Melanoma
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Melanoma is a malignancy of the skin in which melanocytes (the cells which give the skin it's colour) become cancerous. Melanoma occurs most frequently in white people, and is rare in people with dark skin; it is usually found in adults, though occasionally melanoma may develop in children and adolescents. Over exposure to sunlight can cause skin changes which can lead to melanoma. Half of all melanomas are thought to arise in a benign (non-cancerous) pigmented nevus (a mole). Moles are very common and normally change only slightly over time; however in melanoma there may be a more rapid increase in size - symptoms include a darker or variable discoloration, itching, and possibly ulceration and bleeding

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Information for Patients and the Public
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Latest Research Publications
Intraocular Melanoma
Skin Cancer

Information Patients and the Public (15 links)


Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Tan M, Howard A, Cyr AE
Malignant melanoma of the breast: a case report and review of the literature.
Tumori. 2013 Jan-Feb; 99(1):e11-3 [PubMed]
Primary breast melanoma is a rare entity that on routine histology may be mistaken for triple-negative breast cancer. A high degree of clinical suspicion is necessary to make this diagnosis. This case report describes the presentation and treatment of primary breast melanoma.


Wilson EC, Emery JD, Kinmonth AL, et al.
The cost-effectiveness of a novel SIAscopic diagnostic aid for the management of pigmented skin lesions in primary care: a decision-analytic model.
Value Health. 2013 Mar-Apr; 16(2):356-66 [PubMed]
OBJECTIVES: Pigmented skin lesions are commonly presented in primary care. Appropriate diagnosis and management is challenging because the vast majority are benign. The MoleMate system is a handheld SIAscopy scanner integrated with a primary care diagnostic algorithm aimed at improving the management of pigmented skin lesions in primary care.
METHODS: This decision-model-based economic evaluation draws on the results of a randomized controlled trial of the MoleMate system versus best practice (ISRCTN79932379) to estimate the expected long-term cost and health gain of diagnosis with the MoleMate system versus best practice in an English primary care setting. The model combines trial results with data from the wider literature to inform long-term prognosis, health state utilities, and cost.
RESULTS: Results are reported as mean and incremental cost and quality-adjusted life-years (QALYs) gained, incremental cost-effectiveness ratio with probabilistic sensitivity analysis, and value of information analysis. Over a lifetime horizon, the MoleMate system is expected to cost an extra £18 over best practice alone, and yield an extra 0.01 QALYs per patient examined. The incremental cost-effectiveness ratio is £1,896 per QALY gained, with a 66.1% probability of being below £30,000 per QALY gained. The expected value of perfect information is £43.1 million.
CONCLUSIONS: Given typical thresholds in the United Kingdom (£20,000-£30,000 per QALY), the MoleMate system may be cost-effective compared with best practice diagnosis alone in a primary care setting. However, there is considerable decision uncertainty, driven particularly by the sensitivity and specificity of MoleMate versus best practice, and the risk of disease progression in undiagnosed melanoma; future research should focus on reducing uncertainty in these parameters.


Dong Y, Zhuang L, Ma W
Comprehensive assessment of the association of ERCC2 Lys751Gln polymorphism with susceptibility to cutaneous melanoma.
Tumour Biol. 2013; 34(2):1155-60 [PubMed]
Previous studies evaluating the association between excision repair cross-complimentary group 2 (ERCC2) Lys751Gln polymorphism and susceptibility to cutaneous melanoma reported conflicting findings. We searched PubMed and Wangfang Medical databases up to October 16, 2012 to identify eligible studies. A total of 8 case-control studies including 3,492 cases and 5,381 controls were included in the meta-analysis. Statistical analysis was performed with Review Manage version 5.1. Odds ratios (ORs) with 95 % confidence intervals (95 %CIs) were used to assess the strength of the association. There was no obvious between-study heterogeneity among those eight studies under all four comparison models. Overall, there was a significant association between ERCC2 Lys751Gln polymorphism and susceptibility to cutaneous melanoma under three genetic models (for Gln versus Lys: OR = 1.08, 95 % CI = 1.01-1.15, P = 0.02; for GlnGln versus LysLys: OR = 1.16, 95 % CI = 1.01-1.33, P = 0.03; for GlnGln/LysGln versus LysLys: OR = 1.10, 95 % CI = 1.01-1.21, P = 0.04). Sensitivity analysis by omitting one study a time showed the significance of the pooled ORs was stable under all those three genetic models above. Therefore, the meta-analysis suggests that there is a significant association between ERCC2 Lys751Gln polymorphism and susceptibility to cutaneous melanoma.


