histopathologic prognostic markers like increased mitotic count, absence of tumor infiltrating lymphocytes and the nodular subtype. Furthermore, reduced HAS1 and HAS2 immunostaining in the melanoma cells was associated with increased recurrence of melanoma (p = 0.041 and p = 0.006, respectively) and shortened disease- specific survival (p = 0.013 and p = 0.001, respectively). This study indicates that reduced expression of HAS1 and HAS2 is associated with melanoma progression and suggests that HAS1 and HAS2 have a prognostic significance in cutaneous melanoma.

  13. Emerging targeted therapies for melanoma.

    Science.gov (United States)

    Johnson, Douglas B; Pollack, Megan H; Sosman, Jeffrey A

    2016-06-01

    Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development. This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials. Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.

  14. Current systemic therapies for melanoma.

    Science.gov (United States)

    Palathinkal, Darren M; Sharma, Timmie R; Koon, Henry B; Bordeaux, Jeremy S

    2014-09-01

    Systemic agents are used in melanoma for adjuvant therapy and to treat metastatic disease. Currently, interferon-α is the only agent approved for adjuvant therapy. Six drugs are FDA approved for metastatic disease: dacarbazine, interleukin-2 (IL-2), vemurafenib, ipilimumab, dabrafenib, and trametinib. Vemurafenib and ipilimumab were approved in 2011, whereas dabrafenib and trametinib were approved in 2013. This review will update the practicing dermatologist on the differences in efficacy, adverse events, and cost of systemic therapies available for the treatment of melanoma. This article is a review of the current literature on systemic therapies for advanced melanoma. Key search words included "advanced melanoma," "systemic therapy," and "adjuvant therapy" with particular focus on the past 20 years. Before 2011, dacarbazine and IL-2 were the only FDA approved therapies for metastatic melanoma, and IFN-α is the only approved agent for adjuvant therapy. The new agents vemurafenib, ipilimumab, dabrafenib, and trametinib are the first to have improved overall survival in Phase III studies in comparison with other systemic therapies. Despite new developments, there remains a significant need for better therapies with improved long-term efficacy and decreased toxicity.

  15. Other targeted drugs in melanoma.

    Science.gov (United States)

    González-Cao, María; Rodón, Jordi; Karachaliou, Niki; Sánchez, Jesús; Santarpia, Mariacarmela; Viteri, Santiago; Pilotto, Sara; Teixidó, Cristina; Riso, Aldo; Rosell, Rafael

    2015-10-01

    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.

  16. Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

    International Nuclear Information System (INIS)

    Jandl, Thomas; Revskaya, Ekaterina; Jiang, Zewei; Harris, Matthew; Dorokhova, Olena; Tsukrov, Dina; Casadevall, Arturo; Dadachova, Ekaterina

    2013-01-01

    Introduction: In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium( 188 Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy. Methods: Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi 188 Re-6D2 antibody, saline, unlabeled 6D2 antibody or 188 Re-labeled non-specific IgM. Results: On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells. Conclusions: These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers

  17. Prognostic Value of Melanoma Inhibitory Activity Protein in Localized Cutaneous Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Angela Sandru

    2014-01-01

    Full Text Available Background. Cutaneous malignant melanoma (CMM is a heterogeneous disease, acknowledged for its lack of predictability regarding clinical evolution. In order to appreciate a patient’s individual prognosis, an attempt is made to find new tumor markers that parallel the disease progression. Objective. To identify if melanoma inhibitory activity (MIA protein could represent a tool for selecting high risk early stages melanoma patients. Method. Between 2008 and 2013, 155 patients with CMM were treated in our clinic. 84 of them were classified into stages I and II, according to TNM 2009. MIA serum concentration was measured in all patients and 50 healthy donors. A cut-off value of 9.4 ng/ml was established using the ROC curve. Results. All patients were followed up by periodic investigations every 6 months. We have noticed that 66% of patients with MIA serum values at diagnosis greater than 9.4 ng/mL have relapsed, while only 5% of patients with MIA serum concentration below the estimated threshold, recurred during the follow-up period (P=0.000. The death risk was 12 times higher in pathological MIA group of patients (P=0.0001. Conclusions. Our data suggest that MIA is an independent prognostic factor for patients with localized CMM.

  18. Prognostic value of melanoma inhibitory activity protein in localized cutaneous malignant melanoma.

    Science.gov (United States)

    Sandru, Angela; Panaitescu, Eugenia; Voinea, Silviu; Bolovan, Madalina; Stanciu, Adina; Cinca, Sabin; Blidaru, Alexandru

    2014-01-01

    Background. Cutaneous malignant melanoma (CMM) is a heterogeneous disease, acknowledged for its lack of predictability regarding clinical evolution. In order to appreciate a patient's individual prognosis, an attempt is made to find new tumor markers that parallel the disease progression. Objective. To identify if melanoma inhibitory activity (MIA) protein could represent a tool for selecting high risk early stages melanoma patients. Method. Between 2008 and 2013, 155 patients with CMM were treated in our clinic. 84 of them were classified into stages I and II, according to TNM 2009. MIA serum concentration was measured in all patients and 50 healthy donors. A cut-off value of 9.4 ng/ml was established using the ROC curve. Results. All patients were followed up by periodic investigations every 6 months. We have noticed that 66% of patients with MIA serum values at diagnosis greater than 9.4 ng/mL have relapsed, while only 5% of patients with MIA serum concentration below the estimated threshold, recurred during the follow-up period (P = 0.000). The death risk was 12 times higher in pathological MIA group of patients (P = 0.0001). Conclusions. Our data suggest that MIA is an independent prognostic factor for patients with localized CMM.

  19. Systematic review of psychosocial outcomes for patients with advanced melanoma.

    Science.gov (United States)

    Dunn, Jeff; Watson, Maggie; Aitken, Joanne F; Hyde, Melissa K

    2017-11-01

    New advanced melanoma therapies are associated with improved survival; however, quality of survivorship, particularly psychosocial outcomes, for patients overall and those treated with newer therapies is unclear. Synthesize qualitative and quantitative evidence about psychosocial outcomes for advanced (stage III/IV) melanoma patients. Five databases were searched (01/01/1980 to 31/01/2016). Inclusion criteria were as follows: advanced melanoma patients or sub-group analysis; assessed psychosocial outcomes; and English language. Fifty-two studies met review criteria (4 qualitative, 48 quantitative). Trials comprise mostly medical not psychosocial interventions, with psychosocial outcomes assessed within broader quality of life measures. Patients receiving chemotherapy or IFN-alpha showed decreased emotional and social function and increased distress. Five trials of newer therapies appeared to show improvements in emotional and social function. Descriptive studies suggest that patients with advanced, versus localized disease, had decreased emotional and social function and increased distress. Contributors to distress were largely unexplored, and no clear framework described coping/adjustment trajectories. Patients with advanced versus localized disease had more supportive care needs, particularly amount, quality, and timing of melanoma-related information, communication with and emotional support from clinicians. Limitations included: lack of theoretical underpinnings guiding study design; inconsistent measurement approaches; small sample sizes; non-representative sampling; and cross-sectional design. Quality trial evidence is needed to clarify the impact of treatment innovations for advanced melanoma on patients' psychosocial well-being. Survivorship research and subsequent translation of that knowledge into programs and services currently lags behind gains in the medical treatment of advanced melanoma, a troubling circumstance that requires immediate and focused

  20. FDG PET in early stage cutaneous malignant melanoma

    International Nuclear Information System (INIS)

    McIvor, Jody; Siew, Teck; McCarthy, Michael

    2014-01-01

    Fluorodeoxyglucose positron emission tomography (FDG PET) is not recommended in early stage melanoma; however, a significant number of cases are referred to our institution for FDG PET. We refer to early stage disease as American Joint Committee on Cancer (AJCC) stage I and II, which includes all cases without metastases. A retrospective review was undertaken to determine the clinical utility of FDG PET in this patient group. A retrospective study of FDG scans on all patients presenting to the WA PET Centre with early stage melanoma over a 5½ year period was undertaken. The positivity rate of the initial study for detection of malignant melanoma was determined. In patients with an initially negative FDG PET, the time from initial diagnosis to a positive surveillance study was determined. Both the initial positivity rate and time to a positive study were correlated with Breslow staging. Three hundred twenty-two patients were included in the study, of which 74 had initial positive FDG PET scans (23%). Adequate follow-up was available in 51 patients with the PET result confirmed as true positive in 37 (positive predictive value 73%). One hundred eight of 248 patients initially negative had follow-up scans during the follow-up period, of which 48 became positive. The 73% of recurrences were over 12 months post-diagnosis. No correlation with Breslow thickness was demonstrated. Despite FDG PET not being recommended for early cutaneous malignant melanoma, 27% of melanoma cases referred for FDG PET during the study period were AJCC stage I or II. Our results suggest FDG PET in early stage melanoma demonstrates occult disease in 17% of cases.

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

    Science.gov (United States)

    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.

  2. ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment.

    Science.gov (United States)

    Pérez-Alea, M; McGrail, K; Sánchez-Redondo, S; Ferrer, B; Fournet, G; Cortés, J; Muñoz, E; Hernandez-Losa, J; Tenbaum, S; Martin, G; Costello, R; Ceylan, I; Garcia-Patos, V; Recio, J A

    2017-10-12

    Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.

  3. Alpha-catulin contributes to drug-resistance of melanoma by activating NF-κB and AP-1.

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    Birgit Kreiseder

    Full Text Available Melanoma is the most dangerous type of skin cancer accounting for 48,000 deaths worldwide each year and an average survival rate of about 6-10 months with conventional treatment. Tumor metastasis and chemoresistance of melanoma cells are reported as the main reasons for the insufficiency of currently available treatments for late stage melanoma. The cytoskeletal linker protein α-catulin (CTNNAL1 has been shown to be important in inflammation, apoptosis and cytoskeletal reorganization. Recently, we found an elevated expression of α-catulin in melanoma cells. Ectopic expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. In the current study we showed that α-catulin knockdown reduced NF-κB and AP-1 activity in malignant melanoma cells. Further, downregulation of α-catulin diminished ERK phosphorylation in malignant melanoma cells and sensitized them to treatment with chemotherapeutic drugs. In particular, cisplatin treatment led to decreased ERK-, JNK- and c-Jun phosphorylation in α-catulin knockdown melanoma cells, which was accompanied by enhanced apoptosis compared to control cells. Altogether, these results suggest that targeted inhibition of α-catulin may be used as a viable therapeutic strategy to chemosensitize melanoma cells to cisplatin by down-regulation of NF-κB and MAPK pathways.

  4. Clear cells in acral melanoma.

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    Schmuth, M; Spötl, L; Zelger, B; Weinlich, G; Zelger, B

    2001-01-01

    Acral melanoma may present clinically and histologically with atypical features causing a delay in proper diagnosis. The aim of the present study was to assess the frequency of a histological variant with clear cell changes. Clinical information, hematoxylin & eosin stained paraffin sections and immunohistochemical staining profiles were reviewed in 49 cases of acral melanoma. Twenty-one (43%) specimens contained tumor cells with clear cell changes in focal areas, whereas in 7 (14%) specimens clear cells were the major tumor constituting cells. The tumor thickness ranged from melanoma in situ to 14 mm. Immunohistochemistry demonstrated weak staining for S100 and HMB45 as well as strong positivity for Melan A and NK1C3. Recognition of clear cell features is important since differential diagnosis includes a variety of other clear cell malignancies, among them metastasis from renal cell carcinoma, clear cell sarcoma and hidradenocarcinoma.

  5. Communication Among Melanoma Family Members

    Science.gov (United States)

    Bowen, Deborah J; Albrecht, Terrance; Hay, Jennifer; Eggly, Susan; Harris-Wei, Julie; Meischke, Hendrika; Burke, Wylie

    2017-01-01

    Interventions to improve communication among family members may facilitate information flow about familial risk and preventive health behaviors. This is a secondary analysis of the effects of an interactive website intervention aimed at increasing communication frequency and agreement about health risk among melanoma families. Participants were family units, consisting of one family member with melanoma identified from a previous research study (the case) and an additional first degree relative and a parent of a child 0–17. Family triads were randomized to receive access to the website intervention or to serve as control families. Family communication frequency and agreement about melanoma prevention behaviors and beliefs were measured at baseline and again at one year post randomization. Intervention participants of all three types significantly increased the frequency of communication to their first degree relatives (Parents, siblings, children; range =14–18 percentage points; all pcommunication about cancer risk. PMID:28248624

  6. Genetic alterations and markers of melanoma

    Directory of Open Access Journals (Sweden)

    N. N. Mazurenko

    2014-01-01

    Full Text Available Melanoma remains the most deadly form of malignant skin disease with high risk of metastases. Metastatic melanoma is prognostic highly unfavorable and resistant to traditional chemotherapy and biologic treatment. There is a great progress in understanding of the molecular mechanisms underlying melanoma initiation and progression. The external (ultraviolet irradiation and internal (genetic factors are involved in melanoma genesis. 5–14 % of melanoma cases occur in familial context due to genetic predisposition risk factors. Among them rare germinal mutations in the cell cycle genes regulators CDKN2A and CDK4 and in the master gene of melanocyte homeostasis MITF, as well as single nucleotide polymorphisms of several low-penetrated genes, namely MC1R, have been identified. The main cell signaling pathways and oncogene driver mutations are involved in melanoma pathogenesis. RAS / RAF / MEK / ERK cascade is hyperactivated in 75 % of cutaneous melanoma cases. Activation of PI3K / AKT / mTOR signaling pathway is important for melanoma progression. Recent studies revealed that melanomas are genetically and phenotypically heterogeneous tumors. Spectrum of chromosomal alterations and activating mutations corresponding to tumor molecular portraits varies in melanomas of different location. Most of cutaneous melanomas contain BRAF (50 % or NRAS (20 % mutations, and NRAS mutations occur on chronically sun-exposed skin. Activating KIT mutations have been reported in approximately 20–30 % of certain subtypes of melanoma, including acral and mucosal, and melanoma that develop on photodamaged skin. Cutaneous metastatic melanoma derive from preexisting nevi in 25 % of cases, molecular mechanisms of nevi malignization are discussed. Deepsequencing approaches of melanoma samples of different melanoma types highlighted new melanoma driver genes, that are damaged due to tumorigenic effects of ultraviolet: PPP6C, RAC1, SNX31, TACC1 and STK19. The

  7. Familial skin cancer syndromes: Increased melanoma risk.

    Science.gov (United States)

    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. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  8. Melanoma: oncogenic drivers and the immune system.

    Science.gov (United States)

    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; Rosell, Rafael

    2015-10-01

    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.

  9. Combined endovascular and surgical treatment of melanoma of the nasal cavity: a case report

    International Nuclear Information System (INIS)

    Romero, A.; Delgado, F.; Ramos, M.; Bravo, F.

    2000-01-01

    Melanoma of the nasal cavity is a rare tumor with a worse prognosis than cutaneous melanoma. It usually presents as nasal obstruction and/or epistaxis. The observation of a pigmented mass in the nasal cavity is highly suggestive of this lesion. Computed tomography shows a mass with nonspecific features. In magnetic resonance studies, it has a characteristics signal consisting of hyperintensity of T1-weighted images and hypointensity on T2-weighted images, depending on the amount of melanin. The treatment of choice is surgical resection. We present a case of melanoma of the nasal cavity in which endovascular embolization of the tumor was performed prior to surgical treatment. (Author) 11 refs

  10. Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma.

    Science.gov (United States)

    Puig, Susana; Potrony, Miriam; Cuellar, Francisco; Puig-Butille, Joan Anton; Carrera, Cristina; Aguilera, Paula; Nagore, Eduardo; Garcia-Casado, Zaida; Requena, Celia; Kumar, Rajiv; Landman, Gilles; Costa Soares de Sá, Bianca; Gargantini Rezze, Gisele; Facure, Luciana; de Avila, Alexandre Leon Ribeiro; Achatz, Maria Isabel; Carraro, Dirce Maria; Duprat Neto, João Pedreira; Grazziotin, Thais C; Bonamigo, Renan R; Rey, Maria Carolina W; Balestrini, Claudia; Morales, Enrique; Molgo, Montserrat; Bakos, Renato Marchiori; Ashton-Prolla, Patricia; Giugliani, Roberto; Larre Borges, Alejandra; Barquet, Virginia; Pérez, Javiera; Martínez, Miguel; Cabo, Horacio; Cohen Sabban, Emilia; Latorre, Clara; Carlos-Ortega, Blanca; Salas-Alanis, Julio C; Gonzalez, Roger; Olazaran, Zulema; Malvehy, Josep; Badenas, Celia

    2016-07-01

    CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America. CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained. Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients. The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first- or second-degree relatives.Genet Med 18 7, 727-736.

  11. Choroidal melanoma in a dog.

    Science.gov (United States)

    Miwa, Yasutsugu; Matsunaga, Satoru; Kato, Kumiko; Ogawa, Hiroyuki; Nakayama, Hiroyuki; Tsujimoto, Saori; Sasaki, Nobuo

    2005-08-01

    A 7-year-old intact female golden Retriever was referred for evaluation of an intraorbital mass of the left eye. Based on ophthalmoscopy, ultrasonography and magnetic resonance imaging (MRI), the tentative diagnosis was made as an intraocular neoplasia, especially choroidal melanoma. The orbital exenteration of the affected eye was performed. The mass was histologically diagnosed as malignant choroidal melanoma. No signs of recurrence and metastasis were detected by thoracic radiographs, blood examinations and MR images, and the dog was clinically healthy for 23 months after operation.

  12. The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.

    Science.gov (United States)

    Yen, Jennifer; White, Richard M; Wedge, David C; Van Loo, Peter; de Ridder, Jeroen; Capper, Amy; Richardson, Jennifer; Jones, David; Raine, Keiran; Watson, Ian R; Wu, Chang-Jiun; Cheng, Jiqiu; Martincorena, Iñigo; Nik-Zainal, Serena; Mudie, Laura; Moreau, Yves; Marshall, John; Ramakrishna, Manasa; Tarpey, Patrick; Shlien, Adam; Whitmore, Ian; Gamble, Steve; Latimer, Calli; Langdon, Erin; Kaufman, Charles; Dovey, Mike; Taylor, Alison; Menzies, Andy; McLaren, Stuart; O'Meara, Sarah; Butler, Adam; Teague, Jon; Lister, James; Chin, Lynda; Campbell, Peter; Adams, David J; Zon, Leonard I; Patton, E Elizabeth; Stemple, Derek L; Futreal, P Andy

    2013-01-01

    Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAF(V600E) or NRAS(Q61K) driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAF(V600E) and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation.

  13. Oral mucosal melanoma: A case report

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    Ramlal Gantala

    2017-01-01

    Full Text Available Malignant melanoma is most deadly of all primary skin cancers. Over 90% of melanomas occur on the skin. Half of such melanomas occur in the oral cavity, followed by nasal cavity (44% and sinuses (8%. In the oral cavity, the most frequent sites of occurrence are hard palate and maxillary gingiva. Mucosal melanomas represent a diagnostic challenge than the more common cutaneous melanomas because oral melanomas demonstrate significant heterogeneity in morphological features, developmental process, and biological behaviour. This case report highlights an exophytic, lobulated oral malignant melanoma involving maxillary gingiva and is presented to reemphasize the fact that any pigmented lesion in the oral cavity should be examined with suspicion; proper investigation should be carried out to rule out any untoward experiences later.

  14. The regulation of miRNA-211 expression and its role in melanoma cell invasiveness.

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    Joseph Mazar

    2010-11-01

    Full Text Available The immediate molecular mechanisms behind invasive melanoma are poorly understood. Recent studies implicate microRNAs (miRNAs as important agents in melanoma and other cancers. To investigate the role of miRNAs in melanoma, we subjected human melanoma cell lines to miRNA expression profiling, and report a range of variations in several miRNAs. Specifically, compared with expression levels in melanocytes, levels of miR-211 were consistently reduced in all eight non-pigmented melanoma cell lines we examined; they were also reduced in 21 out of 30 distinct melanoma samples from patients, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic. The levels of several predicted target mRNAs of miR-211 were reduced in melanoma cell lines that ectopically expressed miR-211. In vivo target cleavage assays confirmed one such target mRNA encoded by KCNMA1. Mutating the miR-211 binding site seed sequences at the KCNMA1 3'-UTR abolished target cleavage. KCNMA1 mRNA and protein expression levels varied inversely with miR-211 levels. Two different melanoma cell lines ectopically expressing miR-211 exhibited significant growth inhibition and reduced invasiveness compared with the respective parental melanoma cell lines. An shRNA against KCNMA1 mRNA also demonstrated similar effects on melanoma cells. miR-211 is encoded within the sixth intron of TRPM1, a candidate suppressor of melanoma metastasis. The transcription factor MITF, important for melanocyte development and function, is needed for high TRPM1 expression. MITF is also needed for miR-211 expression, suggesting that the tumor-suppressor activities of MITF and/or TRPM1 may at least partially be due to miR-211's negative post transcriptional effects on the KCNMA1 transcript. Given previous reports of high KCNMA1 levels in metastasizing melanoma, prostate cancer and glioma, our findings that miR-211 is a direct posttranscriptional regulator of KCNMA1 expression as well

  15. Tumor-suppressive effects of natural-type interferon-β through CXCL10 in melanoma

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    Kobayashi, Hikaru; Nobeyama, Yoshimasa, E-mail: nobederm@jikei.ac.jp; Nakagawa, Hidemi

    2015-08-21

    Introduction: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-β (IFN-β) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-β treatment of lymphatic endothelial cells. Materials and methods: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-β, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-β treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-β and CXCL10 in melanoma cells. Results: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-β in lymphatic endothelial cells. IFN-β treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-β. CXCL10 reduced melanoma cell proliferation in IFN-β-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-β. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-β and down-regulated in melanoma cells with medium to low sensitivity. Conclusions: Our data suggest that IFN-β suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-β may be associated with resistance to IFN-β. - Highlights: • We search melanoma-suppressive molecules induced by IFN-β. • IFN-β induces a high amount of CXCL10 from lymphatic endothelial cells. • CXCL10 induction level in melanoma cells is correlated

  16. Human-derived physiological heat shock protein 27 complex protects brain after focal cerebral ischemia in mice.

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    Shinichiro Teramoto

    Full Text Available Although challenging, neuroprotective therapies for ischemic stroke remain an interesting strategy for countering ischemic injury and suppressing brain tissue damage. Among potential neuroprotective molecules, heat shock protein 27 (HSP27 is a strong cell death suppressor. To assess the neuroprotective effects of HSP27 in a mouse model of transient middle cerebral artery occlusion, we purified a "physiological" HSP27 (hHSP27 from normal human lymphocytes. hHSP27 differed from recombinant HSP27 in that it formed dimeric, tetrameric, and multimeric complexes, was phosphorylated, and contained small amounts of αβ-crystallin and HSP20. Mice received intravenous injections of hHSP27 following focal cerebral ischemia. Infarct volume, neurological deficit scores, physiological parameters, and immunohistochemical analyses were evaluated 24 h after reperfusion. Intravenous injections of hHSP27 1 h after reperfusion significantly reduced infarct size and improved neurological deficits. Injected hHSP27 was localized in neurons on the ischemic side of the brain. hHSP27 suppressed neuronal cell death resulting from cytochrome c-mediated caspase activation, oxidative stress, and inflammatory responses. Recombinant HSP27 (rHSP27, which was artificially expressed and purified from Escherichia coli, and dephosphorylated hHSP27 did not have brain protective effects, suggesting that the phosphorylation of hHSP27 may be important for neuroprotection after ischemic insults. The present study suggests that hHSP27 with posttranslational modifications provided neuroprotection against ischemia/reperfusion injury and that the protection was mediated through the inhibition of apoptosis, oxidative stress, and inflammation. Intravenously injected human HSP27 should be explored for the treatment of acute ischemic strokes.

