The updated Swiss guidelines 2016 for the treatment and follow-up of cutaneous melanoma.

Cutaneous melanoma is the most deadly cutaneous neoplasm. In order to guide treatment decisions and follow-up of melanoma patients, guidelines for the management of melanoma in Switzerland were inaugurated in 2001 and revised in 2006 and 2016. Recent data on surgical and medical treatments from randomised trials necessitated modification of the treatment and follow-up recommendations.

Clinically occult metastases in patients with cutaneous melanoma. Detection with sentinel lymph node biopsy and whole body positron emission tomography

Objective: The aim of this study was to investigate the use of sentinel lymph node biopsy (SLNB) and whole body positron emission tomography (PET), with emphasis on surgical treatment and prognosis, in the detection of clinically occult metastases in patients with clinically localized cutaneous melanoma. Patients and methods: The study population consisted of 1255 patients with clinical stage I–II cutaneous melanoma, operated at Turku University Hospital between 1983 and 2007. 334 patients underwent SLNB and they were compared to 921 retrospective patients. A subgroup of 30 symptom-free patients with high risk melanoma underwent prospectively whole body PET 6–24 months postoperatively. Results: Overall, the disease-specific survival rate was 84.4 % at five years. Sex, Breslow thickness, age and nodal status were independent prognostic factors for survival. SLNB revealed occult nodal metastases in 17 % of the patients. There was no significant difference in disease-specific overall survival between SLNB patients and controls, but the nodal disease-free time was significantly longer suggesting better local control after SLNB and subsequent completion lymph node dissection. The followup time was different between the study cohorts and initial surgery was performed during different time periods. SLNB detected micrometastases in seven of 155 patients (4.5 %) with thin T1 primary melanoma and in four of 25 patients (16 %) with head and neck melanoma. In six of 30 asymptomatic patients with high risk melanoma (20 %), whole body PET detected occult distant metastases. Conclusion: Both SLNB and whole body PET were reliable methods to detect clinically occult metastases in patients with cutaneous melanoma. This upstaging altered the treatment in each case.

Evaluation of outpatient discharge in patients with cutaneous melanoma

OBJECTIVE: to evaluate discharge in a group of patients with cutaneous melanoma according to recently established criteria. METHODS: we conducted an observational, cross-sectional study with 32 patients at the Hospital Universitário Clementino Fraga Filho (HUCFF) / Universidade Federal do Rio de Janeiro (UFRJ), between 1995 and 2013, in the following stages: IA (17 cases, 53.12%), IB (4 cases, 12.5%), IIA (3 cases, 9.37%), IIC (1 case, 3.12%), IIIB (1 case, 3.12%), IIIC (3 cases, 9.37%), melanomas in situ (2 cases, 6.25%), Tx (1 case, 3.12%). RESULTS: the follow-up time varied from one to 20 years (stage IA), five to 15 years (stage IB), six to 17 years (stage IIA), 20 years (stage IIC), 23 years (stage IIIB) and 14 to 18 years (stage IIIC). One melanoma in situ (subungueal) was discharged in the fourth year of follow-up and the other was promptly discharged. The Tx melanoma was followed for 12 years. We observed no relapses or recurrences in the period. CONCLUSION: although a controversial issue, it was possible to endorse the discharge of the patients since our follow-up time had already exceeded the one recommended by the other authors.

COM-Poisson cure rate survival models and an application to a cutaneous melanoma data

In this paper, we develop a flexible cure rate survival model by assuming the number of competing causes of the event of interest to follow the Conway-Maxwell Poisson distribution. This model includes as special cases some of the well-known cure rate models discussed in the literature. Next, we discuss the maximum likelihood estimation of the parameters of this cure rate survival model. Finally, we illustrate the usefulness of this model by applying it to a real cutaneous melanoma data. (C) 2009 Elsevier B.V. All rights reserved.

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

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

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

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

Vaccination of patients with cutaneous melanoma with telomerase-specific peptides

A phase I study was conducted to investigate the safety, tolerability, and immunological responses to vaccination with a combination of telomerase-derived peptides GV1001 (hTERT: 611-626) and p540 (hTERT: 540-548) using granulocyte-macrophage colony-stimulating factor (GM-CSF) or tuberculin as adjuvant in patients with cutaneous melanoma.