Shah K, Esmaeli B, Ginsberg LE
Perineural tumor spread along the nasociliary branch of the ophthalmic nerve: imaging findings.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):282-5 [PubMed]
Perineural spread along the nasociliary branch of the ophthalmic nerve has not been previously described, to our knowledge. One case of cutaneous squamous carcinoma at the medial canthus and another of melanoma of the nasal ala, with nasociliary nerve perineural spread, are illustrated here. Whereas magnetic resonance imaging is preferred to search for perineural spread, computed tomography may also demonstrate perineural thickening and enhancement. Awareness of the computed tomography appearance of perineural spread will aid in avoiding misdiagnosis.


Fink EC, Fisher DE
BRAF and MC1R in melanoma: different in head and neck tumors?
J Invest Dermatol. 2013; 133(4):878-80 [PubMed]
In this issue, Hacker et al. (2012) report the largest study to date on the association between MC1R variants and BRAF mutant melanoma. Although they did not observe a significant overall correlation, there was a significant negative association between BRAF and MC1R mutations for head/neck melanomas. This suggests a fundamental difference in pathogenesis between head/neck and truncal melanomas, which could contribute to their divergent prognoses.


Pisano M, DE Paola I, Nieddu V, et al.
In vitro activity of the αvβ3 integrin antagonist RGDechi-hCit on malignant melanoma cells.
Anticancer Res. 2013; 33(3):871-9 [PubMed]
BACKGROUND: In malignant melanoma (MM), overexpression of αvβ3 integrin is linked to a more metastatic phenotype. Development of anti-αvβ3 agents able to counteract melanoma progression would be helpful for disease treatment. A new selective ligand of αvβ3, RGDechi-hCit, has anti-angiogenic properties against endothelial cells in animal angiogenesis models. The aim of this study was to evaluate the in vitro effects of the RGDechi-hCit peptide on MM cell lines.
MATERIALS AND METHODS: Cytofluorimetric analysis characterized the cell surface expression of αvβ3 integrin on seven MM cell lines: A375, WM266-4, SK-Mel-28, Sbcl2, LB24Dagi, PR-Mel and PNP-Mel. Cell proliferation, adhesion, and migration assays were carried out using the αvβ3-antagonist RGDechi-hCit.
RESULTS: Proliferation was not significantly inhibited by RGDechi-hCit, although striking morphological changes were detected in MM cell lines highly expressing αvβ3. Conversely, assays on fibronectin-coated plates showed a significant RGDechi-hCit dose-dependent inhibitory effect on both adhesion and migration.
CONCLUSION: The data demonstrate anti-adhesion and anti-migration, but not antiproliferative, activities of RGDechi-hCit against MM cells.


McCannel TA
Fine-needle aspiration biopsy in the management of choroidal melanoma.
Curr Opin Ophthalmol. 2013; 24(3):262-6 [PubMed]
PURPOSE OF REVIEW: Fine-needle aspiration biopsy of choroidal melanoma offers an opportunity to determine the prognosis for metastasis and provide tissue resources for further study to develop molecular-based targeted therapies. Patients increasingly desire as much information as possible about their cancer so that they may plan their lives and investigate new treatments. Physicians who treat choroidal melanoma must become skilled in the technique so that even the smallest tumors, in patients who might benefit most from early treatment, may be safely biopsied. Individualized molecular therapies of the future will be predicated on the results of a patient's fine-needle biopsy.
RECENT FINDINGS: Fine-needle aspiration biopsy for metastatic prognostication was first performed in North America at the Jules Stein Eye Institute, the University of California, Los Angeles in 2004. Subsequent reports from the major ophthalmic oncology centers have since evaluated several platforms for prognostication using mainly DNA-based approaches. Monosomy 3 of the primary tumor is the cytogenetic abnormality most strongly associated with the development of metastasis. The longest clinical follow-up of a cohort of patients at the Jules Stein Eye Institute who underwent biopsy for prognostication reported in 2012 revealed no increase in ocular morbidity or metastatic risk.
SUMMARY: Fine-needle aspiration biopsy for prognostication in choroidal melanoma is the current standard of care because of new molecular knowledge and a more patient-centered approach to healthcare. Future targeted molecular therapies and metastatic surveillance in patients with choroidal melanoma may be directed by the results of fine-needle aspiration biopsy of the primary tumor.