  17. Characterization of human γδ T lymphocytes infiltrating primary malignant melanomas.

    Directory of Open Access Journals (Sweden)

    Adriana Cordova

    Full Text Available T lymphocytes are often induced naturally in melanoma patients and infiltrate tumors. Given that γδ T cells mediate antigen-specific killing of tumor cells, we studied the representation and the in vitro cytokine production and cytotoxic activity of tumor infiltrating γδ T cells from 74 patients with primary melanoma. We found that γδ T cells represent the major lymphocyte population infiltrating melanoma, and both Vδ1(+ and Vδ2(+ cells are involved. The majority of melanoma-infiltrating γδ cells showed effector memory and terminally-differentiated phenotypes and, accordingly, polyclonal γδ T cell lines obtained from tumor-infiltrating immune cells produced IFN-γ and TNF-α and were capable of killing melanoma cell lines in vitro. The cytotoxic capability of Vδ2 cell lines was further improved by pre-treatment of tumor target cells with zoledronate. Moreover, higher rate of γδ T cells isolation and percentages of Vδ2 cells correlate with early stage of development of melanoma and absence of metastasis. Altogether, our results suggest that a natural immune response mediated by γδ T lymphocytes may contribute to the immunosurveillance of melanoma.

  18. Human melanoma metastasis in NSG mice correlates with clinical outcome in patients.

    Science.gov (United States)

    Quintana, Elsa; Piskounova, Elena; Shackleton, Mark; Weinberg, Daniel; Eskiocak, Ugur; Fullen, Douglas R; Johnson, Timothy M; Morrison, Sean J

    2012-11-07

    Studies of human cancer metastasis have been limited by a lack of experimental assays in which cancer cells from patients metastasize in vivo in a way that correlates with clinical outcome. This makes it impossible to study intrinsic differences in the metastatic properties of cancers from different patients. We recently developed an assay in which human melanomas readily engraft in nonobese diabetic/severe combined immunodeficient interleukin-2 receptor-γ chain null (NSG) mice. We show that melanomas from 25 patients exhibited reproducible differences in the rate of spontaneous metastasis after transplantation into NSG mice and that these differences correlated with clinical outcome in the patients. Stage IIIB/C melanomas that formed distant metastases within 22 months in patients also formed tumors that metastasized widely in NSG mice, whereas stage IIIB/C melanomas that did not form distant metastases within 22 to 50 months in patients metastasized more slowly in NSG mice. These differences in the efficiency of metastasis correlated with the presence of circulating melanoma cells in the blood of NSG mice, suggesting that the rate of entry into the blood is one factor that limits the rate of metastasis. The study of NSG mice can therefore yield information about the metastasis of human melanomas in vivo, in this case revealing intrinsic differences among stage III melanomas in their ability to circulate/survive in the blood and to metastasize.

  19. Cell division cycle-associated protein 1 as a new melanoma-associated antigen.

    Science.gov (United States)

    Tokuzumi, Aki; Fukushima, Satoshi; Miyashita, Azusa; Nakahara, Satoshi; Kubo, Yosuke; Yamashita, Junji; Harada, Miho; Nakamura, Kayo; Kajihara, Ikko; Jinnin, Masatoshi; Ihn, Hironobu

    2016-12-01

    Immune checkpoint inhibitors have increased the median survival of melanoma patients. To improve their effects, antigen-specific therapies utilizing melanoma-associated antigens should be developed. Cell division cycle-associated protein 1 (CDCA1), which has a specific function at the kinetochores for stabilizing microtubule attachment, is overexpressed in various cancers. CDCA1, which is a member of cancer-testis antigens, does not show detectable expression levels in normal tissues. Quantitative reverse transcription polymerase chain reaction and immunoblotting analyses revealed that CDCA1 was expressed in all of the tested melanoma cell lines, 74% of primary melanomas, 64% of metastatic melanomas and 25% of nevi. An immunohistochemical analysis and a Cox proportional hazards model showed that CDCA1 could be a prognostic marker in malignant melanoma (MM) patients. CDCA1-specific siRNA inhibited the cell proliferation of SKMEL2 and WM115 cells, but did not reduce the migration or invasion activity. These results suggest that CDCA1 may be a new therapeutic target of melanoma. © 2016 Japanese Dermatological Association.

  20. Risk factors and outcomes of cutaneous melanoma in women less than 50 years of age.

    Science.gov (United States)

    Tellez, Alejandra; Rueda, Steven; Conic, Ruzica Z; Powers, Kristin; Galdyn, Izabela; Mesinkovska, Natasha Atanaskova; Gastman, Brian

    2016-04-01

    Melanoma is the fifth most common cancer in the United States, with recent reports indicating increasing incidence among young women. This study sought to investigate histopathology, staging, risk factors, and outcomes of cutaneous melanoma in women younger than 50 years. All female patients aged up to 49 years with biopsy-proven diagnosis of melanoma between 1988 and 2012 were included. Patients with a follow-up of less than 2 years were excluded. A total of 462 patients were identified, with mean age of 34.7 years. Invasive melanoma was less common in women 19 years of age or younger (P melanoma had a significantly worse prognosis in comparison with a control group of nonpregnant patients, with a 9-fold increase in recurrence (P melanoma for women younger than 50 years suggests that regular skin checks and self-examinations are warranted. In addition, in women given the diagnosis of melanoma during or within 1 year after childbirth, regular follow-up and monitoring for recurrence are recommended. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  1. A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells.

    Directory of Open Access Journals (Sweden)

    Ke-Jia Wu

    Full Text Available The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

  2. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    International Nuclear Information System (INIS)

    Abschuetz, Oliver; Osen, Wolfram; Frank, Kathrin; Kato, Masashi; Schadendorf, Dirk; Umansky, Viktor

    2012-01-01

    Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy

  3. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Dirk Schadendorf

    2012-04-01

    Full Text Available Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA tyrosinase, tyrosinase related protein (TRP-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.

  4. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Abschuetz, Oliver [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Osen, Wolfram [Division of Translational Immunology, German Cancer Center, Heidelberg 69120 (Germany); Frank, Kathrin [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Kato, Masashi [Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501 (Japan); Schadendorf, Dirk [Department of Dermatology, University Hospital Essen, Essen 45122 (Germany); Umansky, Viktor, E-mail: v.umansky@dkfz.de [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany)

    2012-04-26

    Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.

  5. Liposomal C6 Ceramide Activates Protein Phosphatase 1 to Inhibit Melanoma Cells.

    Directory of Open Access Journals (Sweden)

    Fangzhen Jiang

    Full Text Available Melanoma is one common skin cancer. In the present study, the potential anti-melanoma activity by a liposomal C6 ceramide was tested in vitro. We showed that the liposomal C6 (ceramide was cytotoxic and anti-proliferative against a panel of human melanoma cell lines (SK-Mel2, WM-266.4 and A-375 and WM-115. In addition, liposomal C6 induced caspase-dependent apoptotic death in the melanoma cells. Reversely, its cytotoxicity was attenuated by several caspase inhibitors. Intriguingly, liposomal C6 was non-cytotoxic to B10BR mouse melanocytes and primary human melanocytes. Molecularly, liposomal C6 activated protein phosphatase 1 (PP1 to inactivate Akt-mammalian target of rapamycin (mTOR signaling in melanoma cells. On the other hand, PP1 shRNA knockdown or exogenous expression of constitutively activate Akt1 (CA-Akt1 restored Akt-mTOR activation and significantly attenuated liposomal C6-mediated cytotoxicity and apoptosis in melanoma cells. Our results suggest that liposomal C6 activates PP1 to inhibit melanoma cells.

  6. Fluorescence in situ hybridization for the differential diagnosis between Spitz naevus and spitzoid melanoma.

    Science.gov (United States)

    Requena, Celia; Rubio, Luis; Traves, Victor; Sanmartín, Onofre; Nagore, Eduardo; Llombart, Beatriz; Serra, Carlos; Fernández-Serra, Antonio; Botella, Rafael; Guillén, Carlos

    2012-11-01

    The differential diagnosis between Spitz naevus and spitzoid melanoma can be extremely difficult, or even impossible. In recent years, many attempts have been made to find specific histopathological or immunohistochemical markers, although none has proved successful. Because the prognosis and treatment of each are very different, it is important to distinguish between these entities. We evaluated the ability of the fluorescence in situ hybridization (FISH) assay-designed to detect the copy number of the RREB1 (6p25), MYB (6q23) and CCND1 (11q13) genes and of centromere 6 (Cep 6)-in order to distinguish between Spitz naevus and spitzoid melanoma. We evaluated 12 spitzoid melanomas and six Spitz naevi from our records. The diagnosis of both conditions was based on previously described histopathological criteria. We obtained valuable results for FISH in eight spitzoid melanomas and five Spitz naevi. Chromosomal aberrations were detected in seven of the eight spitzoid melanomas (FISH-positive) and in none of the five Spitz naevi. The FISH-negative spitzoid melanoma was the least typical in its group. FISH was able to distinguish between Spitz naevus and spitzoid melanoma, with a sensitivity of 87.5% and a specificity of 100%. Our findings suggest that FISH could prove a useful tool in the differential diagnosis between these entities. © 2012 Blackwell Publishing Limited.

  7. Age-related characteristics of cutaneous melanoma in a Spanish Mediterranean population.

    Science.gov (United States)

    Montero, Iria; Requena, Celia; Traves, Victor; García-Casado, Zaida; Kumar, Rajiv; Nagore, Eduardo

    2015-07-01

    Melanoma is considered a heterogeneous tumor with genetic and environmental factors involved in its pathogenesis. The impact of these factors varies depending on age. The aim of this study was to characterize the epidemiological, phenotypic, and histological features of patients with melanoma according to three age groups: ≤40, 41-65, and >65 years. A total of 1122 consecutive patients with invasive melanoma definitively treated in our institution since January 2000 were selected from our melanoma database. Epidemiological, phenotypic, and histological data were retrieved and analyzed as a function of age. Female patients predominated in the younger age group. The location of cutaneous malignant melanoma differed with age. In the younger and middle age groups, tumors presented mainly on the trunk, while in the older group they were mainly found on the head/neck. Signs of actinic damage such as actinic keratoses, solar lentigines, or other skin tumors increased with age, while genetic factors such as family history of melanoma or a high number of common melanocytic nevi were more frequent in the younger group. Our results suggest that melanoma development in younger patients is the result of genetic factors, particularly related to multiple nevi, whereas in older patients environmental factors such as severe chronic sun exposure play a major role. © 2015 The International Society of Dermatology.

  8. Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma.

    Science.gov (United States)

    Pritchard-Jones, R O; Dunn, D B A; Qiu, Y; Varey, A H R; Orlando, A; Rigby, H; Harper, S J; Bates, D O

    2007-07-16

    Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis - the growth of new vessels from preexisting vasculature - is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF(xxx)b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF(xxx)b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF(xxx)b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) Pxxx)b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

  9. Open to Suggestion.

    Science.gov (United States)

    Journal of Reading, 1987

    1987-01-01

    Offers (1) suggestions for improving college students' study skills; (2) a system for keeping track of parent, teacher, and community contacts; (3) suggestions for motivating students using tic tac toe; (4) suggestions for using etymology to improve word retention; (5) a word search grid; and (6) suggestions for using postcards in remedial reading…

  10. Cutavirus in Cutaneous Malignant Melanoma

    DEFF Research Database (Denmark)

    Mollerup, Sarah; Fridholm, Helena; Vinner, Lasse

    2017-01-01

    A novel human protoparvovirus related to human bufavirus and preliminarily named cutavirus has been discovered. We detected cutavirus in a sample of cutaneous malignant melanoma by using viral enrichment and high-throughput sequencing. The role of cutaviruses in cutaneous cancers remains...

  11. Prognostic stratification of ulcerated melanoma

    DEFF Research Database (Denmark)

    Bønnelykke-Behrndtz, Marie L; Schmidt, Henrik; Christensen, Ib J

    2014-01-01

    OBJECTIVES: For patients with melanoma, ulceration is an important prognostic marker and interestingly also a predictive marker for the response of adjuvant interferon. A consensual definition and accurate assessment of ulceration are therefore crucial for proper staging and clinical management. We...

  12. Stages of Intraocular (Uveal) Melanoma

    Science.gov (United States)

    ... or tans poorly. Blue or green or other light-colored eyes. Older age. Being white. Signs of intraocular melanoma include blurred vision ... to treat small tumors. This is also called light coagulation. ... are being tested in clinical trials. Information about clinical trials ...

  13. Prognostic Factors in Uveal Melanoma

    NARCIS (Netherlands)

    E. Kiliç (Emine)

    2006-01-01

    textabstractUveal melanoma is the most common intra-ocular tumour in the western world with an annual incidence of seven per million. Approximately 50% of the patients treated by enucleation dye eventually due to metastatic disease. Besides enucleation there are nowadays more conservative treatment

  14. Synchronized Targeting of Notch and ERBB Signaling Suppresses Melanoma Tumor Growth through Inhibition of Notch1 and ERBB3.

    Science.gov (United States)

    Zhang, Keman; Wong, Poki; Salvaggio, Christine; Salhi, Amel; Osman, Iman; Bedogni, Barbara

    2016-02-01

    Despite significant advances in melanoma therapy, melanoma remains the deadliest form of skin cancer, with a 5-year survival rate of only 15%. Thus, novel treatments are required to address this disease. Notch and ERBB are evolutionarily conserved signaling cascades required for the maintenance of melanocyte precursors. We show that active Notch1 (Notch1(NIC)) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild-type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival. Whereas blocking either pathway triggers modest effects, combining a ?-secretase inhibitor to block Notch activation and a tyrosine kinase inhibitor to inhibit ERBB3/2 elicits synergistic effects, reducing cell viability by 90% and hampering melanoma tumor growth. Specific inhibition of Notch1 and ERBB3 mimics these results, suggesting these are the critical factors triggering melanoma tumor expansion. Notch and ERBB inhibition blunts AKT and NF?B signaling. Constitutive expression of NF?B partially rescues cell death. Blockade of both Notch and ERBB signaling inhibits the slow cycling JARID1B-positive cell population, which is critical for long-term maintenance of melanoma growth. We propose that blocking these pathways is an effective approach to treatment of melanoma patients regardless of whether they carry mutated or wild-type BRAF. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Teng, E-mail: tengyu33@yahoo.com [Department of Dermatology, Shandong Ji-ning No. 1 People’s Hospital, Shandong Province 272011 (China); Ji, Jiang [Department of Dermatology, The Second Hospital Affiliated of Soochow University, SuZhou, Jiangsu Province 215000 (China); Guo, Yong-li [Department of Oncology, Shandong Ji-ning No. 1 People’s Hospital, Shandong Province 272011 (China)

    2013-11-08

    Highlights: •Curcumin activates MST1 in melanoma cells. •MST1 mediates curcumin-induced apoptosis of melanoma cells. •ROS production is involved in curcumin-induced MST1 activation. •MST1 mediates curcumin-induced JNK activation in melanoma cells. •MST1 mediates curcumin-induced Foxo3a nuclear translocation and Bim expression. -- Abstract: Different groups including ours have shown that curcumin induces melanoma cell apoptosis, here we focused the role of mammalian Sterile 20-like kinase 1 (MST1) in it. We observed that curcumin activated MST1-dependent apoptosis in cultured melanoma cells. MST1 silencing by RNA interference (RNAi) suppressed curcumin-induced cell apoptosis, while MST1 over-expressing increased curcumin sensitivity. Meanwhile, curcumin induced reactive oxygen species (ROS) production in melanoma cells, and the ROS scavenger, N-acetyl-cysteine (NAC), almost blocked MST1 activation to suggest that ROS might be required for MST1 activation by curcumin. c-Jun N-terminal protein kinase (JNK) activation by curcumin was dependent on MST1, since MST1 inhibition by RNAi or NAC largely inhibited curcumin-induced JNK activation. Further, curcumin induced Foxo3 nuclear translocation and Bim-1 (Foxo3 target gene) expression in melanoma cells, such an effect by curcumin was inhibited by MST1 RNAi. In conclusion, we suggested that MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells.

  16. MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells

    International Nuclear Information System (INIS)

    Yu, Teng; Ji, Jiang; Guo, Yong-li

    2013-01-01

    Highlights: •Curcumin activates MST1 in melanoma cells. •MST1 mediates curcumin-induced apoptosis of melanoma cells. •ROS production is involved in curcumin-induced MST1 activation. •MST1 mediates curcumin-induced JNK activation in melanoma cells. •MST1 mediates curcumin-induced Foxo3a nuclear translocation and Bim expression. -- Abstract: Different groups including ours have shown that curcumin induces melanoma cell apoptosis, here we focused the role of mammalian Sterile 20-like kinase 1 (MST1) in it. We observed that curcumin activated MST1-dependent apoptosis in cultured melanoma cells. MST1 silencing by RNA interference (RNAi) suppressed curcumin-induced cell apoptosis, while MST1 over-expressing increased curcumin sensitivity. Meanwhile, curcumin induced reactive oxygen species (ROS) production in melanoma cells, and the ROS scavenger, N-acetyl-cysteine (NAC), almost blocked MST1 activation to suggest that ROS might be required for MST1 activation by curcumin. c-Jun N-terminal protein kinase (JNK) activation by curcumin was dependent on MST1, since MST1 inhibition by RNAi or NAC largely inhibited curcumin-induced JNK activation. Further, curcumin induced Foxo3 nuclear translocation and Bim-1 (Foxo3 target gene) expression in melanoma cells, such an effect by curcumin was inhibited by MST1 RNAi. In conclusion, we suggested that MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells

  17. Biochemical mechanism of acetylsalicylic acid (Aspirin) selective toxicity toward melanoma cell lines.

    Science.gov (United States)

    Vad, Nikhil M; Yount, Garret; Moridani, Majid Y

    2008-12-01

    In the current work, we investigated the biochemical toxicity of acetylsalicylic acid (ASA; Aspirin) in human melanoma cell lines using tyrosinase enzyme as a molecular cancer therapeutic target. At 2 h, ASA was oxidized 88% by tyrosinase. Ascorbic acid and NADH, quinone reducing agents, were significantly depleted during the enzymatic oxidation of ASA by tyrosinase to quinone. The 50% inhibitory concentration (48 h) of ASA and salicylic acid toward SK-MEL-28 cells were 100 micromol/l and 5.2 mmol/l, respectively. ASA at 100 micromol/l was selectively toxic toward human melanocytic SK-MEL-28, MeWo, and SK-MEL-5 and murine melanocytic B16-F0 and B16-F10 melanoma cell lines. However, ASA was not significantly toxic to human amelanotic C32 melanoma cell line, which does not express tyrosinase enzyme, and human nonmelanoma BJ, SW-620, Saos, and PC-3 cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased ASA toxicity toward SK-MEL-28 cells indicating quinone formation and intracellular GSH depletion played important mechanistic roles in ASA-induced melanoma toxicity. Ascorbic acid, a quinone reducing agent, and GSH, an antioxidant and quinone trap substrate, prevented ASA cell toxicity. Trifluoperazine, inhibitor of permeability transition pore in mitochondria, prevented ASA toxicity. ASA led to significant intracellular GSH depletion in melanocytic SK-MEL-28 melanoma cells but not in amelanotic C32 melanoma cells. ASA also led to significant reactive oxygen species (ROS) formation in melanocytic SK-MEL-28 melanoma cells but not in amelanotic C32 melanoma cells. ROS formation was exacerbated by dicoumarol and 1-bromoheptane in SK-MEL-28. Our investigation suggests that quinone species, intracellular GSH depletion, ROS formation, and mitochondrial toxicity significantly contributed toward ASA selective toxicity in melanocytic SK-MEL-28 melanoma cells.

  18. Melanoma Thickness and Survival Trends in the United States, 1989 to 2009.

    Science.gov (United States)

    Shaikh, Waqas R; Dusza, Stephen W; Weinstock, Martin A; Oliveria, Susan A; Geller, Alan C; Halpern, Allan C

    2016-01-01

    With melanoma incidence rising and mortality stable, some question whether the melanoma epidemic is real. Melanoma thickness and survival trends may provide insights, but previous studies have been limited because of missing data on thickness. With a validated imputation method for missing thickness data, we characterized melanoma thickness and survival trends among men and women in the Surveillance, Epidemiology, and End Results (SEER)-9 registries between 1989 and 2009. A total of 98,498 cases of invasive melanoma were identified. All statistical tests were two-sided. Incidence per 100 000 person-years increased (13.94, 95% confidence interval [CI] = 13.65 to 14.23, to 21.87, 95% CI = 21.56 to 22.19, P 4.00mm) and nodular melanomas; acral lentiginous melanomas approached statistical significance. Thickness remained unchanged among some racial minorities. Melanoma-specific survival improved (hazard ratio [HR] = 0.89, 95% CI = 0.88 to 0.91) every three years in multivariable analysis. Improvements in survival occurred across all subgroups except nonblack minorities, and nodular and acral lentiginous subtypes. Increasing incidence across all thickness groups coupled with T3/T4 lesions becoming thicker suggests that the melanoma epidemic is real and not simply an artifact of increased detection pressure of earlier-stage T1/T2 lesions. Survival is generally improving independent of thickness, but improvements in survival have not been experienced by certain minorities, and nodular and acral lentiginous subtypes. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Characteristics, rates, and trends of melanoma incidence among Hispanics in the USA.

    Science.gov (United States)

    Garnett, Erin; Townsend, Julie; Steele, Brooke; Watson, Meg

    2016-05-01

    The purpose of this study is to describe the epidemiology of melanoma among Hispanics using data that cover nearly 100 % of the US population. The study used population-based cancer incidence data from the National Program of Cancer Registries and the Surveillance, Epidemiology and End Results Program to examine melanoma incidence rates and trends among Hispanics by sex, age, race, histology, anatomic location, stage, and tumor thickness. From 2008 to 2012, 6,623 cases of melanoma were diagnosed among Hispanics. Rates were higher among males (4.6) than among females (4.0), but females younger than age 55 had higher rates than males. The most common histologic subtype was superficial spreading melanoma (23 %). Melanomas with poorer outcomes, such as nodular (NM) and acral lentiginous melanoma (ALM), were more common among males. Hispanic females had the highest proportion of melanoma on the lower limb and hip (33.7 %), while Hispanic males had the highest proportion on the trunk (29.9 %). Incidence rates for later-stage diagnosis and thicker tumors were significantly higher among Hispanic men than among women. Incidence rates decreased significantly during 2003-2012 (AAPC = -1.4). Clinicians and public health practitioners will need to reach the growing Hispanic population in the USA with strategies for primary prevention and early diagnosis of melanoma. Results suggest Hispanics and providers need education to increase awareness about the characteristics of melanoma among Hispanics, including types that occur on non-sun-exposed areas (ALM and NM). Skin cancer prevention and awareness interventions targeting Hispanics should be culturally relevant.

  20. Pre-clinical assessment of A-674563 as an anti-melanoma agent

    Energy Technology Data Exchange (ETDEWEB)

    Zou, Ying; Fan, Guobiao; Wang, Xuemin, E-mail: wangxuemeidr@yeah.net

    2016-08-12

    The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A-674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A-674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A-674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms. - Highlights: • A-674563 inhibits human melanoma cell survival and proliferation. • A-674563 induces melanoma cell apoptotic death, inhibited by caspase inhibitors. • A-674563 inhibits melanoma cells via Akt-dependent and -independent mechanisms. • A-674563 induces ceramide production in melanoma cells, independent of Akt inhibition. • A-674563 oral administration potently inhibits A375 xenograft growth in mice.

  1. Pre-clinical assessment of A-674563 as an anti-melanoma agent

    International Nuclear Information System (INIS)

    Zou, Ying; Fan, Guobiao; Wang, Xuemin

    2016-01-01

    The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A-674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A-674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A-674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms. - Highlights: • A-674563 inhibits human melanoma cell survival and proliferation. • A-674563 induces melanoma cell apoptotic death, inhibited by caspase inhibitors. • A-674563 inhibits melanoma cells via Akt-dependent and -independent mechanisms. • A-674563 induces ceramide production in melanoma cells, independent of Akt inhibition. • A-674563 oral administration potently inhibits A375 xenograft growth in mice.