Anticancer activity of anandamide in human cutaneous melanoma cells

Cannabinoids are implicated in the control of cell proliferation, but little is known about the role of the endocannabinoid system in human malignant melanoma. This study was aimed at characterizing the in vitro antitumor activity of anandamide (AEA) in A375 melanoma cells. The mRNA expression of genes that code for proteins involved in the metabolism and in the mechanism of AEA action was assessed by RT-PCR. Cell viability was tested using WST-1 assay and the apoptotic cell death was determined by measuring caspase 3/7 activities. A375 cells express high levels of fatty acid amide hydrolase (FAAH), cyclooxygenase (COX)-2, cannabinoid receptor 1 (CB1), transient receptor potential cation channel subfamily V member 1 (TRPV1) and G-protein-coupled receptor 55 (GPR55) genes. AEA induced a concentration-dependent cytotoxicity with an IC50 of 5.8±0.7 µM and such an effect was associated to a caspase-dependent apoptotic pathway. AEA cytotoxicity was potentiated by FAAH inhibition (2-fold increase, p<0.05) and mitigated by COX-2 or lipoxygenase (LOX) inhibition (5- and 3-fold decrease, respectively; p<0.01). Blocking CB1 receptors partially decreased AEA cytotoxicity, whereas selective antagonism on the TRPV1 barely affected the mechanism of AEA action. Finally, methyl-β-cyclodextrin, a membrane cholesterol depletory, completely reversed the cytotoxicity induced by the selective GPR55 agonist, O-1602, and AEA. Overall, these findings demonstrate that AEA induces cytotoxicity against human melanoma cells in the micromolar range of concentrations through a complex mechanism, which involves COX-2 and LOX-derived product synthesis and CB1 activation. Lipid raft modulation, probably linked to GPR55 activation, might also have a role.

NRAS and BRAF mutations in primary cutaneous melanoma: A comparison of mutation rates between radial and vertical growth phases in individual tumors

Primary cutaneous melanoma is a cancer arising from melanocytes in the skin. In recent decades the incidence of this malignancy has increased significantly. Mortality rates are high for patients with tumors measuring over a few millimeters in thickness. Response rates to conventional radiation and chemotherapy are very low in patients with metastatic melanoma. New therapies targeting melanoma’s aberrant cell signaling pathways such as the MAP Kinase pathway are being developed. Mutations of NRAS and BRAF genes are quite common in cutaneous melanoma and lead to constitutive activation of the MAP Kinase pathway. This study tests the hypothesis that NRAS and BRAF mutations increase as a tumor progresses from the noninvasive radial growth phase (RGP) to the invasive vertical growth phase (VGP). Laser capture microdissection was used to obtain separate, pure tumor DNA samples from the RGP and VGP of thirty primary cutaneous melanomas. PCR was used to amplify NRAS exon 2 and BRAF exon 15 tumor DNA. The amplified DNA was sequenced and analyzed for mutations. An overall mutation rate of 74% was obtained for the twenty-three melanomas in which there were complete sequence results. With the exception of one melanoma NRAS and BRAF mutations were mutually exclusive. All seven NRAS exon 2 mutations involved codon 61. Three of these melanomas had mutations in both the RGP and VGP. The remaining four tumors were wild type for NRAS exon 2 in the RGP but mutated in the VGP. Of the fifteen BRAF exon 15 mutated melanomas all but one involved codon 600. Twelve of the fifteen BRAF exon 15 mutations were the T1799A type. Nine of the fifteen BRAF mutated tumors had the same mutation in both the RGP and VGP. Five of fifteen melanomas had wild type RGP DNA and BRAF exon 15 mutated VGP DNA. A single melanoma had BRAF exon 15 mutated DNA in the RGP and wild type DNA in the VGP. Overall, these results suggest a trend toward the acquisition of NRAS and BRAF mutations as cutaneous melanomas change from a noninvasive to an invasive, potentially deadly cancer.^

Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation.