Knight DA, Ngiow SF, Li M, et al.
Host immunity contributes to the anti-melanoma activity of BRAF inhibitors.
J Clin Invest. 2013; 123(3):1371-81 [PubMed] Free Access to Full Article
The BRAF mutant, BRAF(V600E), is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF(V600E) metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF(V600E)-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf(V600E)-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf(V600E) mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8(+) T/FoxP3(+)CD4(+) T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.


Karagiannis P, Gilbert AE, Josephs DH, et al.
IgG4 subclass antibodies impair antitumor immunity in melanoma.
J Clin Invest. 2013; 123(4):1457-74 [PubMed] Free Access to Full Article
Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.


Haley AC, MacLean M, Bierman J, et al.
Melanoma opportunistic surveillance by physician assistant and medical students: analysis of a novel educational trainer.
J Physician Assist Educ. 2012; 23(4):6-15 [PubMed]
PURPOSE: The objective was to identify first-year physician assistant (PA) students' and third-year medical students' knowledge, attitudes, and behaviors about melanoma and to assess an educational intervention.
METHODS: Thirty first-year PA students and 29 third-year medical students (M3) at Northwestern University completed a questionnaire on participants' views of barriers and facilitators to performing melanoma screening. The students were given a pretest with a melanoma education model trainer to identify suspicious lesions, and following an educational intervention, students were given a posttest model trainer assessment.
RESULTS: Apart from time constraints (87% PA; 79% M3) and comorbidities (53% PA; 57% M3), lack of training was a frequently reported barrier to performing opportunistic surveillance (27% PA; 31% M3). Commonly reported facilitators included identification of patients at high risk for developing melanoma (60% PA; 69% M3) and skin-examination training to recognize melanoma (67% PA; 55% M3). With the melanoma trainer pretest, 35% of PA students and 27% of M3 students identified all of the melanomas (P = .61). Following educational intervention, 67% of PA students and 10% of M3 students identified all of the melanomas (P<.01). PA student identification of melanoma significantly increased from pretest to posttest (P = .035), while M3 decreased, but not appreciably (P = .063).
CONCLUSIONS: Education in melanoma detection may enhance the students' cognitive and technical skills necessary to perform accurate opportunistic surveillance. Although PA and medical students reported the same significant barriers and facilitators to performing skin exams, there was a difference in implementation of skills and in the management decisions.


Posch C, Moslehi H, Feeney L, et al.
Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo.
Proc Natl Acad Sci U S A. 2013; 110(10):4015-20 [PubMed] Article available free on PMC after 05/09/2013
Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.


Jiang G, Jiang AJ, Cheng Q, et al.
A dual-regulated oncolytic adenovirus expressing interleukin-24 sensitizes melanoma cells to temozolomide via the induction of apoptosis.
Tumour Biol. 2013; 34(2):1263-71 [PubMed]
Malignant melanoma is one of the most lethal and aggressive human malignancies. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to malignant melanoma. The alkylating agent temozolomide (TMZ) is one of the most effective single chemotherapeutic agents for patients with malignant melanoma, but resistance develops quickly and with high frequency. We constructed a dual-regulated oncolytic adenovirus expressing interleukin 24 (IL-24) gene (Ki67-ZD55-IL-24) by utilizing the Ki67 promoter to replace the native viral promoter of E1A gene. We investigated whether a combination of Ki67-ZD55-IL-24-mediated gene virotherapy and chemotherapy using TMZ produces increased cytotoxicity against human melanoma cells via the induction of apoptosis. Our data indicate that this novel strategy thus holds promising potentials for further developing an effective approach to treat malignant melanoma.