  2. The burden of malignant melanoma--lessons to be learned from Austria.

    Science.gov (United States)

    Monshi, Babak; Vujic, Marin; Kivaranovic, Danijel; Sesti, Alma; Oberaigner, Willi; Vujic, Igor; Ortiz-Urda, Susana; Posch, Christian; Feichtinger, Hans; Hackl, Monika; Rappersberger, Klemens

    2016-03-01

    Incidence rates of melanoma, generated by cancer registries (CRs), are susceptible to reporting inconsistencies due to increasing decentralisation of diagnosis. We therefore independently assessed the burden of melanoma in Austria. We collected histopathological reports on melanoma of all patients diagnosed in Austria in 2011. Demographic and clinical characteristics, histopathological tumour stages were assessed. Their regional distributions and incidence rates were analysed and compared with data of national and international CRs. A total of 5246 patients were diagnosed with 1951 in-situ and 3295 invasive melanomas in Austria in 2011 (population 8.4 million). Age, sex and anatomic distribution corresponded to findings in other European countries, however, the incidence of 25/100,000 (world age-standardised rate) for invasive melanomas was two-fold higher than published by the Austrian CR (12/100,000). Varying frequencies in diagnosing thin melanomas (≤1 mm; n = 4415) accounted exclusively for significant regional disparities, while advanced tumours (>1 mm; n = 761) were evenly distributed. Western Austria showed the highest rates (36/100,000). Patients from eastern Austria whose melanomas were diagnosed in laboratories in western Austria (n = 76) showed significantly higher proportions of in-situ lesions (n = 43; 57%) compared to those whose tumours were diagnosed in eastern Austria (n = 4014; in-situ = 1369; 34%) (p Austria, the melanoma burden and its potential socio-economic implications are significantly underestimated. Similarities of incidences indicate this could affect other European countries with well-established CRs and compromise international comparability of data. Austrian regional disparities suggest overdiagnosis of thin melanomas due to the variability of pathologists' thresholds for the diagnosis of early stage tumours. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. C-kit expression in canine mucosal melanomas.

    Science.gov (United States)

    Newman, S J; Jankovsky, J M; Rohrbach, B W; LeBlanc, A K

    2012-09-01

    The c-kit receptor is responsible for transmission of promigration signals to melanocytes; its downregulation may be involved in malignant progression of human melanocytic neoplasms. Expression of this receptor has not been examined in normal or neoplastic melanocytes from dogs. In this study, 14 benign dermal and 61 malignant mucosal melanocytic tumors were examined for c-kit (KIT) expression. Sites of the mucosal melanomas were gingiva (not further specified; n = 30), buccal gingiva (n = 6), soft palate (n = 4), hard palate (n = 5), tongue (n = 7), lip (n = 6), and conjunctiva (n = 3). Melan A was expressed in all 14 dermal melanocytomas and in 59 of 61 (96.7%) tumors from oral or conjunctival mucosa, confirming melanocytic origin. C-kit receptor expression was strong and diffuse throughout the cytoplasm in all 14 dermal melanocytomas and was identified in basilar mucosal melanocytes over submucosal neoplasms (27 of 61, 44.3%), junctional (neoplastic) melanocytes (17 of 61, 27.9%), and, less commonly, neoplastic melanocytes of the subepithelial tumors (6 of 61, 9.8%). KIT expression anywhere within the resected melanomas correlated with significantly longer survival. These results suggest that c-kit receptor expression may be altered in canine melanomas and may have potential as a prognostic indicator for mucosal melanomas.

  4. Whole genome sequencing of matched primary and metastatic acral melanomas.

    Science.gov (United States)

    Turajlic, Samra; Furney, Simon J; Lambros, Maryou B; Mitsopoulos, Costas; Kozarewa, Iwanka; Geyer, Felipe C; Mackay, Alan; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J; Ashworth, Alan; Thomas, Meirion; Stamp, Gordon; Larkin, James; Reis-Filho, Jorge S; Marais, Richard

    2012-02-01

    Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.

  5. Clonal architectures and driver mutations in metastatic melanomas.

    Directory of Open Access Journals (Sweden)

    Li Ding

    Full Text Available To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1, protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT, as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2. Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9 with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.

  6. Clonal Architectures and Driver Mutations in Metastatic Melanomas

    Science.gov (United States)

    Dees, Nathan D.; Lu, Charles; Griffith, Malachi; Fenstermacher, David; Sung, Hyeran; Miller, Christopher A.; Goetz, Brian; Wendl, Michael C.; Griffith, Obi; Cornelius, Lynn A.; Linette, Gerald P.; McMichael, Joshua F.; Sondak, Vernon K.; Fields, Ryan C.; Ley, Timothy J.; Mulé, James J.; Wilson, Richard K.; Weber, Jeffrey S.

    2014-01-01

    To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3′ base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma. PMID:25393105

  7. Pediatric melanoma: incidence, treatment, and prognosis

    Directory of Open Access Journals (Sweden)

    Saiyed FK

    2017-04-01

    Full Text Available Faiez K Saiyed,1 Emma C Hamilton,1 Mary T Austin,1,2 1Department of Pediatric Surgery, McGovern Medical School, 2Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: The purpose of this review is to outline recent advancements in diagnosis, treatment, and prevention of pediatric melanoma. Despite the recent decline in incidence, it continues to be the deadliest form of skin cancer in children and adolescents. Pediatric melanoma presents differently from adult melanoma; thus, the traditional asymmetry, border irregularity, color variegation, diameter >6 mm, and evolution (ABCDE criteria have been modified to include features unique to pediatric melanoma (amelanotic, bleeding/bump, color uniformity, de novo/any diameter, evolution of mole. Surgical and medical management of pediatric melanoma continues to derive guidelines from adult melanoma treatment. However, more drug trials are being conducted to determine the specific impact of drug combinations on pediatric patients. Alongside medical and surgical treatment, prevention is a central component of battling the incidence, as ultraviolet (UV-related mutations play a central role in the vast majority of pediatric melanoma cases. Aggressive prevention measures targeting sun safety and tanning bed usage have shown positive sun-safety behavior trends, as well as the potential to decrease melanomas that manifest later in life. As research into the field of pediatric melanoma continues to expand, a prevention paradigm needs to continue on a community-wide level. Keywords: melanoma, pediatric, adolescent, childhood

  8. Intracellular targets of RGDS peptide in melanoma cells

    Directory of Open Access Journals (Sweden)

    Capogrossi Maurizio C

    2010-04-01

    Full Text Available Abstract Background RGD-motif acts as a specific integrins-ligand and regulates a variety of cell-functions via extracellular action affecting cell-adhesion properties. However, increasing evidence identifies additional RGDS-functions at intracellular level. Previous reports show RGDS-internalization in endothelial cells, cardiomyocytes and lymphocytes, indicating intracellular targets such as caspase-8 and caspase-9, and suggest RGDS specific activity at cytoplasmic level. Given the role RGDS-peptides play in controlling proliferation and apoptosis in several cell types, investigating intracellular targets of RGDS in melanoma cells may un-reveal novel molecular targets and key pathways, potentially useful for a more effective approach to melanoma treatment. Results In the present study we show for the first time that RGDS-peptide is internalized in melanoma cells in a time-dependent way and exerts strong anti-proliferative and pro-apoptotic effects independently from its extracellular anti-adhesive action. RGES control-peptide did not show biological effects, as expected; nevertheless it is internalized, although with slower kinetics. Survivin, a known cell-cycle and survival-regulator is highly expressed in melanoma cells. Co-immunoprecipitation assays in cell lysates and overlay assays with the purified proteins showed that RGDS interacts with survivin, as well as with procaspase-3, -8 and -9. RGDS-peptide binding to survivin was found to be specific, at high affinity (Kd 27.5 μM and located at the survivin C-terminus. RGDS-survivin interaction appeared to play a key role, since RGDS lost its anti-mitogenic effect in survivin-deprived cells with a specific siRNA. Conclusions RGDS inhibits melanoma growth with an adhesion-independent mechanism; it is internalized in melanoma cells and specifically interacts with survivin. The present data may indicate a novel role of RGDS-containing peptides physiologically released from the extracellular

  9. Guideline on the Management of Melanoma | Board | South African ...

    African Journals Online (AJOL)

    Validation. Melanoma management involves many medical specialties. Guidelines should therefore be developed through a multidisciplinary consensus. The Melanoma Advisory Board consists of a forum of dermatologists, oncologists, plastic surgeons and pathologists. Guideline sponsor. The meetings of the Melanoma ...

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

    DEFF Research Database (Denmark)

    Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian

    2016-01-01

    Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral...... cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma...... is the treatment of choice. The prognosis is poor, with the 5-year survival rate ranging from 0% (gastric melanoma) to 80% (conjunctival melanoma)....

  11. Risk factors for second primary melanoma among Dutch patients with melanoma

    NARCIS (Netherlands)

    Schuurman, M.S.; Waal, A.C. de; Thijs, E.J.M.; Rossum, M.M. van; Kiemeney, L.A.L.M.; Aben, K.K.H.

    2017-01-01

    BACKGROUND: Patients with melanoma are at increased risk of developing subsequent primary melanomas. Knowledge about risk factors for these subsequent primaries is scarce. More evidence may help clinicians in tailoring surveillance schedules by selecting patients who could benefit from intensified

  12. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metalloproteinase (MMP) expression and invasion in A2058 melanoma cells

    International Nuclear Information System (INIS)

    Villano, C.M.; Murphy, K.A.; Akintobi, A.; White, L.A.

    2006-01-01

    There has been a 34% increase in melanoma related mortality in the United States from 1973 to 1992. Although few successful treatments for malignant melanoma exist, it is known that genetic susceptibility and environmental factors contribute to the initiation and progression of melanoma. Excessive UV exposure is considered the main etiological factor in melanoma initiation, however, epidemiological and experimental evidence suggests that exposure to environmental carcinogens contribute to melanoma. We propose that exposure to environmental chemicals that activate the aryl hydrocarbon receptor pathway contribute to melanoma progression, specifically through stimulation of the expression and activity of the matrix metalloproteinases (MMPs). Therefore, we investigated the effect of AhR activation on normal human melanocytes and several melanoma cell lines. The data presented here demonstrate that normal melanocytes and melanoma cells express the AhR and Arnt and are responsive to activation by TCDD. Furthermore, activation of this pathway in transformed melanoma cells (A2058) results in increased expression and activity of MMP-1, MMP-2 and MMP-9, as well as increased invasion using in vitro invasion assays. Furthermore, TCDD-induced expression of the MMP-1 promoter in melanoma cells appears to require different elements than those required in untransformed cells, indicating that this pathway may have multiple mechanisms for activation of MMP expression

  13. Cystatin E/M suppresses legumain activity and invasion of human melanoma

    Directory of Open Access Journals (Sweden)

    Fodstad Øystein

    2010-01-01

    assay. Conclusions These results suggest that the level of cystatin E/M regulates legumain activity and hence the invasive potential of human melanoma cells.

  14. Choroidal malignant melanoma with no extraocular extension presenting as orbital cellulitis.

    Science.gov (United States)

    Nalcaci, Serhad; Palamar, Melis; Yaman, Banu; Akalin, Taner; Mentes, Jale

    2016-10-01

    This report describes a patient with choroidal malignant melanoma presenting as orbital cellulitis without extraocular tumor extension. It is an interventional case report with histopathologic correlation. A 68-year-old male presented with a 3-day history of painful hyperemia and swelling in the right eye. The examination showed edematous eyelids, mechanical ptosis and chemosis with conjunctival injection. B-scan ultrasonography showed a mass with medium level echogenicity that filled the vitreous cavity. Magnetic resonance imaging showed a solid choroidal mass with hemorrhagic and inflammatory changes with no obvious extraocular extension. Due to these suggestive findings of choroidal melanoma the right eye was enucleated. A spindle cell choroidal melanoma including intense pigmentation and necrosis was confirmed by histopathological examination. Although rare; choroidal melanoma may present as orbital cellulitis, particularly when the tumor is necrotic.

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

    Science.gov (United States)

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

    2016-08-01

    Cancer is a public health problem and the second leading cause of death worldwide. The incidence of cutaneous melanoma has been notably increasing, resulting in high aggressiveness and poor survival rates. Taking into account the antitumor activity of biflorin, a substance isolated from Capraria biflora L. roots that is cytotoxic in vitro and in vivo, this study aimed to demonstrate the action of biflorin against three established human melanoma cell lines that recapitulate the molecular landscape of the disease in terms of genetic alterations and mutations, such as the TP53, NRAS and BRAF genes. The results presented here indicate that biflorin reduces the viability of melanoma cell lines by DNA interactions. Biflorin causes single and double DNA strand breaks, consequently inhibiting cell cycle progression, replication and DNA repair and promoting apoptosis. Our data suggest that biflorin could be considered as a future therapeutic option for managing melanoma. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. [Regression in primary cutaneous melanoma is not predictive for sentinel lymph node micrometastasis].

    Science.gov (United States)

    Alquier-Bouffard, A; Franck, F; Joubert-Zakeyh, J; Barthélémy, I; Mansard, S; Ughetto, S; Aublet-Cuvelier, B; Déchelotte, P-J; Mondié, J-M; Souteyrand, P; D'incan, M

    2007-01-01

    The predictive value of regression in melanoma is debated. A retrospective single-centre study to evaluate the correlation between regression in primary skin tumor and the presence of micrometastases in sentinel lymph nodes. Histological signs of regression in 84 melanomas (>1 mm) with corresponding sentinel lymph nodes were studied by two independent pathologists. Regression was seen in 40 skin melanoma tumors while micrometastasis was seen in 24. Of the tumors with micrometastasis, only 10 were regressive (RR: 0.47, p=0.49). Breslow value>2 mm and male sex were predictive for node micrometastasis (RR: 4.6, p=0.03 and RR: 7.6, p=0.006, respectively). On multivariate analysis, these two factors were independent. These data suggest that regression in primary cutaneous melanoma is not predictive for lymph node metastasis.

  17. Melanoma-Derived iPCCs Show Differential Tumorigenicity and Therapy Response

    Directory of Open Access Journals (Sweden)

    Mathias Bernhardt

    2017-05-01

    Full Text Available A point mutation in the BRAF gene, leading to a constitutively active form of the protein, is present in 45%–60% of patients and acts as a key driver in melanoma. Shortly after therapy induction, resistance to MAPK pathway-specific inhibitors develops, indicating that pathway inhibition is circumvented by epigenetic mechanisms. Here, we mimicked epigenetic modifications in melanoma cells by reprogramming them into metastable induced pluripotent cancer cells (iPCCs with the ability to terminally differentiate into non-tumorigenic lineages. iPCCs and their differentiated progeny were characterized by an increased resistance against targeted therapies, although the cells harbor the same oncogenic mutations and signaling activity as the parental melanoma cells. Furthermore, induction of a pluripotent state allowed the melanoma-derived cells to acquire a non-tumorigenic cell fate, further suggesting that tumorigenicity is influenced by the cell state.

  18. The "SWOT" of BRAF inhibition in melanoma: RAF inhibitors, MEK inhibitors or both?

    Science.gov (United States)

    Nissan, Moriah H; Solit, David B

    2011-12-01

    Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.

  19. Metastatic melanoma masquerading as a furuncle

    Directory of Open Access Journals (Sweden)

    Imran Aslam

    2017-10-01

    Full Text Available Melanoma metastasizes to the skin in about 10-17% of patients. Although there are reports of metastatic melanoma masquerading as panniculitis and erysipelas, it is very uncommon for it to present as an inflammatory skin lesion. When malignant melanoma cells invade the superficial dermal lymphatic vessels it can result in erythema, edema and induration of the overlying skin. This presentation can be problematic for clinicians if they do not suspect melanoma and choose not to biopsy the lesion. We report a case of an elderly man with a history of invasive melanoma who presented with a furuncle-like lesion that was found to be in-transit metastatic melanoma.

  20. Molecular insights into melanoma brain metastases.

    Science.gov (United States)

    Westphal, Dana; Glitza Oliva, Isabella C; Niessner, Heike

    2017-06-01

    Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society. © 2017 American Cancer Society.

  1. Pulse-mediated chemotherapy enhances local control and survival in a spontaneous canine model of primary mucosal melanoma.

    Science.gov (United States)

    Spugnini, Enrico P; Dragonetti, Emanuele; Vincenzi, Bruno; Onori, Nicoletta; Citro, Gennaro; Baldi, Alfonso

    2006-02-01

    Mucosal melanomas account for 1% of all malignant melanomas in humans. Treatment options include surgery, chemotherapy, immunotherapy and radiation therapy; however, local recurrence and distant dissemination are still frequent. We treated locally aggressive spontaneous canine oral melanomas that, because of their advanced stage, were not treatable with conventional strategies. A cohort of 10 dogs with oral melanoma was enrolled over a 4-year period. The dogs received two sessions of local bleomycin, followed by the application of trains of biphasic pulses. The treatment was well tolerated and resulted in an overall response rate of 80% with 50% long-term control. Of interest, only one of the dogs died of metastatic disease, and four of the long-term survivors showed a vitiligo-like discoloration at the site of treatment, potentially suggesting a recruitment of the immune system by the therapy. Further studies are needed to characterize this approach and to determine its suitability for head and neck mucosal melanoma.

  2. Melanoma-specific marker expression in skin biopsy tissues as a tool to facilitate melanoma diagnosis.

    Science.gov (United States)

    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.

  3. Melanoma mortality following skin cancer screening in Germany.

    Science.gov (United States)

    Boniol, Mathieu; Autier, Philippe; Gandini, Sara

    2015-09-15

    In 2003, a skin cancer screening campaign based on total body skin examination was launched in the federal state of Schleswig-Holstein, Germany. 20% of adults aged 20 and over were screened. In 2008, a 48% decline in melanoma mortality was reported. In the same year, skin screening was extended to the rest of Germany. We evaluated whether melanoma mortality trends decreased in Germany as compared with surrounding countries where skin screening is uncommon. We also evaluated whether the initial decreasing mortality trend observed in Schleswig-Holstein was maintained with a longer follow-up. Regional and national melanoma mortality data from 1995 to 2013 were extracted from the GEKID database and the Federal Statistical Office. Mortality data for Germany and surrounding countries from 1980 to 2012 were extracted from the WHO mortality database. Age-adjusted (European Standard Population) mortality rates were computed and joinpoint analysis performed for Schleswig-Holstein, Germany and surrounding countries. In Schleswig-Holstein, melanoma mortality rates declined by 48% from 2003 to 2008, and from 2009 to 2013 returned to levels observed before screening initiation. During the 5 years of the national programme (2008-2012), melanoma mortality rates increased by 2.6% (95% CI -0.1 to 5.2) in men and 0.02% (95% CI -1.8 to 1.8) in women. No inflexion point in trends was identified after 2008 that could have suggested a decreasing melanoma mortality. Trends of cutaneous melanoma mortality in Germany from 1980 to 2012 did not differ from those observed in surrounding countries. The transient decrease mortality in Schleswig-Holstein followed by return to pre-screening levels could reflect a temporal modification in the reporting of death causes. An in-depth evaluation of the screening programme is required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  4. Embryonic vasculogenesis in nodular melanomas and tumour differentiation.

    Science.gov (United States)

    Iyengar, Bhanu; Singh, Avantika V

    2011-09-01

    The relationship of vasculogenic mimicry to pigment in nodular vertical growth phase [VGP] cutaneous melanomas is assessed in this study. 10 nodules each from 27 tumors, 15 pigmented and 12 amelanotic were sampled in proportion to the pigment level. Serial frozen and paraffin sections subjected to HE, Reticulin, PAS to assess the vascular pattern; Dopa Oxidase and Immunopositivity for HMB45, LN5 [laminin 5] & integrin[α(5)β(1)], and EM [electron microscopy] to identify Weibel-Palade bodies within endothelial cells. The vascular pattern, pigment and the immunopositivity was mapped to assess the percentage VM [vasculogenic sinusoids] vs INC [incorporated microvasculature]. In pigmented melanomas, INC from pre-existing stromal vessels is predominant. Amelanotic melanomas show embryonic vasculogenic mimicry, a self-propagating system of spaces within the sheets of tumors cells. Both INC and VM co-exist in tumors with both amelanotic and melanotic nodules. In areas with VM, loci of LN5 and α(5)β(1) integrin positive cells appear within the proliferating columns, positivity in these cells suggesting a switch to a more aggressive form. Irregular spaces appear lined by tumor cells, with initial hemopoeitic activity, coalesce and interlink into tubular networks. Spaces lined by tumor cells extend into an intricate network which then connects with the angiogenetic system. The tumor cells lining the vasculogenic spaces are positive for LN5, α(5)β(1) integrin. Statistically, INC is significantly higher in pigmented melanomas, whereas amelanotic melanomas show significantly higher VM. Pigmentation is correlated positively with INC and negatively with VM. INC and VM are negatively correlated with each other.

  5. Primary Tumor Thickness is a Prognostic Factor in Stage IV Melanoma: A Retrospective Study of Primary Tumor Characteristics.

    Science.gov (United States)

    Luen, Stephen; Wong, Siew Wei; Mar, Victoria; Kelly, John W; McLean, Catriona; McArthur, Grant A; Haydon, Andrew

    2018-01-01

    Stage IV melanoma exhibits a diverse range of tumor biology from indolent to aggressive disease. Many important prognostic factors have already been identified. Despite this, the behavior of metastatic melanoma remains difficult to predict. We sought to determine if any primary tumor characteristics affect survival following the diagnosis of stage IV melanoma. All patients diagnosed with stage IV melanoma between January 2003 and December 2012 were identified from the Victorian Melanoma Service database. Retrospective chart review was performed to collect data on primary tumor characteristics (thickness, ulceration, mitotic rate, melanoma subtype, or occult primary). Known and suspected prognostic factors were additionally collected (time to diagnosis of stage IV disease, age, sex, stage, receipt of chemotherapy, and era of recurrence). The effect of primary tumor characteristics on overall survival from the date of diagnosis of stage IV disease was assessed. A total of 227 patients with a median follow-up of 5 years from diagnosis of stage IV disease were identified. Median overall survival of the cohort was 250 days.Of the primary tumor characteristics assessed, only tumor thickness affected survival from diagnosis of stage IV disease, hazard ratio=1.09 (1.02 to 1.16), P=0.008. This remained significant in multivariate analysis, P=0.007. Other primary tumor characteristics did not significantly influence survival. Primary tumor thickness is a significant prognostic factor in stage IV melanoma. Our data suggest that the biology of the primary melanoma may persist to influence the behavior of metastatic disease.

  6. Activation of the Canonical Wnt/β-Catenin Signalling Pathway is Rare in Canine Malignant Melanoma Tissue and Cell Lines

    Science.gov (United States)

    Chon, E.; Thompson, V.; Schmid, S.; Stein, T. J.

    2012-01-01

    Summary Canine malignant melanoma is a highly aggressive tumour associated with a poor overall survival rate due to both local disease recurrence and its highly metastatic nature. Similar to advanced melanoma in man, canine oral melanoma is poorly responsive to conventional anti-cancer therapies. The lack of sustainable disease control warrants investigation of novel therapies, preferably targeting features specific to the tumour and different from normal cells. The Wnt signalling pathway is known to contribute to melanocytic lineage development in vertebrates and perturbation of the Wnt/β-catenin pathway has been implicated in numerous cancer types. Alterations of the Wnt/β-catenin pathway are suggested to occur in a subset of human melanomas, although the precise role of the Wnt/β-catenin pathway in melanoma is yet to be defined. This study investigates the activation status of the canonical Wnt/β-catenin pathway in canine malignant melanoma and its potential as a therapeutic target for treating this disease. The data indicate canonical Wnt/β-catenin pathway activation is a rare event in canine oral malignant melanoma tissue and canine malignant melanoma cell lines. PMID:22901430

  7. Melanoma of unknown origin: a case series.

    LENUS (Irish Health Repository)

    Kelly, J

    2010-12-01

    The natural history of metastatic melanoma involving lymph nodes, in the absence of a known primary site (cutaneous, ocular or mucosal) has, to date, been poorly defined; and the optimal management of this rare subtype of disease is therefore unclear. Melanomas of unknown primary site (MUP) are estimated to comprise between 3.7 and 6% of all melanomas (Anbari et al. in Cancer 79:1861-1821, 1997).