Several studies have established a link between blood coagulation and cancer, and more specifically between tissue factor (TF), a transmembrane protein involved in initiating blood coagulation, and tumor metastasis. In the study reported here, a murine model of human melanoma metastasis was used for two experiments. (i) The first experiment was designed to test the effect of varying the level of TF expression in human melanoma cells on their metastatic potential. Two matched sets of cloned human melanoma lines, one expressing a high level and the other a low level of the normal human TF molecule, were generated by retroviral-mediated transfections of a nonmetastatic parental line. The metastatic potential of the two sets of transfected lines was compared by injecting the tumor cells into the tail vein of severe combined immunodeficiency (SCID) mice and later examining the lungs and other tissues for tumor development. Metastatic tumors were detected in 86% of the mice injected with the high-TF lines and in 5% of the mice injected with the low-TF lines, indicating that a high TF level promotes metastasis of human melanoma in the SCID mouse model. This TF effect on metastasis occurs with i.v.-injected melanoma cells but does not occur with primary tumors formed from s.c.-injected melanoma cells, suggesting that TF acts at a late stage of metastasis, after tumor cells have escaped from the primary site and entered the blood. (ii) The second experiment was designed to analyze the mechanism by which TF promotes melanoma metastasis. The procedure involved testing the effect on metastasis of mutations in either the extracellular or cytoplasmic domains of the transmembrane TF molecule. The extracellular mutations introduced two amino acid substitutions that inhibited initiation by TF of the blood-coagulation cascade; the cytoplasmic mutation deleted most of the cytoplasmic domain without impairing the coagulation function of TF. Several human melanoma lines expressing high levels of either of the two mutant TF molecules were generated by retroviral-mediated transfection of the corresponding TF cDNA into the nonmetastatic parental melanoma line, and the metastatic potential of each transfected line was tested in the SCID mouse model. Metastases occurred in most mice injected with the melanoma lines expressing the extracellular TF mutant but were not detected in most mice injected with the melanoma lines expressing the cytoplasmic TF mutant. Results with the extracellular TF mutant indicate that the metastatic effect of TF in the SCID mouse model does not involve products of the coagulation cascade. Results with the cytoplasmic TF mutant indicate that the cytoplasmic domain of TF is important for the metastatic effect, suggesting that the TF could transduce a melanoma cell signal that promotes metastasis.

Over-Expression of Endothelin 3 Sensitizes Mice to Uv-Induced Melanoma Metastasis

Melanomagenesis is influenced by environmental and genetic factors. In normal cells, ultraviolet (UV) induced photoproducts are successfully repaired by the nucleotide excision repair (NER) pathway. Mice carrying mutations in the xeroderma pigmentosum (Xp) complementation group of genes (Xpa-Xpg) lack the NER pathway and are therefore highly sensitive to UV light; however, they do not develop melanoma after UV exposure. In humans, the Endothelin 3 signaling pathway has been linked to melanoma progression and its metastatic potential. Transgenic mice that over-express Edn3 under the control of the Keratin 5 promoter (K5-Edn3) and exhibit a hyperpigmentation phenotype, were crossed with Xp deficient mice. Because melanoma is highly metastatic and many primary malignancies spread via the lymphatic system, analyzing the lymph nodes may serve useful in assessing the possible spread of tumor cells to other tissues. This study aimed to determine whether the over-expression of Edn3 is sufficient to lead to melanoma metastasis to the lymph nodes. Mice were exposed to UV radiation and analyzed for the presence of skin lesions. Mice presenting skin lesions were sacrificed and the nearest lymph nodes were excised and examined for the presence of metastasis. Mice with melanoma skin lesions presented enlarged and hyperpigmented lymph nodes. Diagnosis of melanoma was established by immunostaining with melanocyte and melanoma cell markers, and while UV radiation caused the development of skin lesions in both K5-Edn3 transgenic and control mice, only those mice carrying the K5-Edn3 transgene were found to develop melanoma metastasis to the lymph nodes. These results indicate that over-expression of Edn3 is sufficient to lead to lymph node metastasis in mice exposed to at least one dose of UV radiation.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.