Pailoor J, Mun KS, Leow M
Cutaneous malignant melanoma: clinical and histopathological review of cases in a Malaysian tertiary referral centre.
Malays J Pathol. 2012; 34(2):97-101 [PubMed]
Melanoma is a lethal skin cancer that occurs predominantly among Caucasians. In Malaysia, the incidence of melanoma is low. This is a retrospective study of clinical and histopathological features of patients with cutaneous melanoma who were seen at the University Malaya Medical Centre from 1998 to 2008. Thirty-two patients with cutaneous melanoma were recorded during that period. Of these, 24 had sought treatment at the onset of disease at our centre. Chinese patients constituted the largest group (19 cases). The median age of these 24 patients at the time of presentation was 62 years. 16 patients had melanoma involving the lower limb with 12 affecting the sole of the foot. None had melanoma arising from the face. Histopathology showed nodular melanoma in 22 cases (91.6%), with superficial spreading and acral lentiginous melanoma diagnosed in 1 case each. The majority of patients (62.5%) were found to be in Stage III of the disease at the time of diagnosis.


Ibrahim ZA, Narihan MZ, Ojep DN, et al.
Cyclin D1 expression in acral melanoma: a case control study in Sarawak.
Malays J Pathol. 2012; 34(2):89-95 [PubMed]
Acral melanoma has been reported to have distinctive clinical presentation and ethnic distribution compared to other histological types of malignant melanoma. Acral melanoma also exhibits distinctive focused gene amplifications, including cyclin D1 overexpression. We reviewed archived histological material of malignant melanoma in the Sarawak General Hospital from year 2004 to 2010. 43 tumours, comprising 28 acral melanoma and 15 non-acral melanoma, had sufficient material to be included in the study. The majority (36%) of acral melanoma tumours occurred in the heel. The tumours were analyzed for cyclin D1 expression by immunohistochemistry. 68% of acral melanoma were cyclin D1 positive compared to a positivity of 33% in non-acral tumours. This difference was statistically significant (p < 0.05). This finding may improve the histological diagnosis of acral melanoma and detection of positive resection margins.


Matin RN, Chikh A, Chong SL, et al.
p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.
J Exp Med. 2013; 210(3):581-603 [PubMed] Article available free on PMC after 11/09/2013
The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.


Shenoy S, Cassim R
Metastatic melanoma to the gastrointestinal tract: role of surgery as palliative treatment.
W V Med J. 2013 Jan-Feb; 109(1):30-3 [PubMed]
BACKGROUND: Malignant melanoma is an uncommon metastatic tumor found in the gastrointestinal tract but most commonly involves the small bowel. Less than 5% of patients with metastases to the gastrointestinal tract are diagnosed antemortem. Clinical presentation could be an acute abdominal emergency such as a bowel obstruction, intussusception, bleeding and perforation or chronic symptoms with weight loss, abdominal pain and anemia.
METHODS: We report two unusual cases with acute gastrointestinal complications related to metastatic melanoma. Case 1 developed acute upper gastrointestinal bleeding and was diagnosed with gastric mass. Biopsy revealed metastatic melanoma. The patient died of his advanced disease. Case 2 with unknown primary melanoma presented with acute abdomen secondary to small bowel perforation. He underwent laparotomy and small bowel resection with palliative intent. The patient remains alive and free of symptoms at 4 year follow up.
CONCLUSIONS: Metastatic melanoma of the gastrointestinal tract should be suspected in any patient with history of cutaneous melanoma and new gastrointestinal symptoms. Surgical interventions for symptomatic patients with melanoma of the gastrointestinal tract significantly relieve pain and improve quality of life and may confer a survival advantage.