  8. Melanoma epidemiology, prognosis and trends in Latvia.

    Science.gov (United States)

    Azarjana, K; Ozola, A; Ruklisa, D; Cema, I; Rivosh, A; Azaryan, A; Pjanova, D

    2013-11-01

    Melanoma incidence and mortality rates are increasing worldwide within the white population. Clinical and histological factors have been usually used for the prognosis and assessment of the risk for melanoma. The aim of the study was to describe the clinical and histopathological features of the cutaneous melanoma (CM) in the Latvian population, to test the association between melanoma features and patient survival, and to assess the time trends for melanoma incidence. We undertook a descriptive, retrospective analysis of archive data of 984 melanoma patients treated at the largest oncological hospital of Latvia, Riga East University Hospital Latvian Oncology Centre (LOC), between 1998 and 2008. Cox proportional hazards model was used to analyse patient survival and autoregressive models were applied to detect trends in melanoma incidence over time for various categories of melanoma. The study showed a significant ascending trend in melanoma incidence in Latvia during the time period from 1998 to 2008 (ß = 1.83, 95% CI = 1.15-2.91, P = 0.011). Nodular melanoma was the most common tumour subtype with a frequency of 39.2%. Ulceration was present in 45.2% of melanomas. The mean Breslow thickness was 6.0 mm (6.8 mm) and no significant decline in median Breslow thickness was observed during the study period (P = 0.609). A better overall prognosis was detected for females in comparison with males (HR = 1.49; 95% CI = 1.22-1.81; P Latvia with the majority of melanomas diagnosed at late stages with poor prognosis for survival. © 2012 The Authors Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

  9. Giant hanging melanoma of the eyelid skin

    Directory of Open Access Journals (Sweden)

    Pai Radha

    2008-01-01

    Full Text Available Cutaneous melanoma of the eyelid is a rare entity. We present a 53-year-old male who had a nevus on the left upper eyelid skin since childhood, which transformed into a huge ulcerated hanging mass in the same region. Excision of the mass was done and histopathology confirmed the diagnosis of nodular malignant melanoma. A small preauricular lymph node showed metastatic melanoma on fine needle aspiration cytology.

  10. RAGE-aptamer Attenuates the Growth and Liver Metastasis of Malignant Melanoma in Nude Mice.

    Science.gov (United States)

    Nakamura, Nobutaka; Matsui, Takanori; Ishibashi, Yuji; Sotokawauchi, Ami; Fukami, Kei; Higashimoto, Yuichiro; Yamagishi, Sho-Ichi

    2017-11-06

    Epidemiological studies have suggested the link between cumulative diabetic exposure and cancer. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) may contribute to the phenomenon. We examined here the effects of DNA aptamer raised against RAGE (RAGE-aptamer) on growth and liver metastasis of G361 melanoma in nude mice. Malignant melanoma cells were intradermally injected into the upper flank region of nude mice, which received continuous administration of RAGE-aptamer (38.4 pmol/day/g body weight) or vehicle intraperitoneally by an osmotic pump up to 42 days. RAGE-aptamer significantly reduced levels of 8-hydroxy-2'-deoxy-guanosine, AGEs, RAGE, proliferating nuclear antigen, cyclin D1, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and CD31 and Mac-3, respective markers of endothelial cells and macrophages in tumors of nude mice and suppressed the proliferation and liver metastasis of malignant melanoma. Furthermore, RAGE-aptamer attenuated the AGE-induced oxidative stress generation, proliferation, and VEGF and MCP-1 gene expression in both G361 melanoma cells and endothelial cells. The present findings suggest that RAGE-aptamer could attenuate melanoma growth and liver metastasis in nude mice by suppressing the tumor angiogenesis and macrophage infiltration via inhibition of the AGE-RAGE system. RAGE-aptamer may be a novel therapeutic tool for the treatment of malignant melanoma.

  11. Lacunarity analysis: a promising method for the automated assessment of melanocytic naevi and melanoma.

    Directory of Open Access Journals (Sweden)

    Stephen Gilmore

    Full Text Available The early diagnosis of melanoma is critical to achieving reduced mortality and increased survival. Although clinical examination is currently the method of choice for melanocytic lesion assessment, there is a growing interest among clinicians regarding the potential diagnostic utility of computerised image analysis. Recognising that there exist significant shortcomings in currently available algorithms, we are motivated to investigate the utility of lacunarity, a simple statistical measure previously used in geology and other fields for the analysis of fractal and multi-scaled images, in the automated assessment of melanocytic naevi and melanoma. Digitised dermoscopic images of 111 benign melanocytic naevi, 99 dysplastic naevi and 102 melanomas were obtained over the period 2003 to 2008, and subject to lacunarity analysis. We found the lacunarity algorithm could accurately distinguish melanoma from benign melanocytic naevi or non-melanoma without introducing many of the limitations associated with other previously reported diagnostic algorithms. Lacunarity analysis suggests an ordering of irregularity in melanocytic lesions, and we suggest the clinical application of this ordering may have utility in the naked-eye dermoscopic diagnosis of early melanoma.

  12. Lacunarity analysis: a promising method for the automated assessment of melanocytic naevi and melanoma.

    Science.gov (United States)

    Gilmore, Stephen; Hofmann-Wellenhof, Rainer; Muir, Jim; Soyer, H Peter

    2009-10-13

    The early diagnosis of melanoma is critical to achieving reduced mortality and increased survival. Although clinical examination is currently the method of choice for melanocytic lesion assessment, there is a growing interest among clinicians regarding the potential diagnostic utility of computerised image analysis. Recognising that there exist significant shortcomings in currently available algorithms, we are motivated to investigate the utility of lacunarity, a simple statistical measure previously used in geology and other fields for the analysis of fractal and multi-scaled images, in the automated assessment of melanocytic naevi and melanoma. Digitised dermoscopic images of 111 benign melanocytic naevi, 99 dysplastic naevi and 102 melanomas were obtained over the period 2003 to 2008, and subject to lacunarity analysis. We found the lacunarity algorithm could accurately distinguish melanoma from benign melanocytic naevi or non-melanoma without introducing many of the limitations associated with other previously reported diagnostic algorithms. Lacunarity analysis suggests an ordering of irregularity in melanocytic lesions, and we suggest the clinical application of this ordering may have utility in the naked-eye dermoscopic diagnosis of early melanoma.

  13. Human mitochondrial NAD(P)(+)-dependent malic enzyme participates in cutaneous melanoma progression and invasion.

    Science.gov (United States)

    Chang, Yung-Lung; Gao, Hong-Wei; Chiang, Chien-Ping; Wang, Wei-Ming; Huang, Shih-Ming; Ku, Chien-Fen; Liu, Guang-Yaw; Hung, Hui-Chih

    2015-03-01

    Cutaneous melanoma is the most life-threatening neoplasm of the skin, accounting for most of the skin cancer deaths. Accumulating evidence suggests that targeting metabolism is an appealing strategy for melanoma therapy. Mitochondrial NAD(P)(+)-dependent malic enzyme (ME2), an oxidative decarboxylase, was evaluated for its biological significance in cutaneous melanoma progression. ME2 mRNA and protein expression significantly increased during melanoma progression, as evidenced by Gene Expression Omnibus analysis and immunohistochemistry on clinically annotated tissue microarrays, respectively. In addition, ME2 knockdown attenuated melanoma cell proliferation in vitro. ME2 ablation resulted in reduced cellular ATP levels and elevated cellular reactive oxygen species production, which activated the AMP-activated protein kinase pathway and inhibited acetyl-CoA carboxylase. Furthermore, ME2 expression was associated with cell migration and invasion. ME2 knockdown decreased anchorage-independent growth in vitro and tumor cell growth in vivo. These results suggested that ME2 might be an important factor in melanoma progression and a novel biomarker of invasion.

  14. Timely Healthcare Checkup Catches Melanoma Early

    Science.gov (United States)

    ... Skin Cancer" Articles Skin Cancer Can Strike Anyone / Skin Cancer: Biology, Risk Factors & Treatment / Timely Healthcare Checkup Catches Melanoma Early / NIH Research to Results / Skin and Sun – ...

  15. Melanoma of the skin in the Danish Cancer Registry and the Danish Melanoma Database: A Validation Study.

    Science.gov (United States)

    Pedersen, Sidsel Arnspang; Schmidt, Sigrun Alba Johannesdottir; Klausen, Siri; Pottegård, Anton; Friis, Søren; Hölmich, Lisbet Rosenkrantz; Gaist, David

    2018-01-15

    The nationwide Danish Cancer Registry and the Danish Melanoma Database both record data on melanoma for purposes of monitoring, quality assurance and research. However, the data quality of the Cancer Registry and the Melanoma Database has not been formally evaluated. We estimated the positive predictive value (PPV) of melanoma diagnosis for random samples of 200 patients from the Cancer Registry (n=200) and the Melanoma Database (n=200) during 2004-2014, using the Danish Pathology Registry as 'gold-standard' reference. We further validated tumor characteristics in the Cancer Registry and the Melanoma Database. Additionally, we estimated the PPV of in situ melanoma diagnoses in the Melanoma Database, and the sensitivity of melanoma diagnoses in 2004-2014. The PPVs of melanoma in the Cancer Registry and the Melanoma Database were 97% (95% CI, 94-99) and 100%. The sensitivity was 90% in the Cancer Registry and 77% in the Melanoma Database. The PPV of in situ melanomas in the Melanoma Database was 97% and the sensitivity was 56%. In the Melanoma Database, we observed PPVs of ulceration of 75% and Breslow thickness of 96%. The PPV of histologic subtypes varied between 87%-100% in the Cancer Registry and 93%-100% in the Melanoma Database. The PPVs for anatomical localization were 83%-95.0% in the Cancer Registry and 93%-100% in the Melanoma Database. The data quality in both the Cancer Registry and the Melanoma Database are high, supporting their use in epidemiologic studies.

  16. UVB: suscetibilidade no melanoma maligno

    OpenAIRE

    Nasser,Nilton

    2010-01-01

    FUNDAMENTOS: Está bem definido que a radiação ultravioleta provoca depleção imunológica na pele, permitindo o desenvolvimento de tumores cutâneos malignos. A maioria dos pacientes de cânceres da pele não melanomas são considerados UVB-suscetíveis. OBJETIVOS: Estudar a UVB-suscetibilidade nos pacientes com melanoma maligno e se este é um fator de risco para o desenvolvimento desse câncer. MÉTODOS: Foram selecionados 88 voluntários divididos em dois grupos: grupo-controle saudável (n=61) e grup...

  17. [Acute dyspnea in malignant melanoma].

    Science.gov (United States)

    Franzen, A M; Günzel, T

    2011-09-01

    Metastases to the larynx are rare. The current article presents the case of a 75-year-old patient with a history of shortness of breath due to a supraglottic exophytic lesion that was identified as a metastasis of a cutaneous melanoma treated 2.5 years previously. As a result of our medline analysis we found approximately 30 cases of metastatic melanoma to the larynx published to date. Primary tumors are always cutaneous in origin and spread over the whole integument of trunk and extremities. The time interval between diagnosis of the primary and the laryngeal metastasis is often several years. In most reports a supraglottic exophytic, red coloured lesion is described. Diagnosis can only be proven by histological examination. Laryngeal metastasis is usually an indication of tumor dissemination and always has a fatal prognosis.

  18. Neutron capture therapy for melanoma

    International Nuclear Information System (INIS)

    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

  19. BRAF mutations in conjunctival melanoma

    DEFF Research Database (Denmark)

    Larsen, Ann-Cathrine; Dahl, Christina; Dahmcke, Christina M.

    2016-01-01

    with atypia. BRAF mutations were identified in 39 of 111 (35%) cases. The rate ratio of BRAF-mutated versus BRAF-wild-type melanoma did not change over time. BRAF mutations were associated with T1 stage (p = 0.007), young age (p = 0.001), male gender (p = 0.02), sun-exposed location (p = 0.01), mixed....../non-pigmented tumour colour (p = 0.02) and nevus origin (p = 0.005), but did not associate with prognosis. BRAF status in conjunctival melanoma and paired premalignant lesions corresponded in 19 of 20 cases. Immunohistochemistry detected BRAF V600E mutations with a sensitivity of 0.94 and a specificity of 1...

  20. Neutron capture therapy for melanoma

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. Giant nodular posterior scleritis simulating choroidal melanoma

    Directory of Open Access Journals (Sweden)

    Shukla Dhananjay

    2006-01-01

    Full Text Available A 45-year-old woman, complaining of sudden visual loss in the right eye (best-corrected visual acuity: 17/200, was suspected of having a malignant melanoma of the choroid. Fundus examination revealed a massive pale-colored subretinal mass temporal to the fovea, with adjoining choroidal folds and exudative retinal detachment. Ultrasonography was suggestive of posterior scleritis. Systemic evaluation was unremarkable. The patient was treated with high-dose systemic corticosteroids. The mass lesion resolved completely, with visual recovery to 20/20. Posterior scleritis should be suspected when evaluating subretinal mass-lesions, even when large and without overt inflammation. Early treatment may improve the visual prognosis and avoid misdirected management, including enucleation.

  2. Thigmotropism of Malignant Melanoma Cells

    OpenAIRE

    Quatresooz, Pascale; Pi?rard-Franchimont, Claudine; No?l, Fanchon; Pi?rard, G?rald E.

    2011-01-01

    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)....

  3. Dermoscopic evaluation of nodular melanoma.

    Science.gov (United States)

    Menzies, Scott W; Moloney, Fergal J; Byth, Karen; Avramidis, Michelle; Argenziano, Giuseppe; Zalaudek, Iris; Braun, Ralph P; Malvehy, Josep; Puig, Susana; Rabinovitz, Harold S; Oliviero, Margaret; Cabo, Horacio; Bono, Riccardo; Pizzichetta, Maria A; Claeson, Magdalena; Gaffney, Daniel C; Soyer, H Peter; Stanganelli, Ignazio; Scolyer, Richard A; Guitera, Pascale; Kelly, John; McCurdy, Olivia; Llambrich, Alex; Marghoob, Ashfaq A; Zaballos, Pedro; Kirchesch, Herbert M; Piccolo, Domenico; Bowling, Jonathan; Thomas, Luc; Terstappen, Karin; Tanaka, Masaru; Pellacani, Giovanni; Pagnanelli, Gianluca; Ghigliotti, Giovanni; Ortega, Blanca Carlos; Crafter, Greg; Ortiz, Ana María Perusquía; Tromme, Isabelle; Karaarslan, Isil Kilinc; Ozdemir, Fezal; Tam, Anthony; Landi, Christian; Norton, Peter; Kaçar, Nida; Rudnicka, Lidia; Slowinska, Monika; Simionescu, Olga; Di Stefani, Alessandro; Coates, Elliot; Kreusch, Juergen

    2013-06-01

    Nodular melanoma (NM) is a rapidly progressing potentially lethal skin tumor for which early diagnosis is critical. To determine the dermoscopy features of NM. Eighty-three cases of NM, 134 of invasive non-NM, 115 of nodular benign melanocytic tumors, and 135 of nodular nonmelanocytic tumors were scored for dermoscopy features using modified and previously described methods. Lesions were separated into amelanotic/hypomelanotic or pigmented to assess outcomes. Predominantly hospital-based clinics from 5 continents. Sensitivity, specificity, and odds ratios for features/models for the diagnosis of melanoma. Nodular melanoma occurred more frequently as amelanotic/hypomelanotic (37.3%) than did invasive non-NM (7.5%). Pigmented NM had a more frequent (compared with invasive non-NM; in descending order of odds ratio) symmetrical pigmentation pattern (5.8% vs 0.8%), large-diameter vessels, areas of homogeneous blue pigmentation, symmetrical shape, predominant peripheral vessels, blue-white veil, pink color, black color, and milky red/pink areas. Pigmented NM less frequently displayed an atypical broadened network, pigment network or pseudonetwork, multiple blue-gray dots, scarlike depigmentation, irregularly distributed and sized brown dots and globules, tan color, irregularly shaped depigmentation, and irregularly distributed and sized dots and globules of any color. The most important positive correlating features of pigmented NM vs nodular nonmelanoma were peripheral black dots/globules, multiple brown dots, irregular black dots/globules, blue-white veil, homogeneous blue pigmentation, 5 to 6 colors, and black color. A model to classify a lesion as melanocytic gave a high sensitivity (>98.0%) for both nodular pigmented and nonnodular pigmented melanoma but a lower sensitivity for amelanotic/hypomelanotic NM (84%). A method for diagnosing amelanotic/hypomelanotic malignant lesions (including basal cell carcinoma) gave a 93% sensitivity and 70% specificity for NM. When

  4. Dermoscopy of eccrine acrospiroma masquerading as nodular malignant melanoma.

    Science.gov (United States)

    Gatti, A; di Meo, N; Trevisan, G

    2010-12-01

    Eccrine acrospiroma, better known as eccrine poroma, is a benign adnexal neoplasm of the skin. Its clinical aspect can masquerade as some other nodular and cystic lesions. The current dermoscopy literature offers very few case studies. Moreover, these very few examples present a totally different appearance pattern compared to the one we examined. Its homogeneous blue pattern suggested the better-known nodular malignant melanoma; in fact, this dermoscopic appearance was due to the Tyndall effect.

  5. Termoterapia transpupilar em melanoma maligno da coróide Transpupillary thermotherapy for malignant choroidal melanoma

    Directory of Open Access Journals (Sweden)

    Martha M. Motomo Chojniak

    2001-04-01

    diameter was 1.4 mm. The visual acuity remained unaffected in 5 cases and worsened after treatment in 6 cases. Nine patients presented compli- cations. A major complication occurred in a single patient who presented retinal detachment. Minor compli-cations were observed as follows: small retinal hemorrhages (7 patients, vitreous inflammation associated with tenuous vitreous membranes (1 patient and conjunctiva and eyelid edema (1 patient. Local tumor control and conservation of the eyeball was accomplished in all the patients; they are all alive without evidence of metastatic disease in this initial follow-up period. Conclusion: This preliminary study suggests that the transpupillary thermotherapy is a promi-sing, effective and safe method for treatment of selected small choroidal melanomas. Further studies with longer follow-up period are necessary to better evaluate this treatment.

  6. UVB: suscetibilidade no melanoma maligno UVB: susceptibility in malignant melanoma

    Directory of Open Access Journals (Sweden)

    Nilton Nasser

    2010-12-01

    Full Text Available FUNDAMENTOS: Está bem definido que a radiação ultravioleta provoca depleção imunológica na pele, permitindo o desenvolvimento de tumores cutâneos malignos. A maioria dos pacientes de cânceres da pele não melanomas são considerados UVB-suscetíveis. OBJETIVOS: Estudar a UVB-suscetibilidade nos pacientes com melanoma maligno e se este é um fator de risco para o desenvolvimento desse câncer. MÉTODOS: Foram selecionados 88 voluntários divididos em dois grupos: grupo-controle saudável (n=61 e grupo de portadores de melanoma (n=27, todos identificados de acordo com os critérios: tipo histológico, nível de invasão, fotótipos de pele, sexo e idade. A suscetibilidade à radiação ultravioleta B (UVB foi medida pela reação de hipersensibilidade ao contato com o difenciprone nos voluntários sensibilizados em áreas previamente irradiadas. RESULTADOS: A suscetibilidade à radiação UVB foi de 81,5% nos pacientes com melanoma maligno e de 31,2% no grupo-controle. O risco de um indivíduo desenvolver o melanoma maligno foi 9,7 vezes maior do que nos indivíduos UVB-resistentes. CONCLUSÕES: A UVB-suscetibilidade pode ser considerada um fator de risco importante para o desenvolvimento do melanoma maligno.BACKGROUND: It is well established that UV radiation provokes an immunological depletion in the skin, enabling the development of malignant cutaneous tumors. Most nonmelanoma skin cancer patients are considered to be UVB-susceptible. OBJECTIVE: To study the behavior of UVB- susceptibility in malignant melanoma (MM patients and whether this is a risk factor to the development of MM. METHODS: Eighty-eight volunteers were selected and divided into two groups: healthy control group (n = 61 and MM group (n = 27, which were identified according to the following clinical criteria: histopathological type, level of invasion, skin phototype, sex and age. Susceptibility to ultraviolet B (UVB radiation was measured by the onset of a contact

  7. Spontaneous Splenic Rupture in Melanoma

    Directory of Open Access Journals (Sweden)

    Hadi Mirfazaelian

    2014-01-01

    Full Text Available Spontaneous rupture of spleen due to malignant melanoma is a rare situation, with only a few case reports in the literature. This study reports a previously healthy, 30-year-old man who came with chief complaint of acute abdominal pain to emergency room. On physical examination, abdominal tenderness and guarding were detected to be coincident with hypotension. Ultrasonography revealed mild splenomegaly with moderate free fluid in abdominopelvic cavity. Considering acute abdominal pain and hemodynamic instability, he underwent splenectomy with splenic rupture as the source of bleeding. Histologic examination showed diffuse infiltration by tumor. Immunohistochemical study (positive for S100, HMB45, and vimentin and negative for CK, CD10, CK20, CK7, CD30, LCA, EMA, and chromogranin confirmed metastatic malignant melanoma. On further questioning, there was a past history of a nasal dark skin lesion which was removed two years ago with no pathologic examination. Spontaneous (nontraumatic rupture of spleen is an uncommon situation and it happens very rarely due to neoplastic metastasis. Metastasis of malignant melanoma is one of the rare causes of the spontaneous rupture of spleen.

  8. Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: A systematic review

    Directory of Open Access Journals (Sweden)

    Rodolfo Chicas-Sett

    2018-02-01

    Conclusion: Early clinical outcomes reports suggest that the combination of ipilimumab and RT may improve survival in metastatic melanoma patients. The abscopal responses become a clinically relevant effect of such combination and should be studied in controlled randomized trials.

  9. Do melanoma patients with melanoma of unknown primary have better survival than patients with melanoma of known primary?

    DEFF Research Database (Denmark)

    Rødgaard, Jes Christian; Kjerkegaard, Ulrik; Sørensen, Jens Ahm

    2018-01-01

    Background: Several studies have compared the survival rate of melanoma of unknown primary (MUP) patients with patients with a known primary melanoma (MKP). Some studies found improved survival in MUP patients, whereas others found similar or poorer outcomes. The aim of this study was to evaluate...

  10. Is the prognosis and course of acral melanoma related to site-specific clinicopathological features?

    NARCIS (Netherlands)

    Paolino, G.; Bekkenk, M. W.; Didona, D.; Eibenschutz, L.; Richetta, A. G.; Cantisani, C.; Viti, G.; Carbone, A.; Buccini, P.; de Simone, P.; Ferrari, A.; Scali, E.; Calvieri, S.; Silipo, V.; Cigna, E.; Viti, G. P.; Bottoni, U.

    2016-01-01

    Acral melanoma is an uncommon type of melanoma in Caucasian patients. However, acral melanoma is the most common type of melanoma in African and Asian patients. Comparison analyses between hand-acral melanoma and foot-acral melanoma have been rarely reported in the literature. Acral melanoma is an

  11. CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies.

    Science.gov (United States)

    Helgadottir, Hildur; Höiom, Veronica; Tuominen, Rainer; Jönsson, Göran; Månsson-Brahme, Eva; Olsson, Håkan; Hansson, Johan

    2015-11-01

    Germline CDKN2A mutations are found in 5-20% of melanoma families. Numerous studies have shown that carriers of CDKN2A mutations have increased risks of non-melanoma cancers, but so far there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. In this prospective cohort study, index melanoma cases (n = 224) and their first-degree relatives (n = 944) were identified from 154 confirmed CDKN2A wt melanoma families. Cancer diagnoses in family members and matched controls were obtained from the Swedish Cancer Registry. Relative risks (RR), odds ratios (OR) and two-sided 95% confidence intervals (95% CI) were calculated. In index cases and first-degree relatives, the prospective RR for melanoma was 56.9 (95% CI 31.4-102.1) and 7.0 (95% CI 4.2-11.4), respectively, and for squamous cell skin cancers 9.1 (95% CI 6.0-13.7) and 3.4 (95% CI 2.2-5.2), respectively. In neither group, elevated risks were seen for non-skin cancers. In a subgroup analysis, CDKN2A wt melanoma families with young (melanoma cases were found to have increased risk of non-skin cancers (RR 1.5, 95% CI 1.0-1.5). Further, MC1R gene variants were increased in familial melanoma cases compared to controls (OR 2.4, 95% CI 1.6-3.4). Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low-risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high-risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases. This study further supports an implication of CDKN2A mutation screening as a clinical test that determines counseling and follows up routines of melanoma families. © 2015 UICC.