Chen X, He D, Dong XD, et al.
MicroRNA-124a is epigenetically regulated and acts as a tumor suppressor by controlling multiple targets in uveal melanoma.
Invest Ophthalmol Vis Sci. 2013; 54(3):2248-56 [PubMed]
PURPOSE: MicroRNA-124a (miR-124a), an abundant microRNA in the central neuron system, has been linked to tumor progression. Here, we investigated the role of miR-124a in uveal melanoma development.
METHODS: Expression of miR-124a in uveal melanoma cells was examined using real time RT-PCR. The effect of miR-124a on cell proliferation, migration, and invasion was analyzed using MTS assay, flow cytometry, and transwell experiments. The ability of miR-124a to repress tumor growth was tested in vivo. Target genes of miR-124a were first predicted by bioinformatics, confirmed using a luciferase assay, and their expression determined by Western blotting. DNA methylation and histone modification of miR-124a was analyzed by methylation-specific PCR and ChIP assay. Finally, epigenetic drugs were used to alter the expression of miR-124a.
RESULTS: miR-124a expression was downregulated in both uveal melanoma cells and clinical specimens. Transient transfection of miR-124a into uveal melanoma cells inhibited cell growth, migration, and invasion. Moreover, introduction of miR-124a suppressed in vivo growth of tumor. Potential targets of miR-124a were found to include CDK4, CDK6, cyclin D2, and EZH2. Knockdown of EZH2 by siRNA resulted in inhibition of uveal melanoma cell migration and invasion. In addition, miR-124a expression was found to be regulated via epigenetic mechanisms, with its expression restored when cells were treated with a DNA hypomethylating agent, 5-aza-2'-deoxycytidine, and a histone deacetylase inhibitor, trichostatin A.
CONCLUSIONS: Our results demonstrated that miR-124a could function as a potent tumor suppressor by regulation of multiple targets, and was epigenetically silenced in the development of uveal melanoma.


Wilmott JS, Menzies AM, Haydu LE, et al.
BRAF(V600E) protein expression and outcome from BRAF inhibitor treatment in BRAF(V600E) metastatic melanoma.
Br J Cancer. 2013; 108(4):924-31 [PubMed] Article available free on PMC after 05/03/2014
Background:To examine the association between level and patterns of baseline intra-tumoural BRAF(V600E) protein expression and clinical outcome of BRAF(V600E) melanoma patients treated with selective BRAF inhibitors.Methods:Fifty-eight BRAF(V600E) metastatic melanoma patients treated with dabrafenib or vemurafenib on clinical trials had pre-treatment tumour BRAF(V600E) protein expression immunohistochemically (IHC) assessed using the BRAF V600E mutant-specific antibody VE1. Sections were examined for staining intensity (score 1-3) and percentage of immunoreactive tumour cells, and from this an immunoreactive score (IRS) was derived (intensity × per cent positive/10). The presence of intra-tumoural heterogeneity for BRAF(V600E) protein expression was also assessed. BRAF(V600E) expression was correlated with RECIST response, time to best response (TTBR), progression-free survival (PFS) and overall survival (OS).Results:Expression was generally high (median IRS 28 (range 5-30)) and homogeneous (78%). Expression of mutated protein BRAF(V600E) as measured by intensity, per cent immunoreactive cells, or IRS did not correlate with RECIST response, TTBR, PFS or OS, including on multivariate analysis. Heterogeneity of staining was seen in 22% of cases and did not correlate with outcome.Conclusion:In the current study population, IHC-measured pre-treatment BRAF(V600E) protein expression does not predict response or outcome to BRAF inhibitor therapy in BRAF(V600E) metastatic melanoma patients.


O'Day SJ, Eggermont AM, Chiarion-Sileni V, et al.
Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma.
J Clin Oncol. 2013; 31(9):1211-8 [PubMed]
PURPOSE: Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with paclitaxel versus paclitaxel alone in patients with advanced melanoma.
PATIENTS AND METHODS: Patients with stage IV chemotherapy-naive melanoma (n = 651) were randomly assigned 1:1 to paclitaxel 80 mg/m(2) either alone or in combination with elesclomol 213 mg/m(2) administered weekly for 3 weeks of a 4-week cycle. Patients were stratified by prior systemic treatment, M1 subclass, and baseline lactate dehydrogenase (LDH) levels. The primary end point was PFS.
RESULTS: The study did not achieve its PFS end point (hazard ratio, 0.89; P = .23). The study was stopped when an early overall survival data analysis indicated an imbalance in total deaths favoring paclitaxel, predominantly in patients with high LDH levels. A prospectively defined subgroup analysis revealed a statistically significant improvement in median PFS for the combination in patients with normal baseline LDH.
CONCLUSION: The addition of elesclomol to paclitaxel did not significantly improve PFS in unselected patients with advanced melanoma. The association between baseline LDH and clinical outcomes suggests that LDH may be a predictive factor for treatment with this combination, consistent with recent findings on the association between elesclomol anticancer activity and cellular metabolic state.


Dzepina D, Kalogjera L, Baudoin T
Recurrent sinonasal melanoma--report of five surgical cases and short literature review.
Coll Antropol. 2012; 36 Suppl 2:179-84 [PubMed]
The aim of this study is to present five surgical cases of recurrent sinonasal melanoma. We report the clinical course of this highly malignant disease and give a brief overview of the relevant literature. For the purpose of our presentation, inclusion criteria for all patients were initally negative surgical margins, surgery with curative intent without implementation of radiotherapy, and absence of distant metastatic spread at presentation (MO). They were diagnosed and treated at the same ENT/Head and Neck Surgery department and had clear surgical margins following first resection. The majority of five cases had local recurrences (average two) which were all amenable to at least one salvage operation. In conclusion, despite extensive disease at presentation, we recommend repeated attempts at local surgical salvage. However, this decision must be carefully considered, respecting postoperative quality of life, the estimated life expectancy as well as general socioeconomic issues in each particular case.


Hyter S, Indra AK
Nuclear hormone receptor functions in keratinocyte and melanocyte homeostasis, epidermal carcinogenesis and melanomagenesis.
FEBS Lett. 2013; 587(6):529-41 [PubMed]
Skin homeostasis is maintained, in part, through regulation of gene expression orchestrated by type II nuclear hormone receptors in a cell and context specific manner. This group of transcriptional regulators is implicated in various cellular processes including epidermal proliferation, differentiation, permeability barrier formation, follicular cycling and inflammatory responses. Endogenous ligands for the receptors regulate actions during skin development and maintenance of tissue homeostasis. Type II nuclear receptor signaling is also important for cellular crosstalk between multiple cell types in the skin. Overall, these nuclear receptors are critical players in keratinocyte and melanocyte biology and present targets for cutaneous disease management.


Sugimoto M, Gotohda N, Kato Y, et al.
Pancreatic resection for metastatic melanoma originating from the nasal cavity: a case report and literature review.
Anticancer Res. 2013; 33(2):567-73 [PubMed]
Metastatic pancreatic malignant melanoma is considered to be a highly aggressive neoplasm, and only few metastasectomies for lesions originating from the skin or the ocular region have been reported. We report a case of resection of pancreatic metastasis of malignant melanoma originating from the nasal cavity. An isolated pancreatic tumor was detected in a 46-year-old man who had undergone proton-beam therapy for nasal melanoma 12 months earlier. He underwent distal pancreatectomy with splenectomy and the pathological diagnosis was metastatic malignant melanoma. We review cases of malignant melanoma metastatic to the pancreas and further discuss their incidence, therapeutic strategy, and outcome of mucosal melanoma of the head and neck.


Smith OJ, Rimouche S, Oudit D, et al.
Is superficial inguinal node dissection adequate for regional control of malignant melanoma in patients with N1 disease?
J Plast Reconstr Aesthet Surg. 2013; 66(4):472-7 [PubMed]
INTRODUCTION: The optimum extent of surgery for inguinal nodal metastases due to melanoma remains controversial. Recent evidence suggests a conservative superficial groin dissection (SGD) may provide adequate regional control.
AIM: To evaluate patients with N1 stage disease treated with SGD to determine the recurrence rates and to evaluate whether SGD was adequate for regional control in these patients.
MATERIALS AND METHODS: Patients undergoing SGD between April 2005 and April 2012 were retrospectively analysed from a prospectively collected database.
RESULTS: Sixty patients were treated by SGD of which 40 had palpable disease and 20 had a positive sentinel node. Overall median follow-up was 38 months, with median follow-up for the SNB group being 29 months and that of the PD group 49 months. Three patients (5%) developed groin recurrence following SGD. All patients recurred within the superficial site of surgery; there was no deep inguinal or pelvic recurrence. Distant recurrence occurred in 22 patients (36.7%), with 21 of these patients coming from the PD group and one from the SNB group. This difference was statistically significant (p < 0.05). Overall survival at 5 years was 70.3%. Survival at 5 years in the PD group was 63.8% and in the SNB group it was 90.9%, this difference was approaching significance (p = 0.08).
CONCLUSION: SGD appears adequate for local disease control in patients with N1 sentinel node positive disease. Longer term followup for N1 palpable disease is required to determine the suitability of SGD for this group of patients.