  12. The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis.

    Science.gov (United States)

    Vogelsang, Matjaz; Martinez, Carlos N; Rendleman, Justin; Bapodra, Anuj; Malecek, Karolina; Romanchuk, Artur; Kazlow, Esther; Shapiro, Richard L; Berman, Russell S; Krogsgaard, Michelle; Osman, Iman; Kirchhoff, Tomas

    2016-07-01

    The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5). Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. ©2016 AACR. ©2016 American Association for Cancer Research.

  13. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.

    Science.gov (United States)

    Aoude, Lauren G; Pritchard, Antonia L; Robles-Espinoza, Carla Daniela; Wadt, Karin; Harland, Mark; Choi, Jiyeon; Gartside, Michael; Quesada, Víctor; Johansson, Peter; Palmer, Jane M; Ramsay, Andrew J; Zhang, Xijun; Jones, Kristine; Symmons, Judith; Holland, Elizabeth A; Schmid, Helen; Bonazzi, Vanessa; Woods, Susan; Dutton-Regester, Ken; Stark, Mitchell S; Snowden, Helen; van Doorn, Remco; Montgomery, Grant W; Martin, Nicholas G; Keane, Thomas M; López-Otín, Carlos; Gerdes, Anne-Marie; Olsson, Håkan; Ingvar, Christian; Borg, Ake; Gruis, Nelleke A; Trent, Jeffrey M; Jönsson, Göran; Bishop, D Timothy; Mann, Graham J; Newton-Bishop, Julia A; Brown, Kevin M; Adams, David J; Hayward, Nicholas K

    2015-02-01

    The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Genetic variations of patients with familial or multiple melanoma in Southern Brazil.

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    Grazziotin, T C; Rey, M C W; Bica, C G; Pinto, L A; Bonamigo, R R; Puig-Butille, J A; Cuellar, F; Puig, S

    2013-02-01

    Patients with familial melanoma or multiple primary melanoma represent a high-risk population to hereditary melanoma. Mutations in susceptibility genes, such as CDKN2A, CDK4 and MC1R, have been associated with the development of melanoma. The purpose of this study was to determine the genotypic background of patients with familial and/or multiple melanoma in southern Brazil. This study analysed 33 cases (5 patients with multiple primary melanoma and 28 patients from families with at least two well documented cases) and 29 controls. Genomic analysis of CDKN2A and CDK4 genes by PCR-SSCP analysis and sequencing and direct sequencing of MC1R were performed in all individuals. No functional mutations in CDKN2A or CDK4 were detected in the 62 individuals. Infrequent variants in polymorphic loci of CDKN2A gene were identified in 15 participants (24.2%) and 24/33 (72.8%) cases and 19/27 (70.4%) controls reported at least one infrequent variant in MC1R (P = 0.372). Furthermore, a non-significant tendency towards an association between melanoma risk and MC1R variants G274A and C451T and a non-significant linear tendency to the number of infrequent high-risk variants in MC1R were observed. These results suggest that in southern Brazilian population, CDKN2A or CDK4 germinal alterations may have a weaker influence than previously thought and environmental risk factors may play a central role in melanoma susceptibility. However, considering the tendency observed for gene MC1R, low-penetrance genes may be a relevant aetiological factor in southern Brazil with fair skin population and high sunlight exposure. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

  15. Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition.

    Science.gov (United States)

    Caini, Saverio; Masala, Giovanna; Saieva, Calogero; Kvaskoff, Marina; Savoye, Isabelle; Sacerdote, Carlotta; Hemmingsson, Oskar; Hammer Bech, Bodil; Overvad, Kim; Tjønneland, Anne; Petersen, Kristina E N; Mancini, Francesca Romana; Boutron-Ruault, Marie-Christine; Cervenka, Iris; Kaaks, Rudolf; Kühn, Tilman; Boeing, Heiner; Floegel, Anna; Trichopoulou, Antonia; Valanou, Elisavet; Kritikou, Maria; Tagliabue, Giovanna; Panico, Salvatore; Tumino, Rosario; Bueno-de-Mesquita, H B As; Peeters, Petra H; Veierød, Marit B; Ghiasvand, Reza; Lukic, Marko; Quirós, José Ramón; Chirlaque, Maria-Dolores; Ardanaz, Eva; Salamanca Fernández, Elena; Larrañaga, Nerea; Zamora-Ros, Raul; Maria Nilsson, Lena; Ljuslinder, Ingrid; Jirström, Karin; Sonestedt, Emily; Key, Timothy J; Wareham, Nick; Khaw, Kay-Tee; Gunter, Marc; Huybrechts, Inge; Murphy, Neil; Tsilidis, Konstantinos K; Weiderpass, Elisabete; Palli, Domenico

    2017-05-15

    In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma. © 2017 UICC.

  16. MicroRNA-193b represses cell proliferation and regulates cyclin D1 in melanoma.

    Science.gov (United States)

    Chen, Jiamin; Feilotter, Harriet E; Paré, Geneviève C; Zhang, Xiao; Pemberton, Joshua G W; Garady, Cherif; Lai, Dulcie; Yang, Xiaolong; Tron, Victor A

    2010-05-01

    Cutaneous melanoma is an aggressive form of human skin cancer characterized by high metastatic potential and poor prognosis. To better understand the role of microRNAs (miRNAs) in melanoma, the expression of 470 miRNAs was profiled in tissue samples from benign nevi and metastatic melanomas. We identified 31 miRNAs that were differentially expressed (13 up-regulated and 18 down-regulated) in metastatic melanomas relative to benign nevi. Notably, miR-193b was significantly down-regulated in the melanoma tissues examined. To understand the role of miR-193b in melanoma, functional studies were undertaken. Overexpression of miR-193b in melanoma cell lines repressed cell proliferation. Gene expression profiling identified 314 genes down-regulated by overexpression of miR-193b in Malme-3M cells. Eighteen of these down-regulated genes, including cyclin D1 (CCND1), were also identified as putative miR-193b targets by TargetScan. Overexpression of miR-193b in Malme-3M cells down-regulated CCND1 mRNA and protein by > or = 50%. A luciferase reporter assay confirmed that miR-193b directly regulates CCND1 by binding to the 3'untranslated region of CCND1 mRNA. These studies indicate that miR-193b represses cell proliferation and regulates CCND1 expression and suggest that dysregulation of miR-193b may play an important role in melanoma development.

  17. Risk Factors for Melanoma Among Survivors of Non-Hodgkin Lymphoma

    Science.gov (United States)

    Lam, Clara J.K.; Curtis, Rochelle E.; Dores, Graça M.; Engels, Eric A.; Caporaso, Neil E.; Polliack, Aaron; Warren, Joan L.; Young, Heather A.; Levine, Paul H.; Elmi, Angelo F.; Fraumeni, Joseph F.; Tucker, Margaret A.; Morton, Lindsay M.

    2015-01-01

    Purpose Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified. Patients and Methods We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims. Results A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n = 18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n = 10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n = 36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n = 49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs). Conclusion Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma. PMID:26240221

  18. BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma.

    Science.gov (United States)

    Liu, Fen; Jiang, Chen Chen; Yan, Xu Guang; Tseng, Hsin-Yi; Wang, Chun Yan; Zhang, Yuan Yuan; Yari, Hamed; La, Ting; Farrelly, Margaret; Guo, Su Tang; Thorne, Rick F; Jin, Lei; Wang, Qi; Zhang, Xu Dong

    2017-09-19

    The expression of CD47 on the cancer cell surface transmits "don't eat me" signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47. The increase in CD47 expression was mediated by ERK signalling, as it was associated with rebound activation of ERK and co-knockdown of ERK1/2 by siRNA diminished upregulation of CD47 in melanoma cells after exposure to BRAF/MEK inhibitors. Furthermore, ERK1/2 knockdown also reduced the constitutive expression of CD47 in melanoma cells. We identified a DNA fragment that was enriched with the consensus binding sites for NRF-1 and was transcriptionally responsive to BRAF/MEK inhibitor treatment. Knockdown of NRF-1 inhibited the increase in CD47, indicating that NRF-1 has a critical role in transcriptional activation of CD47 by ERK signalling. Functional studies showed that melanoma cells resistant to vemurafenib were more susceptible to macrophage phagocytosis when CD47 was blocked. So these results suggest that NRF-1-mediated regulation of CD47 expression is a novel mechanism by which ERK signalling promotes the pathogenesis of melanoma, and that the combination of CD47 blockade and BRAF/MEK inhibitors may be a useful approach for improving their therapeutic efficacy.

  19. Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma.

    Science.gov (United States)

    Gammons, M V; Lucas, R; Dean, R; Coupland, S E; Oltean, S; Bates, D O

    2014-07-29

    Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab). Tumour progression also requires angiogenesis, which is regulated by VEGF-A, itself alternatively spliced to form two families of isoforms, pro- and anti-angiogenic. Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1. Here, we show a novel approach to preventing angiogenesis-targeting splicing factor kinases that are highly expressed in melanomas. We used RT-PCR, western blotting and immunohistochemistry to investigate SRPK1, SRSF1 and VEGF expression in tumour cells, and in vivo xenograft assays to investigate SRPK1 knockdown and inhibition in vivo. In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms. Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro. These results suggest that selective blocking of pro-angiogenic isoforms by inhibiting splice-site selection with SRPK1 inhibitors reduces melanoma growth. SRPK1 inhibitors may be used as therapeutic agents.

  20. A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers.

    Directory of Open Access Journals (Sweden)

    Lauren G Aoude

    Full Text Available Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1 have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.

  1. Human malignant melanoma-derived progestagen-associated endometrial protein immunosuppresses T lymphocytes in vitro.

    Directory of Open Access Journals (Sweden)

    Suping Ren

    Full Text Available Progestagen-associated endometrial protein (PAEP is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow's 2.5mm or greater and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment.

  2. MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma.

    Science.gov (United States)

    Zhan, Yao; Guo, Jun; Yang, William; Goncalves, Christophe; Rzymski, Tomasz; Dreas, Agnieszka; Żyłkiewicz, Eliza; Mikulski, Maciej; Brzózka, Krzysztof; Golas, Aniela; Kong, Yan; Ma, Meng; Huang, Fan; Huor, Bonnie; Guo, Qianyu; da Silva, Sabrina Daniela; Torres, Jose; Cai, Yutian; Topisirovic, Ivan; Su, Jie; Bijian, Krikor; Alaoui-Jamali, Moulay A; Huang, Sidong; Journe, Fabrice; Ghanem, Ghanem E; Miller, Wilson H; Del Rincón, Sonia V

    2017-11-01

    Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.

  3. Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma

    International Nuclear Information System (INIS)

    Flørenes, Vivi Ann; Emilsen, Elisabeth; Dong, Hiep Phuc; Førsund, Mette; Holm, Ruth; Slipicevic, Ana

    2015-01-01

    Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an important oncogene contributing to cancer progression partially by regulating cMYC and AKT. We examined CIP2A expression in cutaneous melanomas, its association with clinicopathological parameters and mapped molecular mechanisms regulated by CIP2A in vitro. CIP2A expression was analyzed by immunohistochemistry in 17 nevi, 132 primary melanomas and 49 metastases. Effects of siRNA-mediated down-regulation on proliferation, apoptosis and signaling pathways were assessed in melanoma cell lines. In superficial spreading melanomas (SSM), high nuclear CIP2A expression was associated with poor overall survival (OS) (P = 0.0018). Surprisingly, high cytoplasmic expression was related to improved relapse-free (P = 0.031) and OS (P = 0.014) in nodular melanomas (NM). In vitro experiments revealed that CIP2A can regulate proliferation and/or apoptosis partially through the PI3K/AKT pathway but also independently. In summary, CIP2A could represent a potential therapeutic target in SSM. However, in NM cytoplasmic CIP2A is associated with improved prognosis indicating that CIP2A has distinct, complex functions dependent on the molecular context and histological subtype. As seen in other cancer types, CIP2A can influence cMYC and AKT, but our data also suggest that in melanoma it has additional targets which need to be identified

  4. Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma.

    Science.gov (United States)

    Flørenes, Vivi Ann; Emilsen, Elisabeth; Dong, Hiep Phuc; Førsund, Mette; Holm, Ruth; Slipicevic, Ana

    2015-06-01

    Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an important oncogene contributing to cancer progression partially by regulating cMYC and AKT. We examined CIP2A expression in cutaneous melanomas, its association with clinicopathological parameters and mapped molecular mechanisms regulated by CIP2A in vitro. CIP2A expression was analyzed by immunohistochemistry in 17 nevi, 132 primary melanomas and 49 metastases. Effects of siRNA-mediated down-regulation on proliferation, apoptosis and signaling pathways were assessed in melanoma cell lines. In superficial spreading melanomas (SSM), high nuclear CIP2A expression was associated with poor overall survival (OS) (P = 0.0018). Surprisingly, high cytoplasmic expression was related to improved relapse-free (P = 0.031) and OS (P = 0.014) in nodular melanomas (NM). In vitro experiments revealed that CIP2A can regulate proliferation and/or apoptosis partially through the PI3K/AKT pathway but also independently. In summary, CIP2A could represent a potential therapeutic target in SSM. However, in NM cytoplasmic CIP2A is associated with improved prognosis indicating that CIP2A has distinct, complex functions dependent on the molecular context and histological subtype. As seen in other cancer types, CIP2A can influence cMYC and AKT, but our data also suggest that in melanoma it has additional targets which need to be identified. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  5. Activation of Wnt/β-catenin signaling increases apoptosis in melanoma cells treated with trail.

    Directory of Open Access Journals (Sweden)

    Zachary F Zimmerman

    Full Text Available While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/β-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/β-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone. This apoptosis correlates with increased abundance of the pro-apoptotic proteins BCL2L11 and BBC3, and with decreased abundance of the anti-apoptotic regulator Mcl1. We then confirmed the involvement of the Wnt/β-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular β-catenin antagonist, AXIN1, or treating cells with an inhibitor of GSK-3 also enhanced melanoma cell sensitivity to TRAIL. These studies describe a novel regulation of TRAIL sensitivity in melanoma by Wnt/β-catenin signaling, and suggest that strategies to enhance Wnt/β-catenin signaling in combination with TRAIL agonists warrant further investigation.

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

    Directory of Open Access Journals (Sweden)

    Xiaoliang L. Xu

    2015-01-01

    Full Text Available 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.

  7. Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death.

    Science.gov (United States)

    Lv, Da-Lun; Chen, Lei; Ding, Wei; Zhang, Wei; Wang, He-Li; Wang, Shuai; Liu, Wen-Bei

    2018-01-01

    Melanoma is a leading cause of cancer death worldwide, and SMI-4a and G-Rh2 exert anti-tumor activity in multiple cancer. However, SMI-4a as well as a synergistic relationship between SMI-4a and G-Rh2 in anti-melanoma capacity are still unknown. Therefore, we investigated the effects of SMI-4a and combined SMI-4a with G-Rh2 on the viability, apoptosis and autophagy of melanoma, and to preliminarily explore the underlying mechanism of SMI-4a and combined SMI-4a with G-Rh2 in inhibiting tumor growth. Cell viability was examined with cell counting Kit 8 assay and colony formation assay; Apoptosis was evaluated by flow cytometry and Caspase 3/7 activity assay; Western blotting was used to test proteins related to autophagy and the AKT/mammalian target of rapamycin (mTOR) signaling pathway; Tumor xenograft model in BALB/c nude mice was performed to evaluate the effects of SMI-4a and combined SMI-4a with G-Rh2 in anti-melanoma in vivo. SMI-4a, a pharmacological inhibitor of PIM-1, could decrease cell viability, induce apoptosis, and promote Caspase 3/7 activity in both A375 and G361 melanoma cells, and SMI-4a inhibited tumor growth by inducing autophagy via down-regulating AKT/mTOR axis in melanoma cells. Furthermore, G-Rh2 amplified the anti-tumor activity of SMI-4a in melanoma cells via strengthening autophagy. Our results suggested that SMI-4a could enhance autophagy-inducing apoptosis by inhibiting AKT/mTOR signaling pathway in melanoma cells, and G-Rh2 could enhance the effects of SMI-4a against melanoma cancer via amplifying autophagy induction. This study demonstrates that combined SMI-4a and G-Rh2 might be a novel alternative strategy for melanoma treatment.

  8. Multiplex fluorescence in situ hybridization identifies novel rearrangements of chromosomes 6, 15, and 18 in primary uveal melanoma.

    Science.gov (United States)

    Sisley, Karen; Tattersall, Nicola; Dyson, Michael; Smith, Kath; Mudhar, Hardeep S; Rennie, Ian G

    2006-09-01

    Uveal melanomas are the commonest ocular tumour of adults and are characterized by reproducible alterations of chromosomes 1, 3, 6 and 8. These alterations are of prognostic relevance and have also be shown to correlate to high risk and low risk metastatic categories of uveal melanoma as defined by micro-array analysis. It is, however, possible that a catalogue of relevant genetic alterations, involving gene rearrangement rather than amplification, have as yet eluded identification. To address this point we examined 14 primary uveal melanomas, using 24 colour multiplex fluorescence in situ hybridization (M-FISH). All tumours were karyotyped following G-Banding, and M-FISH was performed to confirm and clarify the identity of abnormal chromosomes. M-FISH data were obtained from all tumours and was able to establish the nature of most abnormalities not fully characterized by cytogenetics. Abnormalities of chromosome 6 were far more frequent than previously indicated, in approximately 70% of cases, indicating they have been substantially underrepresented in past studies of uveal melanoma. Spindle melanomas were found to have novel rearrangements affecting in particular chromosomes 6, 15 and 18, suggesting that juxtaposition of genes through translocational events may play a role in the development of some uveal melanomas. In conclusion, this study is the largest of primary uveal melanoma analysed by M-FISH and indicates that alterations of chromosome 6 have previously been underestimated. Furthermore spindle melanomas are prone to rearrangements affecting chromosomes 6, 15 and 18, which may relate to early changes in uveal melanoma development or associate with those melanomas of a more differentiated status.

  9. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis.

    Science.gov (United States)

    Hemon, Patrice; Jean-Louis, Francette; Ramgolam, Kiran; Brignone, Chrystelle; Viguier, Manuelle; Bachelez, Hervé; Triebel, Frédéric; Charron, Dominique; Aoudjit, Fawzi; Al-Daccak, Reem; Michel, Laurence

    2011-05-01

    Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3-transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis. Altogether, our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3-MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.

  10. Nodular melanoma: a distinct clinical entity and the largest contributor to melanoma deaths in Victoria, Australia.

    Science.gov (United States)

    Mar, Victoria; Roberts, Hugh; Wolfe, Rory; English, Dallas R; Kelly, John W

    2013-04-01

    There is a growing body of evidence that nodular melanoma (NM), because of its association with increased growth rate and thickness at diagnosis, accounts for a substantial proportion of melanoma deaths. We sought to assess the contribution of NM to melanoma deaths in comparison with other tumor subtypes. Four cohorts were established comprising 5775 cases of invasive primary cutaneous melanoma reported to the Victorian Cancer Registry during 1989, 1994, 1999, and 2004. Original pathology reports were reviewed. Age-standardized melanoma incidence rates were compared from 1989 to 2004 with annual percentage change using Poisson regression. The incidence of thick tumors (>4 mm) increased by 3.8% (95% confidence interval 1.4 to 6.2) and 2.5% (95% confidence interval -0.5 to 5.5) per year for male and female patients, respectively. The median thickness of NM at diagnosis was 2.6 mm compared with 0.6 mm for superficial spreading melanoma. A third of patients who died from melanoma during the follow-up period had thick tumors (>4 mm), most of which were nodular subtype (61%). NM accounted for 14% of invasive melanomas, but was responsible for 43% of melanoma deaths in a total of 57,461 person-years of follow-up. By comparison, superficial spreading melanoma contributed 56% of invasive melanoma but only 30% of deaths. Pathology review was limited to reports only. Mortality information relied mostly on death certificate information. The incidence of thick melanomas continues to increase. Nodular melanoma is clinically distinct and the predominant contributor to melanoma-related deaths, representing a public health challenge in reducing skin cancer mortality. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  11. Nodular melanoma is less likely than superficial spreading melanoma to be histologically associated with a naevus.

    Science.gov (United States)

    Pan, Yan; Adler, Nikki R; Wolfe, Rory; McLean, Catriona A; Kelly, John W

    2017-10-16

    To determine the frequency of naevus-associated melanoma among superficial spreading and nodular subtypes; and to investigate associations between naevus-associated melanoma and other clinico-pathological characteristics. Cross-sectional study of all patients with nodular and superficial spreading melanomas diagnosed between 1994 and 2015 at the Victorian Melanoma Service, Melbourne. Clinical and pathological characteristics of naevus-associated and de novo melanomas were assessed in univariable and multivariable logistic regression analyses. Of 3678 primary melanomas, 1360 (37.0%) were histologically associated with a naevus and 2318 (63.0%) were de novo melanomas; 71 of 621 nodular (11.4%) and 1289 of 3057 superficial spreading melanomas (42.2%) were histologically associated with a naevus. In multivariable analyses, the odds of being associated with a naevus were higher for melanomas located on the trunk (v head and neck: adjusted odds ratio [OR], 2.27; 95% CI, 1.73-2.96; P melanomas (adjusted OR, 0.68; 95% CI, 0.48-0.97; P = 0.035), and older age (patients 70 years or older v patients under 30 at diagnosis: adjusted OR, 0.28; 95% CI, 0.20-0.40; P melanomas as for nodular melanomas (adjusted OR, 3.05; 95% CI, 2.24-4.17; P Melanomas are most likely to arise in the absence of a pre-existing naevus, particularly nodular melanomas. Public health campaigns should therefore emphasise the detection of suspicious de novo lesions, as well as of changing lesions.

  12. Isolated Pancreatic Metastasis from Malignant Melanoma: Is ...

    African Journals Online (AJOL)

    Isolated pancreatic metastasis from malignant melanoma (IPMMM) is rare because most melanoma patients already have a widespread disease at diagnosis. No adjuvant systemic treatment is known to be effi cient in this setting. Experience with pancreatic resection for IPMMM is limited and controversial. We report here ...

  13. Primary malignant melanoma of the nasal cavity.

    Science.gov (United States)

    Uysal, Ismail Önder; Misir, Mustafa; Polat, Kerem; Altuntaş, Emine Elif; Atalar, Mehmet Haydar; Tuncer, Ersin; Müderris, Suphi

    2012-01-01

    Primary malignant melanoma of the nose and paranasal sinus mucosa is a rare disease and seen in less than 1% among all melanomas. Malignant melanomas have 2 origins: cutaneous and mucosal. The mucosal form has a worse prognosis because of its aggressiveness compared with that of the cutaneous form. Mucosal melanomas often occur at a rate of 2% to 3% among all melanomas and are typically found in the nasal cavity and paranasal sinuses. Generally, it is more common in males and in those older than 50 years. In this study, 4 patients were observed at the Cumhuriyet University Faculty of Medicine; 2 of them were a 64-year-old man and an 82-year-old woman who had a malignant melanoma originating from the nasal septal mucosa, 1 patient was a 72-year-old woman whose malignant melanoma originated from the inferior turbinate, and 1 patient was a 77-year-old woman with a sinonasally located melanoma. The conditions of these patients were discussed under the light of literature instructions.

  14. PRIMARY MALIGNANT MELANOMA OF ARYEPIGLOTTIC FOLD

    African Journals Online (AJOL)

    2015-12-01

    Dec 1, 2015 ... ing including positron emission tomography (PET) scan failed to reveal a primary source of malignant melanoma. So, the patient was diagnosed as primary malignant melanoma of aryepiglottic mucosa. Figure 1 Photomicrograph showing origin of melano- ma (H&E, 100x). Figure 2 Photomicrograph ...