Wen X, Rao P, Carreño LJ, et al.
Human CD1d knock-in mouse model demonstrates potent antitumor potential of human CD1d-restricted invariant natural killer T cells.
Proc Natl Acad Sci U S A. 2013; 110(8):2963-8 [PubMed] Article available free on PMC after 05/03/2014
Despite a high degree of conservation, subtle but important differences exist between the CD1d antigen presentation pathways of humans and mice. These differences may account for the minimal success of natural killer T (NKT) cell-based antitumor therapies in human clinical trials, which contrast strongly with the powerful antitumor effects in conventional mouse models. To develop an accurate model for in vivo human CD1d (hCD1d) antigen presentation, we have generated a hCD1d knock-in (hCD1d-KI) mouse. In these mice, hCD1d is expressed in a native tissue distribution pattern and supports NKT cell development. Reduced numbers of invariant NKT (iNKT) cells were observed, but at an abundance comparable to that in most normal humans. These iNKT cells predominantly expressed mouse Vβ8, the homolog of human Vβ11, and phenotypically resembled human iNKT cells in their reduced expression of CD4. Importantly, iNKT cells in hCD1d knock-in mice exert a potent antitumor function in a melanoma challenge model. Our results show that replacement of mCD1d by hCD1d can select a population of functional iNKT cells closely resembling human iNKT cells. These hCD1d knock-in mice will allow more accurate in vivo modeling of human iNKT cell responses and will facilitate the preclinical assessment of iNKT cell-targeted antitumor therapies.



Vemurafenib. Value unclear in metastatic melanoma.
Prescrire Int. 2012; 21(133):288-90 [PubMed]
In patients with metastatic melanoma, standard cytotoxic drugs such as dacarbazine have no proven impact on survival. Vemurafenib is the first BRAF protein inhibitor to be approved for the treatment of melanoma. In about half of patients with melanoma, this protein, important for cell growth, is dysregulated owing to a mutation (V600) in the gene that encodes it. An unblinded clinical trial that included 675 patients with metastatic melanoma harbouring a V600 BRAF mutation compared oral vemurafenib with intravenous dacarbazine. An interim analysis showed a statistically significant increase in the median overall survival time of about 1.5 months with vemurafenib (9.2 versus 7.7 months). These results are too preliminary to determine the survival advantage, if any, conferred by vemurafenib. About 20% of patients treated with vemurafenib developed skin cancer. The most common adverse effects were skin rash (37%), photosensitivity (33%), diarrhoea (28%), and arthralgia (54%). Vemurafenib also causes ocular disorders, including uveitis, and prolongs the QT interval in a dose-dependent manner. The potential for pharmacokinetic interactions is high: vemurafenib inhibits P-glycoprotein and CYP 1A2, and induces CYP 3A4. In practice, vemurafenib should only be used in rigorous clinical trials, on a case-by-case basis.


Jang S, Atkins MB
Which drug, and when, for patients with BRAF-mutant melanoma?
Lancet Oncol. 2013; 14(2):e60-9 [PubMed]
Patients with metastatic melanoma had few treatment options until 2011, when two drugs-ipilimumab and vemurafenib-were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5-7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.


Pulitzer M, Brady MS, Blochin E, et al.
Anaplastic large cell lymphoma: a potential pitfall in the differential diagnosis of melanoma.
Arch Pathol Lab Med. 2013; 137(2):280-3 [PubMed]
The diagnosis of metastatic melanoma can be complicated by absent characteristic cytology, melanin, or antigen expression in a suspect tumor, putting the pathologist at risk for incorrectly diagnosing recurrent melanoma while missing a second malignancy. We report a 69-year-old man with a history of acral melanoma, metastatic to inguinal nodes, presenting with an ipsilateral thigh nodule. Histology showed a proliferation of pleomorphic cells in the dermis and subcutis, suspicious for melanoma. S100, Melan-A, and HMB-45 immunohistochemistry were negative. However, microphthalmia-associated transcription factor and CD117 labeled the neoplasm, prompting consideration of a late metastatic melanoma with loss of antigen expression. Subsequent immunolabeling for CD4, CD43, and CD30 and clonal T-cell gene rearrangements enabled the correct diagnosis of cutaneous anaplastic large cell lymphoma. This case illustrates a pitfall in evaluating tumors in patients with known metastatic melanoma, and emphasizes the need for broad-spectrum immunohistochemistry in cases that are not clear-cut.


Dar AA, Majid S, Rittsteuer C, et al.
The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression.
J Natl Cancer Inst. 2013; 105(6):433-42 [PubMed] Article available free on PMC after 05/03/2014
BACKGROUND: Although p53 is inactivated by point mutations in many tumors, melanomas infrequently harbor mutations in the p53 gene. Here we investigate the biological role of microRNA-18b (miR-18b) in melanoma by targeting the MDM2-p53 pathway.
METHODS: Expression of miR-18b was examined in nevi (n = 48) and melanoma (n = 92) samples and in melanoma cell lines and normal melanocytes. Immunoblotting was performed to determine the expression of various proteins regulated by miR-18b. The effects of miR-18b overexpression in melanoma cell lines were investigated using assays of colony formation, cell viability, migration, invasion, and cell cycle and in a xenograft model (n = 10 mice per group). Chromatin immunoprecipitation and methylation assays were performed to determine the mechanism of microRNA silencing.
RESULTS: Expression of miR-18b was substantially reduced in melanoma specimens and cell lines by virtue of hypermethylation and was reinduced (by 1.5- to 5.3-fold) in melanoma cell lines after 5-AZA-deoxycytidine treatment. MDM2 was identified as a target of miR-18b action, and overexpression of miR-18b in melanoma cells was accompanied by 75% reduced MDM2 expression and 2.5-fold upregulation of p53, resulting in 70% suppression of melanoma cell colony formation. The effects of miR-18b overexpression on the p53 pathway and on melanoma cell growth were reversed by MDM2 overexpression. Stable overexpression of miR-18b produced potent tumor suppressor activity, as evidenced by suppressed melanoma cell viability, induction of apoptosis, and reduced tumor growth in vivo. miR-18b overexpression suppressed melanoma cell migration and invasiveness and reversed epithelial-to-mesenchymal transition.
CONCLUSIONS: Our results demonstrate a novel role for miR-18b as a tumor suppressor in melanoma, identify the MDM2-p53 pathway as a target of miR-18b action, and suggest miR-18b overexpression as a novel strategy to reactivate the p53 pathway in human tumors.


Lee C, Siu A, Chang J, et al.
Alphavbeta3 suppresses the RhoA-LIMK1 pathway in K1735 melanoma.
J Calif Dent Assoc. 2012; 40(12):921-7 [PubMed]
Mucocutaneous melanoma has a five-year survival rate of less than 10 percent. The alphavbeta3 integrin promotes invasion, which requires actin reorganization by cofilin. The authors previously showed that cofilin and alphavbeta3 promote invasion. K1735 melanoma has several clones, each with different levels of alphavbeta3. The authors found that expression of alphavbeta3 suppresses activation of RhoA thus inhibiting LIMK1 phosphorylation of cofilin. This indicates that alphavbeta3 integrin suppresses the RhoA/ ROCK/LIMK1 pathway.


Hetz SP, Tomasone JR
Supportive care needs of Canadian melanoma patients and survivors.
Can Oncol Nurs J. 2012; 22(4):248-56 [PubMed]
The purpose of this study was to determine the supportive care needs of melanoma patients and survivors in Canada. Thirty-one melanoma patients and survivors completed the Supportive Needs Questionnaire--Melanoma Supplementary Module in addition to questions pertaining to information delivery and screening behaviour. Results demonstrated that the majority of patients in the study are having their needs met (61.1% of total participant responses). Unfortunately, a substantial proportion of individuals have unmet needs. Of the examined needs, educational and increased informational resource needs were among the greatest reported, particularly among individuals with less education (high school diploma or less). Although overall it appears the majority of needs are being met, more can be done to improve the care of melanoma patients in Canada.


This page last updated: 22nd May 2013
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