  15. Histopathological study of malignant melanoma in highlanders ...

    African Journals Online (AJOL)

    Histopathological study of malignant melanoma in highlanders. AZ Mohammed, AN Manasseh, BM Mandong, ST Edino. Abstract. Background:Malignant melanoma is a fatal skin cancer that is curable when detected and treated early. Recent reports indicate a rising incidence globally. This study aims at identifying the ...

  16. Intraoral malignant melanoma | Babburi | Nigerian Medical Journal

    African Journals Online (AJOL)

    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 ...

  17. Towards new therapeutic approaches for malignant melanoma.

    Science.gov (United States)

    Pacheco, Ivan; Buzea, Cristina; Tron, Victor

    2011-11-01

    Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

  18. Checkpoint Inhibitors Hold Promise for Rare Melanoma

    Science.gov (United States)

    Patients with a rare form of melanoma, called desmoplastic melanoma, may be particularly likely to benefit from immune checkpoint inhibitors, a new study shows. As this Cancer Currents post explains, an NCI-sponsored clinical trial is already testing one such drug, pembrolizumab (Keytruda) in patients with this cancer.

  19. Mistletoe in the treatment of malignant melanoma

    Directory of Open Access Journals (Sweden)

    Esin Sakallı Çetin

    2014-03-01

    Full Text Available Malignant melanoma is a malignant neoplasia drives from melanocytes. Malignant melanoma, the most causing death, is seen in the third place at skin cancer. Malignant melanoma shows intrinsic resistance to chemotherapeutic agents and variability in the course of the disease which are distinct features separating from other solid tumors. These features prevent the development and standardization of non-surgical treatment models of malignant melanoma. Although there is a large number of chemotherapeutic agents used in the treatment of metastatic malignant melanoma, it hasn’t been demonstrated the survival advantage of adjuvant treatment with chemotherapeutic agents. Because of the different clinical course of malignant melanoma, the disease is thought to be closely associated with immune system. Therefore, immunomodulatory therapy models were developed. Mistletoe stimulates the immune system by increasing the number and activity of dendritic cells, thus it has been shown to effect on tumor growth and metastasis of malignant melanoma patient. Outlined in this review are the recent developments in the understanding the role of mistletoe as a complementary therapy for malignant melanoma. J Clin Exp Invest 2014; 5 (1: 145-152

  20. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1{beta} secretion

    Energy Technology Data Exchange (ETDEWEB)

    Ellis, Lixia Z.; Liu, Weimin; Luo, Yuchun; Okamoto, Miyako; Qu, Dovina; Dunn, Jeffrey H. [Department of Dermatology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Fujita, Mayumi, E-mail: mayumi.fujita@ucdenver.edu [Department of Dermatology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Denver Veterans Affairs Medical Center, Denver, CO 80220 (United States)

    2011-10-28

    Highlights: Black-Right-Pointing-Pointer EGCG inhibits melanoma cell growth at physiological doses (0.1-1 {mu}M). Black-Right-Pointing-Pointer EGCG inhibits melanoma cell growth via inflammasomes and IL-1{beta} suppression. Black-Right-Pointing-Pointer Inflammasomes and IL-1{beta} could be potential targets for future melanoma therapeutics. -- Abstract: Epigallocatechin-3-gallate (EGCG), the major polyphenolic component of green tea, has been demonstrated to possess anti-inflammatory, antioxidant, anti-mutagenic and anti-carcinogenic properties. The anti-melanoma effect of EGCG has been previously suggested, but no clear mechanism of action has been established. In this study, we demonstrated that EGCG inhibits melanoma cell growth at physiological doses (0.1-1 {mu}M). In the search for mechanisms of EGCG-mediated melanoma cell suppression, we found that NF-{kappa}B was inhibited, and that reduced NF-{kappa}B activity was associated with decreased IL-1{beta} secretion from melanoma cells. Since inflammasomes are involved in IL-1{beta} secretion, we investigated whether IL-1{beta} suppression was mediated by inflammasomes, and found that EGCG treatment led to downregulation of the inflammasome component, NLRP1, and reduced caspase-1 activation. Furthermore, silencing the expression of NLRP1 abolished EGCG-induced inhibition of tumor cell proliferation both in vitro and in vivo, suggesting a key role of inflammasomes in EGCG efficacy. This paper provides a novel mechanism for EGCG-induced melanoma inhibition: inflammasome downregulation {yields} decreased IL-1{beta} secretion {yields} decreased NF-{kappa}B activities {yields} decreased cell growth. In addition, it suggests inflammasomes and IL-1{beta} could be potential targets for future melanoma therapeutics.

  1. Primary malignant melanoma of aryepiglottic fold | Chhabra | Ghana ...

    African Journals Online (AJOL)

    Background: Primary malignant melanoma rarely arises from noncutaneous tissues that contain melanocytes. Head and neck mucosal melanomas account for 0.7% to 3.8% of all melanomas. Here we report a case of primary malignant melanoma of aryepiglottic fold. Result: Here we reported a case of primary malignant ...

  2. Digital imaging biomarkers feed machine learning for melanoma screening.

    Science.gov (United States)

    Gareau, Daniel S; Correa da Rosa, Joel; Yagerman, Sarah; Carucci, John A; Gulati, Nicholas; Hueto, Ferran; DeFazio, Jennifer L; Suárez-Fariñas, Mayte; Marghoob, Ashfaq; Krueger, James G

    2017-07-01

    We developed an automated approach for generating quantitative image analysis metrics (imaging biomarkers) that are then analysed with a set of 13 machine learning algorithms to generate an overall risk score that is called a Q-score. These methods were applied to a set of 120 "difficult" dermoscopy images of dysplastic nevi and melanomas that were subsequently excised/classified. This approach yielded 98% sensitivity and 36% specificity for melanoma detection, approaching sensitivity/specificity of expert lesion evaluation. Importantly, we found strong spectral dependence of many imaging biomarkers in blue or red colour channels, suggesting the need to optimize spectral evaluation of pigmented lesions. © 2016 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd.

  3. Cataract extraction after brachytherapy for malignant melanoma of the choroid

    International Nuclear Information System (INIS)

    Fish, G.E.; Jost, B.F.; Snyder, W.I.; Fuller, D.G.; Birch, D.G.

    1991-01-01

    Thirteen eyes of 55 consecutive patients treated with brachytherapy for malignant melanoma of the choroid developed postirradiation cataracts. Cataract development was more common in older patients and in patients with larger and more anterior tumors. Eleven eyes had extracapsular cataract extraction and intraocular lens implantation. Initial visual improvement occurred in 91% of eyes, with an average improvement of 5.5 lines. Visual acuity was maintained at 20/60 or better in 55% of the eyes over an average period of follow-up of 24 months (range, 6 to 40 months). These data suggest that, visually, cataract extraction can be helpful in selected patients who develop a cataract after brachytherapy for malignant melanoma of the choroid

  4. Progression of cutaneous melanoma: implications for treatment

    Science.gov (United States)

    Leong, Stanley P. L.; Mihm, Martin C.; Murphy, George F.; Hoon, Dave S. B.; Kashani-Sabet, Mohammed; Agarwala, Sanjiv S.; Zager, Jonathan S.; Hauschild, Axel; Sondak, Vernon K.; Guild, Valerie; Kirkwood, John M.

    2015-01-01

    The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials. PMID:22892755

  5. From Melanocyte to Metastatic Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Bizhan Bandarchi

    2010-01-01

    Full Text Available Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to briefly review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classification and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the final version of 2009 AJCC malignant melanoma staging and classification is presented.

  6. A rare case of rynopharyngeal melanoma

    Directory of Open Access Journals (Sweden)

    Francesco Grecchi

    2012-01-01

    Full Text Available Primary mucosal melanomas (MM of the head and neck region constitute 0.5-2% of all malignant melanomas. The rynopharynx is a region that is less often involved by malignant melanomas. Because most of mucosal melanotic lesions are painless in their early stages, the diagnosis is unfortunately often delayed until symptoms resulting from ulceration, growth, and/or bleeding are noted. Here, we document the rare case of a malignant rynopharynx melanoma of a 43 year old woman. Its treatment and the pertinent literature are discussed. No complication was recorded in the post-operative period and no further surgery was performed. The follow up showed no recurrence in the same position and with the same characteristics, even after six years. Mucosal melanomas are aggressive tumours and the prognosis in these patients is poor. Clinicians must use treatment strategies that provide functional benefit, so as to maintain quality of life without excessive toxicity.

  7. Alpha particles for treatment of disseminated melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Link, E.M. [London University (United Kingdom)

    2010-07-01

    Invading melanoma spreads to local and unpredictable distant location at the early stages of its development. It is justifiable, therefore, to classify the disease as a systemic disorder. This requires a systemic treatment that reaches all melanoma cells irrespective of whether they are singly dispersed and in circulation or already forming solid tumours of various sizes. Targeted radiotherapy affects directly and selectively cancer cells provided an appropriate radionuclide and its carrier are chosen. Melanoma is a pigmented tumour. Methylene blue (MTB)) accumulates selectively in melanoma cells due to its exceptionally high affinity to melanin. MTB serves, therefore, as a carrier for radionuclides. {sup 211}At-MTB has proved to be particularly effective in treating disseminated melanoma when administered systemically and, at the same time, non-toxic to normal non-pigmented and pigmented organs. (authors)

  8. Alpha particles for treatment of disseminated melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Link, E.M. [London Univ. (United Kingdom)

    2010-11-15

    Invading melanoma spreads to local and unpredictable distant location at the early stages of its development. It is justifiable, therefore to classify the disease as a systemic disorder. This requires a systemic treatment that reaches all melanoma cells irrespective of whether they are singly dispersed and in circulation or already forming solid tumours of various sizes. Targeted radiotherapy affects directly and selectively cancer cells provided an appropriate radionuclide and its carrier are chosen. Melanoma is a pigmented tumour. Methylene blue (MTB) accumulates selectively in melanoma cells due to its exceptionally high affinity to melanin. MTB serves, therefore, as a carrier for radionuclides. {sup 211}At-MTB has proved to be particularly effective in treating disseminated melanoma when administered systemically and, at the same time, non-toxic to normal non-pigmented and pigmented organs. (author)

  9. Nanomechanical analysis of pigmented human melanoma cells.

    Science.gov (United States)

    Sarna, Michal; Zadlo, Andrzej; Pilat, Anna; Olchawa, Magdalena; Gkogkolou, Paraskevi; Burda, Kvetoslava; Böhm, Markus; Sarna, Tadeusz

    2013-09-01

    Based on hitherto measurements of elasticity of various cells in vitro and ex vivo, cancer cells are generally believed to be much softer than their normal counterparts. In spite of significant research efforts on the elasticity of cancer cells, only few studies were undertaken with melanoma cells. However, there are no reports concerning pigmented melanoma cells. Here, we report for the first time on the elasticity of pigmented human melanoma cells. The obtained data show that melanin significantly increases the stiffness of pigmented melanoma cells and that the effect depends on the amount of melanin inside the cells. The dramatic impact of melanin on the nanomechanical properties of cells puts into question widely accepted paradigm about all cancer cells being softer than their normal counterparts. Our findings reveal significant limitations of the nanodiagnosis approach for melanoma and contribute to better understanding of cell elasticity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. UVEAL MELANOMA EXTENSION TO THE OPTIC CHIASM.

    Science.gov (United States)

    Abdellatief, Amro; Pulido, Jose S; Bartley, George B; Salomao, Diva R; Quinn, Timothy A

    2016-01-01

    Case report describing a patient who developed intracranial extension of a uveal melanoma through the optic nerve. We reviewed the patient's medical history and images. A 41-year-old woman who was blind in one eye had a uveal melanoma that extended through the optic nerve into the optic chiasm and involved the hypophysis. The patient then developed metastasis. The patient developed uveal melanoma extension into the optic chiasm through the optic nerve resulting in a visual field defect in the fellow eye. Uveal melanoma extension through the optic nerve is a devastating complication, which occurs anywhere from 0.6% to 3.7% in patients with uveal melanoma. If enucleation of the affected eye is performed, a representative portion of the optic nerve should be excised to decrease the risk of extension. Patients with phthisical eyes should undergo appropriate imaging techniques to prevent a missed diagnosis of optic nerve involvement.

  11. Nodular skin melanomas and dermatoscopic diagnostic therein

    Directory of Open Access Journals (Sweden)

    M. V. Zhuchkov

    2016-01-01

    Full Text Available Aim. The study of dermatoscopic pattern characteristics of nodular melanoma with the use of modified Kittler’s pattern analysis. Materials and methods. Clinical and dermatoscopis images of 127 patients with histologically distinctive nodular form of skin melanoma were examined. Nonpolarized dermoscopy of nodular melanoma foci was carried out to patients. Interpretation of obtained dermatoscopic images was performed with the use of pattern analysis modified by Harold Kittler. Main results. The two most important dermatoscopic features of nodular melanoma that distinguish it from other clinical types of this malignant tumor were revealed in our investigation: 1 the prevalence of dermatoscopis images with one pattern (structureless; 2 the prevalence of “grey dots, circles, clods” and “black peripheral dots and clods” as main features of nodular melanoma.

  12. Patterns of tumor initiation in choroidal melanoma.

    Science.gov (United States)

    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 iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P iris color (P = 0.84), or tumor diameter (P = 0.73). Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body. This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere.

  13. Melanoma Surveillance in the US: Collecting Melanoma Data

    Centers for Disease Control (CDC) Podcasts

    2011-10-19

    This podcast accompanies the publication of a series of articles on melanoma surveillance in the United States, available in the November supplement edition of the Journal of the American Academy of Dermatology. Dr. Suephy Chen, a dermatologist from Emory University, discusses why the articles are important, as well as the need to increase dermatologists’ awareness of cancer registries and reporting requirements.  Created: 10/19/2011 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 10/19/2011.

  14. Mutation analysis of genes that control the G1/S cell cycle in melanoma: TP53, CDKN1A, CDKN2A, and CDKN2B

    International Nuclear Information System (INIS)

    Soto, José Luis; Cabrera, Carmen M; Serrano, Salvio; López-Nevot, Miguel Ángel

    2005-01-01

    The role of genes involved in the control of progression from the G1 to the S phase of the cell cycle in melanoma tumors in not fully known. The aim of our study was to analyse mutations in TP53, CDKN1A, CDKN2A, and CDKN2B genes in melanoma tumors and melanoma cell lines We analysed 39 primary and metastatic melanomas and 9 melanoma cell lines by single-stranded conformational polymorphism (SSCP). The single-stranded technique showed heterozygous defects in the TP53 gene in 8 of 39 (20.5%) melanoma tumors: three new single point mutations in intronic sequences (introns 1 and 2) and exon 10, and three new single nucleotide polymorphisms located in introns 1 and 2 (C to T transition at position 11701 in intron 1; C insertion at position 11818 in intron 2; and C insertion at position 11875 in intron 2). One melanoma tumor exhibited two heterozygous alterations in the CDKN2A exon 1 one of which was novel (stop codon, and missense mutation). No defects were found in the remaining genes. These results suggest that these genes are involved in melanoma tumorigenesis, although they may be not the major targets. Other suppressor genes that may be informative of the mechanism of tumorigenesis in skin melanomas should be studied

  15. Increased incidence of melanoma in situ in Denmark from 1997 to 2011: results from a nationwide population-based study

    DEFF Research Database (Denmark)

    Toender, Anita; Kjaer, Susanne K.; Jensen, Allan

    2014-01-01

    during the most recent 5-year calendar period. A markedly higher AAPC was observed for SSM than for LM during the most recent 5-year calendar period for both sexes. The marked increase in incidence of MIS during the last 5 years of the period may indicate a growing awareness of skin cancer among......The incidence of malignant melanoma has increased markedly among white populations in the recent decades. This may suggest that the incidence of melanoma in situ (MIS), the precursor of malignant melanoma, has also increased; however, few studies have assessed the incidence of MIS drawing on large...... the general Danish population and more frequent excision of suspicious skin lesions....

  16. Aloin enhances cisplatin antineoplastic activity in B16-F10 melanoma cells by transglutaminase-induced differentiation.

    Science.gov (United States)

    Tabolacci, Claudio; Rossi, Stefania; Lentini, Alessandro; Provenzano, Bruno; Turcano, Lorenzo; Facchiano, Francesco; Beninati, Simone

    2013-01-01

    Aloin, a natural anthracycline from aloe plant, is a hydroxyanthraquinone derivative shown to have antitumor properties. This study demonstrated that aloin exerted inhibition of cell proliferation, adhesion and invasion abilities of B16-F10 melanoma cells under non-cytotoxic concentrations. Furthermore, aloin induced melanoma cell differentiation through the enhancement of melanogenesis and transglutaminase activity. To improve the growth-inhibiting effect of anticancer agents, we found that the combined treatment of cells with aloin and low doses of cisplatin increases the antiproliferative activity of aloin. The results suggest that aloin possesses antineoplastic and antimetastatic properties, exerted likely through the induction of melanoma cell differentiation.

  17. Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.

    Science.gov (United States)

    Cesarini, V; Guida, E; Todaro, F; Di Agostino, S; Tassinari, V; Nicolis, S; Favaro, R; Caporali, S; Lacal, P M; Botti, E; Costanzo, A; Rossi, P; Jannini, E A; Dolci, S

    2017-08-01

    Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRaf V600E mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.

  18. Current management and novel agents for malignant melanoma

    Directory of Open Access Journals (Sweden)

    Lee Byung

    2012-02-01

    Full Text Available Abstract Advanced malignant melanoma remains a challenging cancer. Over the past year, there have been 3 agents approved for treatment of melanoma by Food and Drug Administration. These include pegylated interferon alpha-2b for stage III melanoma, vemurafenib for unresectable or metastatic melanoma with BRAF V600E mutation, and ipilimumab for treatment of unresectable or metastatic melanoma. This review will also update on the development of novel agents, including tyrosine kinase inhibitors and adoptive cellular therapy.

  19. Glaucoma secundario a melanoma uveal

    Directory of Open Access Journals (Sweden)

    Nairovys Gómez Martínez

    2017-09-01

    Full Text Available Introducción: Los tumores localizados en iris y cuerpo ciliar son poco frecuentes y puede ser valorada su resección local como alternativa terapéutica. El melanoma uveal representa el 79-81% de los melanomas oculares y el 3-5% de todos los melanomas. Objetivo: Dar a conocer el caso de una patología infrecuente con pocos casos reportados en la literatura, enfatizar su importancia dentro de los diagnósticos diferenciales y del estudio histopatológico. Descripción del caso: Paciente femenina de 47 años de edad, quien acudió a la consulta de oftalmología, para valoración de una lesión pigmentada en endotelio corneal y en iris asociada a hipertensión ocular y pérdida de la agudeza visual en el ojo izquierdo de cuatro meses de evolución. La biomicroscopía ultrasónica confirmó la presencia de una masa iridiana, localizada en la periferia del iris. El estudio anatomopatológico mostró una proliferación de células névicas pleomórficas que reemplazaban el estroma normal del iris. Conclusiones: En pacientes que presentan una clínica de glaucoma unilateral refractario a tratamiento farmacológico junto con dispersión de pigmento es importante una exploración exhaustiva destacando el papel de la biomicroscopía ultrasónica.

  20. Future perspectives in melanoma research

    Directory of Open Access Journals (Sweden)

    Paolo A. Ascierto

    2016-11-01

    Full Text Available Abstract The sixth “Melanoma Bridge Meeting” took place in Naples, Italy, December 1st–4th, 2015. The four sessions at this meeting were focused on: (1 molecular and immune advances; (2 combination therapies; (3 news in immunotherapy; and 4 tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS and overall survival (OS of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC, renal cell carcinoma (RCC, bladder cancer, and Hodgkin’s disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4 and the programmed cell death-1 (PD-1 and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.; adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs, chimeric

  1. Melanoma early detection and awareness

    DEFF Research Database (Denmark)

    Wainstein, Alberto; Algarra, Salvador Martin; Bastholt, Lars

    2014-01-01

    Risk factors for melanoma are well known and have guided plans for primary and secondary prevention. The presentation of the disease, however, varies widely depending on the geographic area, ethnicity, and socioeconomic status. For this reason, many countries have developed specific strategies to...... are trying to implement similar measures. Future efforts to further improve the efficacy of preventive strategies should focus on populations that usually escape campaigns, such as elderly men and people with low socioeconomic status. Fast-growing tumors also require specific attention....

  2. PAX3 expression in normal skin melanocytes and melanocytic lesions (naevi and melanomas.

    Directory of Open Access Journals (Sweden)

    Sandra Medic

    2010-04-01

    Full Text Available Cutaneous Malignant Melanoma is an aggressive form of skin cancer, arising in cutaneous melanocytes. The transcription factor PAX3 regulates melanocyte specification from neural crest cells during development but expression in differentiated melanocytes is uncertain. By contrast it is frequently found in melanomas and naevi and is a marker for melanoma staging and detection. In this study we analysed the expression of PAX3 across the spectrum of melanocytic cells, from normal melanocytes to cells of benign and malignant lesions to better assess its function in these various tissues. Pax3 and PAX3 (italicized refer to the mouse and human gene, respectively; whereas Pax3 and PAX3 (non-italicized refer to the corresponding mouse and human protein.PAX3 expression was analysed by immunohistochemistry and qRT-PCR. Immunofluorescence was used for co-expression with differentiation, migration and survival markers. As expected PAX3 expression was observed in naevi and melanoma cells. It was also found in melanocytes of normal skin where it co-expressed with melanocyte markers, MITF and MLANA. Co-expression with its downstream target, antiapoptotic factor BCL2L1 confirms PAX3 as a cell survival regulator. PAX3 was also co-expressed with melanoma cell migration marker MCAM in dermal naevi and melanoma cell nests, but this downstream target of PAX3 was not present in normal epidermal melanocytes, suggesting differential roles for PAX3 in normal epidermal melanocytes and melanoma cells. Most interestingly, a proportion of PAX3-positive epidermal melanocytes in normal skin show HES1 and Ki67 co-expression, indicating their less differentiated proliferative phenotype.Our results suggest that a previously identified role for PAX3, that of regulator of an undifferentiated plastic state, may operate in melanocytes of normal skin. This role, possibly required for cellular response to environmental stimuli, may contribute to formation and development of melanocytic

  3. Stimulation of lymphocyte anti-melanoma activity by co-cultured macrophages activated by complex homeopathic medication

    Directory of Open Access Journals (Sweden)

    Trindade Edvaldo S

    2009-08-01

    Full Text Available Abstract Background Melanoma is the most aggressive form of skin cancer, and the most rapidly expanding cancer in terms of worldwide incidence. Chemotherapeutic approaches to treat melanoma have been uniformly disappointing. A Brazilian complex homeopathic medication (CHM, used as an immune modulator, has been recommended for patients with depressed immune systems. Previous studies in mice have demonstrated that the CHM activates macrophages, induces an increase in the number of leukocytes and improves the murine response against Sarcoma-180. Methods Here we studied the interaction of mouse lymph node lymphocytes, co-cultured in vitro with macrophages in the presence or absence of the CHM, with B16F10 melanoma cells. Results Lymphocytes co-cultured with macrophages in the presence of the CHM had greater anti-melanoma activity, reducing melanoma cell density and increasing the number of lysed tumor cells. There was also a higher proportion of activated (CD25+ lymphocytes with increased viability. Overall, lymphocytes activated by treatment destroyed growing cancer cells more effectively than control lymphocytes. Conclusion Co-culture of macrophages with lymphocytes in the presence of the CHM enhanced the anti-cancer performance of lymphocytes against a very aggressive lineage of melanoma cells. These results suggest that non-toxic therapies using CHMs are a promising alternative approach to the treatment of melanomas. In addition, they are attractive combination-therapy candidates, which may enhance the efficacy of conventional medicines by improving the immune response against tumor cells.

  4. Epigenetic regulation of the transcription factor Foxa2 directs differential elafin expression in melanocytes and melanoma cells.

    Science.gov (United States)

    Yu, Kyung Sook; Jo, Ji Yoon; Kim, Su Jin; Lee, Yangsoon; Bae, Jong Hwan; Chung, Young-Hwa; Koh, Sang Seok

    2011-04-29

    Elafin, a serine protease inhibitor, induces the intrinsic apoptotic pathway in human melanoma cells, where its expression is transcriptionally silenced. However, it remains unknown how the elafin gene is repressed in melanoma cells. We here demonstrate that elafin expression is modulated via epigenetically regulated expression of the transcription factor Foxa2. Treatment of melanoma cells with a DNA methyltransferase inhibitor induced elafin expression, which was specifically responsible for reduced proliferation and increased apoptosis. Suppression of Foxa2 transcription, mediated by DNA hypermethylation in its promoter region, was released in melanoma cells upon treatment with the demethylating agent. Luciferase reporter assays indicated that the Foxa2 binding site in the elafin promoter was critical for the activation of the promoter. Chromatin immunoprecipitation assays further showed that Foxa2 bound to the elafin promoter in vivo. Analyses of melanoma cells with varied levels of Foxa2 revealed a correlated expression between Foxa2 and elafin and the ability of Foxa2 to induce apoptosis. Our results collectively suggest that, in melanoma cells, Foxa2 expression is silenced and therefore elafin is maintained unexpressed to facilitate cell proliferation in the disease melanoma. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma

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    Asunción Fernández-Barral

    2014-06-01

    Full Text Available Pigment epithelium-derived factor (PEDF, a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.

  6. Parthenolide reduces the frequency of ABCB5-positive cells and clonogenic capacity of melanoma cells from anchorage independent melanospheres

    Science.gov (United States)

    Czyz, Malgorzata; Koprowska, Kamila; Sztiller-Sikorska, Malgorzata

    2013-01-01

    Growing evidence suggests that the cancer stem cell phenotype in melanoma is dynamically regulated. Therefore, effective therapies have to target simultaneously bulk tumor cells and melanoma stem-like cells. The aim of the present study was to investigate the effects of parthenolide on heterogeneous cancer cell populations from anchorage-independent melanospheres. Cells derived from nodular melanoma specimens were grown under serum-free sphere-forming conditions. The effects of parthenolide on cellular viability, immunophenotype and self-renewing capacity were assessed with cells from dissociated melanospheres. Its penetration capacity was evaluated with intact melanospheres. In melanoma cells that survived treatment with parthenolide, a different immunophenotype than that in untreated control was found. The frequency of cells expressing the ABCB5 transporter was markedly reduced. Most importantly, melanoma cells that survived parthenolide treatment lost their self-renewing capacity. Significantly lower influence of drug on cellular viability and frequency of ABCB5-positive cells was observed in intact melanospheres. The potential clinical significance of our findings is based on the ability of parthenolide to affect both bulk and melanoma stem-like cells with clonogenic capacity and high expression of the ABCB5 transporter. Its low penetration capacity, however, may limit its action to easily accessible melanoma cells, either circulating in the blood or those in the vicinity to blood vessels within the tumor. Because of limited penetration capacity of parthenolide, this drug should be further explored as a part of multimodal therapies rather than as a stand-alone therapeutic agent. PMID:23192276

  7. High CCL27 immunoreactivity in 'supratumoral' epidermis correlates with better prognosis in patients with cutaneous malignant melanoma.

    Science.gov (United States)

    Martinez-Rodriguez, Miguel; Thompson, Alec K; Monteagudo, Carlos

    2017-01-01

    It has been proposed that the expression of chemokines and chemokine receptors by melanoma cells may have a role in tumour immune escape. Chemokine CCL27 is reported to be expressed specifically on the epidermal keratinocytes. The implication of CCL27 in cutaneous melanomas is currently unresolved. It has been suggested that CCL27 expression in melanomas can induce antitumoral immunity, and that CCL27 may suppress tumour growth probably due to the local lymphocyte recruitment. We studied CCL27 chemokine expression in three different concentric epidermal areas covering the primary cutaneous melanoma in patients with a long clinical follow-up. Our study included 91 cases of primary melanomas of the skin diagnosed during the 10-year period 1992-2002, and a minimum clinical follow-up of 10 years. We evaluated three different concentric and easily reproducible areas in the epidermis: the area covering melanoma (which we called 'supratumoral'), the area adjacent to the tumour ('peritumoral') and the most peripheral epidermal area ('peripheral'). Only CCL27 expression in supratumoral epidermis correlated with clinical outcome. Our study showed that a higher immunostaining of CCL27 in supratumoral epidermis is associated with longer progression-free interval and melanoma-specific survival. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  8. Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors

    DEFF Research Database (Denmark)

    Boyle, Jenny L; Haupt, Helen M; Stern, Jere B

    2002-01-01

    CONTEXT: Pathologists may encounter problems in the differential diagnosis of malignant melanoma, spindle and epithelioid neoplasms of peripheral nerves, and fibrohistiocytic tumors. Tyrosinase has been demonstrated to be a sensitive marker for melanoma. OBJECTIVE: To determine the specificity...... of tyrosinase expression in the differential diagnosis of melanoma, desmoplastic melanoma, and peripheral nerve sheath tumors. DESIGN: Immunoreactivity for tyrosinase, HMB-45 (anti-gp100 protein), S100 protein, CD34, and vimentin was studied in 70 tumors, including 15 melanomas (5 desmoplastic, 4 amelanotic, 6...... at 121 degrees C. RESULTS: All melanomas demonstrated positive immunostaining for tyrosinase, HMB-45, and S100 protein. Immunoreactivity for HMB-45 was generally stronger than that for tyrosinase in amelanotic lesions and significantly stronger in 1 of the desmoplastic lesions. The 4 pigmented...

  9. Pregnancy promotes melanoma metastasis through enhanced lymphangiogenesis.

    Science.gov (United States)

    Khosrotehrani, Kiarash; Nguyen Huu, Sau; Prignon, Aurélie; Avril, Marie-Françoise; Boitier, Françoise; Oster, Michèle; Mortier, Laurent; Richard, Marie-Aleth; Maubec, Eve; Kerob, Delphine; Mansard, Sandrine; Merheb, Charbel; Moguelet, Philippe; Nassar, Dany; Guégan, Sarah; Aractingi, Selim

    2011-04-01

    The relationships of pregnancy and melanoma have been debatable. Our aim was to assess the influence of gestation on the course of melanoma in a classic murine model of tumor progression and in women. B16 mouse melanoma cells were injected in nonpregnant or pregnant mice on day 5 of gestation. Animals were evaluated for tumor progression, metastases, and survival. Tumor sections were analyzed for lymphatic and blood vessel number and relative surface and expression of angiogenic growth factors. Finally, primary melanomas from pregnant and nonpregnant women, matched for age and tumor thickness, were also considered. Tumor growth, metastasis, and mortality were increased in B16-injected pregnant mice. Tumors displayed an increase in intratumoral lymphangiogenesis during gestation. This increased lymphatic angiogenesis was not observed in normal skin during gestation, showing its specificity to the tumor. An analysis of melanoma from pregnant and matched nonpregnant women showed a similar increase in lymphatic vessels. Tumors from pregnant mice had increased expression of vascular endothelial growth factor A at the RNA and protein levels. The increased vascular endothelial growth factor A production by melanoma cells could be reproduced in culture using pregnant mouse serum. In conclusion, pregnancy results in increased lymphangiogenesis and subsequent metastasis. Caution should be applied in the management of patients with advanced-stage melanoma during gestation. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  10. Non Melanoma Skin Cancer Pathogenesis Overview.

    Science.gov (United States)

    Didona, Dario; Paolino, Giovanni; Bottoni, Ugo; Cantisani, Carmen

    2018-01-02

    (1) Background: Non-melanoma skin cancer is the most frequently diagnosed cancer in humans. The process of skin carcinogenesis is still not fully understood. However, several studies have been conducted to better explain the mechanisms that lead to malignancy; (2) Methods: We reviewed the more recent literature about the pathogenesis of non-melanoma skin cancer focusing on basal cell carcinomas, squamous cell carcinoma and actinic keratosis; (3) Results: Several papers reported genetic and molecular alterations leading to non-melanoma skin cancer. Plenty of risk factors are involved in non-melanoma skin cancer pathogenesis, including genetic and molecular alterations, immunosuppression, and ultraviolet radiation; (4) Conclusion: Although skin carcinogenesis is still not fully understood, several papers demonstrated that genetic and molecular alterations are involved in this process. In addition, plenty of non-melanoma skin cancer risk factors are now known, allowing for an effective prevention of non-melanoma skin cancer development. Compared to other papers on the same topic, our review focused on molecular and genetic factors and analyzed in detail several factors involved in non-melanoma skin cancer.

  11. EZH2 as a mediator of treatment resistance in melanoma.

    Science.gov (United States)

    Tiffen, Jessamy C; Gallagher, Stuart J; Tseng, Hsin-Yi; Filipp, Fabian V; Fazekas de St. Groth, Barbara; Hersey, Peter

    2016-09-01

    Direct treatments of cancer such as chemotherapy, radiotherapy and targeted therapy have been shown to depend on recruitment of the immune system for their effectiveness. Recent studies have shown that development of resistance to direct therapies such as BRAF inhibitors in melanoma is associated with suppression of immune responses. We point to emerging data that implicate activation of the polycomb repressive complex 2 (PRC2) and its catalytic component-enhancer of zeste homolog 2 (EZH2)-in progression of melanoma and suppression of immune responses. EZH2 appears to have an important role in differentiation of CD4 T cells and particularly in the function of T regulatory cells, which suppress immune responses to melanoma. We review mechanisms of EZH2 activation at the genomic level and from activation of the MAP kinase, E2F or NF-kB2 pathways. These studies are consistent with activation of EZH2 as a common mechanism for induction of immune suppression in patients failing direct therapies and suggest EZH2 inhibitors may have a role in combination with immunotherapy and targeted therapies to prevent development of immunosuppression. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Brain Metastasis as Initial Manifestation of Melanoma (A Case Report

    Directory of Open Access Journals (Sweden)

    Vitorino Modesto Santos

    2016-06-01

    Full Text Available Background: Melanoma is a malignancy derived from the neural crest, constituted of melanocytes found in the basal layer of epidermis, with the main function of melanin production. Case: A 64-year-old woman was admitted with headache and dyslalia and reported some episodes of vertigo and falls in the last six months. A superficial red and dark skin discoloration in the scalp and a node in the right parotid gland were observed. Computed tomography of the brain showed nodular lesions in the left parietal and right temporal and occipital lobes with hemorrhagic features, in addition to mass effect. Furthermore, PET-CT images were suggestive of brain, lung, and adrenal metastasis. The patient evolved with intracranial hypertension and a neurosurgery was performed. Histopathological and immunohistochemistry studies revealed metastatic melanoma. Conclusions: She underwent schedules of radiation therapy and chemotherapy, but developed uncontrolled sepsis and died in spite of clinical management and intensive care support. Cutaneous primary site of this malignancy in the scalp was previously neglected; therefore, neurological disturbances were the initial manifestations of melanoma. Immunohistochemistry findings allowed ruling out the main differential hypotheses.

  13. Systematic genomic and translational efficiency studies of uveal melanoma.

    Directory of Open Access Journals (Sweden)

    Chelsea Place Johnson

    Full Text Available To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation.

  14. Dermoscopy on subungual melanoma 

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    Grażyna Kamińska-Winciorek

    2013-05-01

    Full Text Available Subungual melanoma is a rare, but one of the diagnostically most difficult variants of melanoma. Unfortunately, due to its late detection, lack of an early reaction from the patient and diagnosis in advanced stages, subungual melanoma is deemed as a prognostically unfavorable variant of this malignancy. Diagnosis of subungual melanoma is very difficult to establish merely on the basis of clinical examination due to the resemblance of subungual hematoma to melanocytic nevus, fungal or bacterial infections. Dermoscopy seems to be the ideal diagnostic tool in the differential diagnosis of this life-threatening disease. Aims. To describe the basic aspects of dermoscopy of subungual melanoma and other conditions involving the nails. Methods. Review of medical database PubMed for the literature of the last 10 years on the dermoscopic patterns of subungual melanoma and other subungual diseases. Results. We collate the fundamental rules of performing dermoscopy in subungual melanoma, as well as basic dermoscopic features and diagnostic algorithms of selected subungual lesions requiring differentiation from melanoma. Conclusions. Dermoscopy is a safe, easily repeatable diagnostic method, and the knowledge of basic dermoscopic patterns of developing melanoma in subungual localization, along with the differential diagnosis of other diseases within the nail plate, will help not only dermatologists, but also the professionals of other specialties, such as surgeons, oncologists, orthopedists, and also general practitioners.

  15. Plasma 25-Hydroxyvitamin D and Risk of Non-Melanoma and Melanoma Skin Cancer

    DEFF Research Database (Denmark)

    Afzal, Shoaib; Nordestgaard, Børge G; Bojesen, Stig E

    2013-01-01

    with increasing cumulative incidence of non-melanoma skin cancer (trend P=2 × 10(-15) and P=3 × 10(-17)) and melanoma skin cancer (P=0.003 and P=0.001). Multivariable adjusted hazard ratios of non-melanoma skin cancer were 5.04 (95% confidence interval (CI): 2.78-9.16) for 25-OH-vitD 50 vs. 60 years, 25-OH...

  16. Primary retroperitoneal melanoma presented in a rare extracutaneous site for malignant melanoma

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    Mohamed Alsharedi

    2016-10-01

    Full Text Available 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.

  17. Identification of an Immunogenic Subset of Metastatic Uveal Melanoma.

    Science.gov (United States)

    Rothermel, Luke D; Sabesan, Arvind C; Stephens, Daniel J; Chandran, Smita S; Paria, Biman C; Srivastava, Abhishek K; Somerville, Robert; Wunderlich, John R; Lee, Chyi-Chia R; Xi, Liqiang; Pham, Trinh H; Raffeld, Mark; Jailwala, Parthav; Kasoji, Manjula; Kammula, Udai S

    2016-05-01

    Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma. We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing. Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8(+) T cells, whereas uveal melanoma TIL were CD4(+) dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL. The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237-49. ©2015 AACR. ©2015 American Association for Cancer Research.

  18. Coping strategies in melanoma patients.

    Science.gov (United States)

    Trapp, Michael; Trapp, Eva-Maria; Richtig, Erika; Egger, Josef Wilhelm; Zampetti, Anna; Sampogna, Francesca; Rohrer, Peter Michael; Komericki, Peter; Strimitzer, Tanja; Linder, Michael Dennis

    2012-11-01

    An observational, questionnaire-based, cross-sectional study was performed to assess whether differences in coping behaviour (positive and negative strategies) between patients with either a recent diagnosis of malignant melanoma (MM) or with benign dermatological disease, were predictive of the diagnosis. Coping strategies were assessed with the German version of the stress-coping questionnaire (SVF 120) in 46 inpatients for whom surgery was planned at the Department of Dermatology, Medical University of Graz, Austria. Subjects were divided into two groups: patients with non-metastatic MM, and patients with benign dermatological diseases (controls). The risk for the diagnosis "melanoma" decreased with higher values of "situation control" (p = 0.007) and increased with higher values of resignation (p = 0.035) and trivialisation (p = 0.039). More-over, the risk for having a MM with thickness > 1 mm decreased in patients with higher values in positive coping strategies (p psychological interventions to improve coping in patients with MM, as differences in coping behaviour seem to appear even in the non-metastatic stage of the disease.

  19. Tumour-associated macrophages are related to progression in patients with metastatic melanoma following interleukin-2 based immunotherapy

    DEFF Research Database (Denmark)

    Hansen, Bettina Dencker; Schmidt, Henrik; von der Maase, Hans

    2006-01-01

    The aim of the present study was to analyze whether leukocyte subsets in peripheral blood and tumour biopsies obtained before treatment were able to predict response or survival in patients with metastatic melanoma following Interleukin-2 (IL-2) based immunotherapy. Flow cytometry was performed...... biopsies were statistically significantly associated with poor response to treatment. Our data suggest that tumour-associated macrophages may correlate negatively with response, which may be of biological importance for IL-2 based immunotherapy of malignant melanoma....

  20. Gingival osteogenic melanoma in two dogs.

    Science.gov (United States)

    Ellis, Angela E; Harmon, Barry G; Miller, Debra L; Northrup, Nicole C; Latimer, Kenneth S; Uhl, Elizabeth W

    2010-01-01

    Osteogenic melanoma is a rare variant of metaplastic malignant melanoma in human medicine and appears to be a similarly rare variant in dogs. Two dogs with oral malignant melanoma with neoplastic bone formation are reported in this study. Both tumors were characterized by malignant melanocytes that transitioned into neoplastic bone at the deep margins of the neoplasm. Immunohistochemical analysis revealed S100- and Melan-A-positive neoplastic cells adjacent to, and occasionally embedded within, an osteoid and chondroblastic matrix. Scattered clusters of neoplastic cells were also positive for osteocalcin. The findings indicate that in dogs, as in humans, neoplastic melanocytes have metaplastic potential and can be osteogenic.

  1. Immunotherapy for advanced melanoma: future directions.

    Science.gov (United States)

    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.

  2. A modified COMS plaque for iris melanoma

    Directory of Open Access Journals (Sweden)

    Daniel J. Scanderbeg

    2011-09-01

    Full Text Available Melanoma of the iris is a rare condition compared to posterior ocular tumors and in this case report we presenta 51-year-old female patient with diffuse iris melanoma. Traditional COMS (Collaborative Ocular Melanoma Studyplaques are used at our institution for radiation therapy, so a novel modification of the traditional plaque was requiredto allow better conformance with placement on the cornea. The usual silastic insert was machined to dimensions incompliance with the cornea, placed without incident, and treatment delivered with excellent patient tolerance of themodified plaque.

  3. Epidemiology of uveal melanomas in Moscow

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    E. E. Grishina

    2017-01-01

    Full Text Available Rationale: Melanoma of the uveal tract of the eye is among the most prevalent malignant intraocular tumors.Aim: To identify epidemiological characteristics of uveal melanoma in Moscow.Materials and methods: We performed a retrospective analysis of out-patient files and follow-up charts of patients with uveal melanoma in the Ophthalmological Clinical Hospital of the Department of Healthcare, Moscow, from 1977 to 2012.Results: Within 36 years, 2547 patients with uveal melanoma have been registered, at the age of 16 to 92 years. The male to female ratio was 1:1.5. The rate of patient referrals with subsequent diagnosis of uveal melanoma has not changed from 1977 to 2000 and was on average 1.07 persons per 100,000 of the adult population. From 2001 to 2012, there was some decline in the number of referrals with uveal melanoma to the average of 0.9 persons per 100,000 of the adult population. We analyzed survival among 359 patients with uveal melanoma after enucleation surgery of the eye; 37% of them were men (63.2 ± 1.8 years and 63% women (69.5 ± 2.7 years. Their 5-year metastasis-free survival was 65 ± 3%, whereas the 7-year survival was 60 ± 4%. The mean time to death was 5.5 years. There were no association between the life longevity and patients gender, but their survival was associated with the age of patients. The risk of death from metastatic uveal melanoma among patients above 60 years of age was on average 10% higher. After the enucleation surgery, patients with Т4 melanoma lived significantly less than those with Т1-3 tumor (5 and 6.5 years, respectively; р = 0.05.Conclusion: The rates of diagnosis of uveal melanoma at referrals within 36 years did not increased. Epidemiology of uveal melanoma in Moscow is characterized by a high proportion of elderly women. Shorter overall and metastasis-free survival of patients with uveal melanoma after the enucleation surgery depends from a higher proportion

  4. Nodular Melanoma Mimicking Keratoacanthoma: Lessons to learn.

    Science.gov (United States)

    Muthupalaniappen, Leelavathi; Das, Srijit; Md Nor, Norazirah; Ali, Siti A M

    2012-08-01

    A 67-year-old man of Chinese descent presented with a painless nodular lesion that had been present on his right forearm for the previous 3 months. A single, well-defined, dome-shaped, firm nodule with a central keratin plug surrounded by erythema was noted. Keratoacanthoma with secondary bacterial infection was suspected and the patient underwent an excision biopsy. Biopsy of the nodule and immunohistochemical staining supported a diagnosis of nodular malignant melanoma. It should be noted both that nodular malignant melanoma may present with a wide variety of clinical appearances, and that the lack of melanin pigment in nodular malignant melanoma may hinder the diagnosis of this aggressive tumour.

  5. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma.

    Science.gov (United States)

    Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

    2014-01-01

    Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. © 2013 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.

  6. Obesity as a risk factor for malignant melanoma and non-melanoma skin cancer.

    Science.gov (United States)

    Karimi, K; Lindgren, T H; Koch, C A; Brodell, Robert T

    2016-09-01

    The dramatic increases in incidence of both obesity and many cancers including skin cancer emphasize the need to better understand the pathophysiology of both conditions and their connections. Melanoma is considered the fastest growing cancer and rates of non-melanoma skin cancer have also increased over the last decade. The molecular mechanisms underlying the association between obesity and skin cancer are not clearly understood but emerging evidence points to changes in the tumor microenvironment including aberrant cell signaling and genomic instability in the chronic inflammatory state many obese individuals experience. This article reviews the literature linking obesity to melanoma and non-melanoma skin cancer.

  7. Experimental boron neutron capture therapy for melanoma: Systemic delivery of boron to melanotic and amelanotic melanoma

    International Nuclear Information System (INIS)

    Coderre, J.A.; Glass, J.D.; Micca, P.; Greenberg, D.; Packer, S.

    1990-01-01

    The boron-containing melanin precursor analogue p-boronophenylalanine (BPA) has previously been shown to selectively deliver boron to pigmented murine melanomas when administered in a single intragastric dose. If boron neutron capture therapy is to become a clinically useful method of radiation therapy for human malignant melanoma, the boron carrier must be capable of delivering useful amounts of boron to remote tumor sites (metastases) and to poorly pigmented melanomas. The authors have now determined the ability of BPA to accumulate in several nonpigmented melanoma models including human melanoma xenografts in nude mice. The absolute amount of boron in the nonpigmented melanomas was about 50% of the observed in the pigmented counterparts but was still selectively concentrated in the tumor relative to normal tissues in amounts sufficient for effective neutron capture therapy. Single intragastric doses of BPA resulted in selective localization of boron in the amelanotic Greene melanoma carried in the anterior chamber of the rabbit eye and in a pigmented murine melanoma growing in the lungs. The ratio of the boron concentration in these tumors to the boron concentration in the immediately adjacent normal tissue was in the range of 3:1 to 4:1. These distribution studies support the proposal that boron neutron capture therapy may be useful as a regional therapy for malignant melanoma

  8. Critical role of glioma-associated oncogene homolog 1 in maintaining invasive and mesenchymal-like properties of melanoma cells.

    Science.gov (United States)

    Gunarta, I Ketut; Li, Rong; Nakazato, Ryota; Suzuki, Ryusuke; Boldbaatar, Jambaldorj; Suzuki, Takeshi; Yoshioka, Katsuji

    2017-08-01

    Cutaneous melanoma is the most aggressive form of skin cancer. This aggressiveness appears to be due to the cancer cells' ability to reversibly switch between phenotypes with non-invasive and invasive potential, and microphthalmia-associated transcription factor (MITF) is known to play a central role in this process. The transcription factor glioma-associated oncogene homolog 1 (GLI1) is a component of the canonical and noncanonical sonic hedgehog pathways. Although GLI1 has been suggested to be involved in melanoma progression, its precise role and the mechanism underlying invasion remain unclear. Here we investigated whether and how GLI1 is involved in the invasive ability of melanoma cells. Gli1 knockdown (KD) melanoma cell lines, established by using Gli1-targeting lentiviral short hairpin RNA, exhibited a markedly reduced invasion ability, but their MITF expression and activity were the same as controls. Gli1 KD melanoma cells also led to less lung metastasis in mice compared with control melanoma cells. Furthermore, the Gli1 KD melanoma cells underwent a mesenchymal-to-epithelial-like transition, accompanied by downregulation of the epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (EMT-TF) Snail1, Zeb1 and Twist1, but not Snail2 or Zeb2. Collectively, these results indicate that GLI1 is important for maintaining the invasive and mesenchymal-like properties of melanoma cells independent of MITF, most likely by modulating a subset of EMT-TF. Our findings provide new insight into how heterogeneity and plasticity are achieved and regulated in melanoma. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  9. Quercetin as an Emerging Anti-Melanoma Agent: A four-focus area therapeutic development strategy

    Directory of Open Access Journals (Sweden)

    Zoey Harris

    2016-10-01

    Full Text Available Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase -- a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes a feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated anti-proliferative and pro-apoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anti-cancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review we explore the potential of Quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a four-focus area strategy to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to i modulate cellular bioreduction potential and associated signaling cascades, ii affect transcription of relevant genes, iii regulate epigenetic processes, and iv develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.

  10. Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    Full Text Available Cutaneous melanoma is an aggressive malignancy; its incidence is increasing worldwide and its prognosis remains poor. Clinical observations indicate that estrogen receptor β (ERβ is expressed in melanoma tissues and its expression decreases with tumor progression, suggesting its tumor suppressive function. These experiments were performed to investigate the effects of ERβ activation on melanoma cell growth.Protein expression was analyzed by Western blot and immunofluorescence assays. Cell proliferation was assessed by counting the cells by hemocytometer. ERβ transcriptional activity was evaluated by gene reporter assay. Global DNA methylation was analyzed by restriction enzyme assay and ERβ isoforms were identified by qRT-PCR. We demonstrated that ERβ is expressed in a panel of human melanoma cell lines (BLM, WM115, A375, WM1552. In BLM (NRAS-mutant cells, ERβ agonists significantly and specifically inhibited cell proliferation. ERβ activation triggered its cytoplasmic-to-nuclear translocation and transcriptional activity. Moreover, the antiproliferative activity of ERβ agonists was associated with an altered expression of G1-S transition-related proteins. In these cells, global DNA was found to be hypomethylated when compared to normal melanocytes; this DNA hypomethylation status was reverted by ERβ activation. ERβ agonists also decreased the proliferation of WM115 (BRAF V600D-mutant cells, while they failed to reduce the growth of A375 and WM1552 (BRAF V600E-mutant cells. Finally, we could observe that ERβ isoforms are expressed at different levels in the various cell lines. Specific oncogenic mutations or differential expression of receptor isoforms might be responsible for the different responses of cell lines to ERβ agonists.Our results demonstrate that ERβ is expressed in melanoma cell lines and that ERβ agonists differentially regulate the proliferation of these cells. These data confirm the notion that melanoma is a

  11. Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture ...

    Indian Academy of Sciences (India)

    Prakash

    2009-12-09

    Dec 9, 2009 ... 2Department of Comparative Anatomy and Anthropology, Institute of Biology, Maria Curie-Skłodowska University, ... in co-cultures of human colon carcinoma cell spheroids obtained from different grades of tumour with normal human ..... expression of HSP72 and MRP in human colon tumour cells.

  12. Anti-SEMA4D Monoclonal Antibody VX15/2503 With Nivolumab or Ipilimumab in Treating Patients With Stage III or IV Melanoma

    Science.gov (United States)

    2018-02-01

    Metastatic Melanoma; Stage III Cutaneous Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7

  13. Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.

    Directory of Open Access Journals (Sweden)

    Laura S Burke

    Full Text Available INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04. The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002. One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002 after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

  14. Recent developments in nanomedicine for melanoma treatment.

    Science.gov (United States)

    Tang, Jian-Qin; Hou, Xiao-Yang; Yang, Chun-Sheng; Li, Ya-Xi; Xin, Yong; Guo, Wen-Wen; Wei, Zhi-Ping; Liu, Yan-Qun; Jiang, Guan

    2017-08-15

    Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side-effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti-tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy. Furthermore, nanomedicine allows delivery of the effector structures into the tumor site via passive or active targeting, thereby allowing increased therapeutic specificity and reduced side effects. In this review, we summarize the latest developments in the application of nanocarrier-mediated targeted drug delivery to melanoma and nanomedicine-related clinical trials in melanoma treatment. We also discuss existing problems and opportunities for future developments, providing direction and new thoughts for further studies. © 2017 UICC.

  15. Pembrolizumab for Ipilimumab-Resistant Melanoma

    Science.gov (United States)

    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

  16. TCGA study of genetic drivers of melanoma

    Science.gov (United States)

    A comprehensive analysis of the genome of cutaneous melanoma has provided new insights into the roles of frequently mutated cancer genes and other genomic alterations that drive the development of this disease.

  17. Metastatic malignant subungal melanoma: Importance of FNAC

    Directory of Open Access Journals (Sweden)

    Radhika Punshi Nandwani

    2014-01-01

    Full Text Available Subungual melanoma is a rare type of skin cancer. It is an uncommon form of acral lentiginous melanoma. Approximately 85% of cases are misdiagnosed initially, and it is generally associated with a poor prognosis. Herein, we describe a case of metastatic subungal melanoma to the axillary lymph node in a 45-year-old male. Diagnosis of metastasis was made based on cytology, where the clinicians were guided to search for primary. This case report highlights the role of fine-needle aspiration cytology (FNAC in the diagnosis of this entity to draw the attention of the reader to the possible underreporting of melanoma because of a variant that evades diagnosis and our reluctance to think about its existence.

  18. Nivolumab-Based Treatments for Advanced Melanoma

    Science.gov (United States)

    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.

  19. Subungual melanoma: Management in the modern era.

    Science.gov (United States)

    Reilly, D J; Aksakal, G; Gilmour, R F; Gyorki, D E; Chauhan, A; Webb, A; Henderson, M A

    2017-12-01

    Subungual melanoma is a rare subtype of cutaneous melanoma that arises from the structures of the nail apparatus. It presents most commonly in older patients and at an advanced stage. A retrospective review of all patients with subungual melanoma in a single institution over a 15-year period was performed. In total, 54 patients were included (26 males, average age 62.9 years), of which 28 cases involved the upper limb. Median tumour thickness was 4.5 mm. Eighteen patients had lymph node metastasis at diagnosis, including 11 of 36 patients with positive sentinel lymph node biopsy. Median survival was 4.6 years. Subungual melanoma has a poor prognosis that is strongly associated with presence of nodal disease at diagnosis. Sentinel lymph node biopsy should be considered to determine stage and prognosis. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  20. A Case of Melanoma Associated Leukoderma

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    Özer Arıcan

    2010-06-01

    Full Text Available Melanoma associated leukoderma is a rare disease characterized by hypopigmented or depigmented macules, which are usualy localized at distant sites from the primary malignant melonoma. Immunologic response to abnormal melanocytes is thought to be responsible for the physiopathology of the disease. A 34-year- old male patient with a facially localized melanoma associated leukoderma is presented and the clinical features, pathogenesis, differential diagnosis, treatment and follow-up of the disease are discussed with the recent literature.

  1. Genital melanoma: prognosis factors and treatment modality.

    Science.gov (United States)

    Ferraioli, Domenico; Lamblin, Gery; Mathevet, Patrice; Hetu, Jessika; Berakdar, Isabelle; Beurrier, Frederic; Chopin, Nicolas

    2016-11-01

    Genital melanoma is a rare pathology. We present the experience of two comprehensive cancer centers in Lyon (France) in the management of genital melanoma in order to identify prognostic factors and optimal treatments. Between April 1992 and Mars 2014, 16 patients with a primary genital melanoma were referred to our department. Nine patients presented a vaginal melanoma, six vulvar melanomas and only one cervical melanoma. The median dimension of the lesion was 33.7 mm (5-100 mm). The AJCC stage ranged from IB to IIIC. 12 cases were the classic dark-blue flat melanoma and the other 4 cases were an atypical amelanotic tumor. Wide local surgery was performed in nine patients. A radical surgery was performed in six patients. In the large cervical melanoma, radiotherapy was performed as first-line treatment. In all the patients regional lymph node staging was performed. Adjuvant treatment was realized in nine patients. Two patients are alive without recurrence. Only one patient was lost to the first follow-up. The other 13 patients experienced a rapid recurrence. The median disease-free survival and the median overall survival were 11.8 months (2-49 m) and of 30.4 m (11-144 m), respectively. The disease-free survival and overall survival could be linked to a clinical presentation (Breslow thickness and morphology of lesion) associated to the early diagnosis. In our small series, the most important prognosis factor remains the tumor thickness. These rare lesions should be treated in experienced centers in order to improve their prognostic.

  2. Extracutaneous melanomas: a primer for the radiologist

    OpenAIRE

    Keraliya, Abhishek R.; Krajewski, Katherine M.; Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Shinagare, Atul B.; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.

    2015-01-01

    Objective: The purpose of this article is to provide a comprehensive review of the imaging features of extracutaneous melanomas. Conclusion: Extracutaneous melanomas are clinically and biologically distinct from their more common cutaneous counterpart with higher frequency of metastatic disease and poorer overall prognosis. Complete surgical excision is the treatment of choice whenever possible; systemic therapy in the form of conventional chemotherapeutic agents as well as novel targeted age...

  3. Vitamin D and melanoma incidence and mortality.

    Science.gov (United States)

    Berwick, Marianne; Erdei, Eszter O

    2013-01-01

    The role of vitamin D (25-OH-D, or 25-hydroxyvitamin D) and its potential confounders in relationship to melanoma risk and mortality is discussed. The paradox that ultraviolet radiation (UVR) exposure is the major environmental risk factor for melanoma etiology as well as a major source of vitamin D might be explained by viewing vitamin D levels as the result of a healthy lifestyle rather than a cause of health. © 2012 John Wiley & Sons A/S.

  4. Peptide-Targeted Radionuclide Therapy for Melanoma

    Science.gov (United States)

    Miao, Yubin; Quinn, Thomas P.

    2011-01-01

    Melanocortin-1 receptor (MC1-R) and melanin are two attractive melanoma-specific targets for peptide-targeted radionuclide therapy for melanoma. Radiolabeled peptides targeting MC1-R/melanin can selectively and specifically target cytotoxic radiation generated from therapeutic radionuclides to melanoma cells for cell killing, while sparing the normal tissues and organs. This review highlights the recent advances of peptide-targeted radionuclide therapy of melanoma targeting MC1R and melanin. The promising therapeutic efficacies of 188Re-(Arg11)CCMSH (188Re-[Cys3,4,10, d-Phe7, Arg11]-α-MSH3-13), 177Lu- and 212Pb-labeled DOTA-Re(Arg11)CCMSH (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[ReO-(Cys3,4,10, d-Phe7, Arg11)]-α-MSH3-13) and 188Re-HYNIC-4B4 (188Re-hydrazinonicotinamide-Tyr-Glu-Arg-Lys-Phe-Trp-His-Gly-Arg-His) in preclinical melanoma-bearing models demonstrate an optimistic outlook for peptide-targeted radionuclide therapy for melanoma. Peptide-targeted radionuclide therapy for melanoma will likely contribute in an adjuvant setting, once the primary tumor has been surgically removed, to treat metastatic deposits and for treatment of end-stage disease. The lack of effective treatments for metastatic melanoma and end stage disease underscores the necessity to develop and implement new treatment strategies, such as peptide-targeted radionuclide therapy. PMID:18387816

  5. TERT promoter mutations in melanoma survival.

    Science.gov (United States)

    Nagore, Eduardo; Heidenreich, Barbara; Rachakonda, Sívaramakrishna; Garcia-Casado, Zaida; Requena, Celia; Soriano, Virtudes; Frank, Christoph; Traves, Victor; Quecedo, Esther; Sanjuan-Gimenez, Josefa; Hemminki, Kari; Landi, Maria Teresa; Kumar, Rajiv

    2016-07-01

    Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter. © 2016 UICC.

  6. Verrucous-Keratotic Malignant Melanoma (VKMM

    Directory of Open Access Journals (Sweden)

    Nikolay Damianov

    2017-07-01

    Full Text Available We report a patient with a verrucous keratotic variant of melanoma visiting the policlinic of Medical Institute of Ministry of Interior (MVR-Sofia, Department of Dermatology and Dermatologic surgery, with a keratotic verrucous lesion, located on the right thigh, partially deeply pigmented at upper right quadrant. The lesion had appeared three years ago before her presentation in the policlinic, and it had gradually enlarged and become darker in the last twelve months. The surface of the lesion was covered with thick hyperkeratotic lobules. The histologic evaluation revealed verrucous melanoma with a tumour thickness of 3 mm and Clark Level IV and focal ulceration. The tumour was staged as stage IIB (T3bN0M0. Sentinel lymph node biopsy was planned. Verrucous-keratotic forms of malignant melanoma occur more commonly in women and favour the extremities, but may be found on any anatomic site. Seventy-one percent of this melanoma type are situated on the upper and lower extremities. Although two-thirds of these neoplasms can be can be histologically graded according to the classification of Clark, one-third of these melanomas with marked verrucous hyperplasia and hyperkeratosis of the epidermis do not fit into his classification. Histological classification of patients with a verrucous keratotic type of melanoma may sometimes be extremely difficult. The marked papilliferous architecture of these lesions made an assessment of Breslow depth difficult. The presented case highlights the clinical existence and features of such benign-looking melanomas. It is therefore important for surgical pathologists to recognise this unusual variant of malignant melanoma, as it may be confused both clinically and pathologically with benign lesions.

  7. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin

    Science.gov (United States)

    Whiteman, David C.; Pavan, William J; Bastian, Boris C.

    2012-01-01

    Summary Converging lines of evidence from varied scientific disciplines suggest that cutaneous melanomas comprise biologically distinct subtypes that arise through multiple causal pathways. Understanding the respective relationships of each subtype with etiologic factors such as UV radiation and constitutional factors is the first necessary step toward developing refined prevention strategies for the specific forms of melanoma. Furthermore, classifying this disease precisely into biologically distinct subtypes is the key to developing mechanism- based treatments, as highlighted by recent discoveries. In this review, we outline the historical developments that underpin our understanding of melanoma heterogeneity, and we do this from the perspectives of clinical presentation, histopathology, epidemiology, molecular genetics, and developmental biology. We integrate the evidence from these separate trajectories to catalog the emerging major categories of melanomas and conclude with important unanswered questions relating to the development of melanoma and its cells of origin. PMID:21707960

  8. Intratumoral Approaches for the Treatment of Melanoma.

    Science.gov (United States)

    Bommareddy, Praveen K; Silk, Ann W; Kaufman, Howard L

    There have been significant advances in the immunotherapy of melanoma over the last decade. The tumor microenvironment is now known to promote an immune-suppressive milieu that can block effective immune-mediated tumor rejection. Several novel strategies designed to overcome local immunosuppression hold promise for treatment of melanoma and other cancers. These approaches include oncolytic viruses, plasmid DNA delivery, Toll-like receptor agonists, inflammatory dyes, cytokines, checkpoint inhibitors, immunomodulatory agents, and host and pathogenic cell-based vectors. In addition, there are several novel methods for local drug delivery, including direct injection, image-guided, electroporation, and nanodelivery techniques under study. The approval of talimogene laherparepvec (Imlygic), an attenuated, recombinant oncolytic herpesvirus, for melanoma treatment is the first intratumoral agent to receive regulatory approval for the treatment of patients with melanoma. This review will focus on the rationale for intratumoral treatment in melanoma, describe the clinical and safety data for some of the agents in clinical development, and provide a perspective for future clinical investigation with intratumoral approaches. Melanoma has been a paradigm tumor for progress in targeted therapy and immunotherapy and will likely also be the tumor to establish the therapeutic role of intratumoral treatment for cancer.

  9. [Systemic treatment of inoperable metastasized malignant melanoma].

    Science.gov (United States)

    Gutzmer, R; Rauschenberg, R; Meier, F

    2016-07-01

    The medical therapy of inoperable malignant melanoma has changed dramatically over the last few years. The purpose of this article is to summarize the current state of systemic medical treatment of malignant melanoma. Clinical studies and guidelines in the therapy of malignant melanoma are reviewed. Medical therapy of inoperable melanoma changed due to developments in immunotherapies (checkpoint inhibitors) and molecular-targeted therapies (BRAF and MEK inhibitors). Checkpoint inhibitors are antibodies administered as infusions every 2-3 weeks, blocking the checkpoints PD-1 or CTLA-4, thus, preventing downregulation of the immune system. BRAF and MEK inhibitors are small molecules, they are given orally and block a certain signaling pathway in tumor cells. The activation of this pathway has to be demonstrated by molecular analysis of tumor tissue first. This strategy is currently registered for 40-50 % of melanomas harboring a BRAF V600 mutation, while the combination of a BRAF plus MEK inhibitor has been proven more efficient than a BRAF inhibitor alone. A fascinating development has started in the melanoma field due to immunotherapeutic and molecular-targeted treatment strategies. The continuation of this development needs further clinical and translational studies. This includes particular clinical studies with the new substances in the adjuvant situation, and sequences and combinations in the metastatic setting. Translational studies are needed to develop biomarkers for response and side effects.

  10. Cellular heterogeneity in vertical growth phase melanoma.

    Science.gov (United States)

    Laga, Alvaro C; Murphy, George F

    2010-12-01

    Melanoma growing as a tumorigenic nodule is one of the most virulent neoplasms to which the flesh is heir. At a considerably small tumor size, it incurs significant risk for widespread metastatic dissemination. There are no effective means of surgical intervention, chemical therapy, or immunologic therapy for advanced and metastatic melanoma. To review the literature and highlight recent cardinal advances in the understanding of melanoma vertical growth, with specific emphasis on how its recognition and characterization may be applied to diagnostic practice and development of novel investigative approaches. Literature review, archival material, personal experience, and research collaborators. The study of tumorigenic melanoma, both in primary lesions and in metastases, is the key to the eventual eradication of this highly virulent neoplasm that may disseminate widely when only occupying the volume of a grain of rice. Morphology often provides the first insight into structure and function. A growing database using meticulous and inclusive criteria to define tumor stem cells in the context of clinically relevant models now indicates that the key to melanoma heterogeneity may reside in a small subpopulation with the ability to self-renew and form tumors despite most cells present being significantly less virulent. Hopefully, from these insights into melanoma tumor progression from radial growth phase to heterogeneous and tumorigenic vertical growth phase will come additional answers to how smart therapies may be developed that specifically target those vertical growth phase cells that most pertain to patient survival.

  11. Targeting Sphingosine Kinase-1 To Inhibit Melanoma

    Science.gov (United States)

    Madhunapantula, SubbaRao V.; Hengst, Jeremy; Gowda, Raghavendra; Fox, Todd E.; Yun, Jong K; Robertson, Gavin P.

    2012-01-01

    SUMMARY Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient’s tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID:22236408

  12. Melanoma m (zero): diagnosis and therapy.

    Science.gov (United States)

    Rastrelli, Marco; Alaibac, Mauro; Stramare, Roberto; Chiarion Sileni, Vanna; Montesco, Maria Cristina; Vecchiato, Antonella; Campana, Luca Giovanni; Rossi, Carlo Riccardo

    2013-01-01

    This paper reviews the epidemiology, diagnosis, and treatment of M zero cutaneous melanoma including the most recent developments. This review also examined the main risk factors for melanoma. Tumor thickness measured according to Breslow, mitotic rate, ulceration, and growth phase has the greatest predictive value for survival and metastasis. Wide excision of the primary tumor is the only potentially curative treatment for primary melanoma. The sentinel node biopsy must be performed on all patients who have a primary melanoma with a Breslow thickness > 1 mm, or if the melanoma is from 0,75 mm to 1 mm thick but it is ulcerated and/or the mitotic index is ≥1. Total lymph node dissection consists in removing the residual lymph nodes in patients with positive sentinel node biopsy, or found positive on needle aspiration biopsy, without radiological evidence of spread. Isolated limb perfusion and isolated limb infusion are employed in patients within transit metastases with a rate of complete remission in around 50% and 38% of cases. Electrochemotherapy is mainly indicated for palliation in cases of metastatic disease, though it may sometimes be useful to complete isolated limb perfusion. The only agent found to affect survival as an adjuvant treatment is interferon alpha-2. Adjuvant radiotherapy improves local control of melanoma in patients at a high risk of recurrence after lymph node dissection.

  13. Treatment and outcomes of anorectal melanoma.

    LENUS (Irish Health Repository)

    Heeney, Anna

    2012-02-01

    INTRODUCTION: anorectal melanoma is an uncommon disease constituting less than 3% of all melanomas. Due to its rarity, there are a lack of randomized control trials regarding appropriate management and current evidence is based mainly on retrospective studies. METHODS: in view of the controversial surgical treatment of anorectal melanoma, we review the most published literature in an attempt to elucidate its typical clinical features along with current thinking with respect to management approaches to this aggressive disease. Using the keywords "anorectal" and "malignant melanoma", a medline search of all articles in English was performed and the relevant articles procured. Additional references were retrieved by cross reference from key articles. RESULTS: anorectal melanoma affects the elderly with a slight preponderance for females. It commonly presents disguised as benign disease with local bleeding or suspicion for haemorrhoidal disease. There is no convincing evidence to indicate that radical resection of primary anorectal melanoma is associated with improvement in local control or survival, and local excision is an acceptable treatment option. CONCLUSION: optimum management depends on several factors and the therapeutic goals should be to lengthen survival and preserve quality-of-life. Given that wide local excision is a more limited intervention with comparable survival it should be considered as the initial treatment choice. Unfortunately prognosis for patients with this disease remains poor despite choice of treatment strategy with overall five year disease-free survival less than twenty percent in most studies.

  14. Anorectal Malignant Melanomas: Experience of Uludag University

    Directory of Open Access Journals (Sweden)

    Berna Aytac

    2010-12-01

    Full Text Available Anorectal melanomas represent a group of mucosal melanomas with unknown etiology and poor prognosis. The lesions can be misdiagnosed as hemorrhoids during clinical examination. We reviewed the morphological and clinical features of 14 anorectal melanomas, and discuss the treatment modalities of this entity. Fourteen patients who were diagnosed with anorectal malignant melanoma between 1997 and 2004 were evaluated with regard to age, sex, size, morphology, lymph node or distant metastasis, treatment modality and survival. Eight patients were female and six were male, and their mean age was 58 years. The size of melanoma ranged from 3 cm to 8 cm. Pathological evaluation revealed epithelioid and spindle cell type tumor in seven and two patients, respectively, whereas, in the remaining seven patients, the tumor was composed of both types. Pigmentation was apparent in all tumors. There was lymph node metastasis in 11 patients and distant metastasis in all patients. Eleven patients underwent abdominoperineal resection and three were treated by local excision. Mean survival was 8.7 months. Prognosis of anorectal melanoma remains poor. Awareness of the diverse clinicopathological features of these lesions, both on the part of the clinicians and pathologists, is crucial for their early detection and proper treatment.

  15. CB2 Receptor Activation Inhibits Melanoma Cell Transmigration through the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    János Haskó

    2014-05-01

    Full Text Available During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB. The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2; therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A, GPR18 (transcriptional variant 1 and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A, GPR18 (transcriptional variants 1 and 2, GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma.

  16. Disruption of GRM1-mediated signalling using riluzole results in DNA damage in melanoma cells.

    Science.gov (United States)

    Wall, Brian A; Wangari-Talbot, Janet; Shin, Seung S; Schiff, Devora; Sierra, Jairo; Yu, Lumeng J; Khan, Atif; Haffty, Bruce; Goydos, James S; Chen, Suzie

    2014-03-01

    Gain of function of the neuronal receptor, metabotropic glutamate receptor 1 (Grm1), was sufficient to induce melanocytic transformation in vitro and spontaneous melanoma development in vivo when ectopically expressed in melanocytes. The human form of this receptor, GRM1, has been shown to be ectopically expressed in a subset of human melanomas but not benign nevi or normal melanocytes, suggesting that misregulation of GRM1 is involved in the pathogenesis of certain human melanomas. Sustained stimulation of Grm1 by the ligand, glutamate, is required for the maintenance of transformed phenotypes in vitro and tumorigenicity in vivo. In this study, we investigate the mechanism of an inhibitor of glutamate release, riluzole, on human melanoma cells that express metabotropic glutamate receptor 1 (GRM1). Various in vitro a