A Prospective, Monocentric Case-Control Study on Uncontrolled Psoriasis as Independent Risk Factor for a Hypercoagulable State.

INTRODUCTION: Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP. METHODS: Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] (n = 87) and HC (n = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI < 3). Amplitude, area under the curve (AUC) and 50% clot lysis time were determined. RESULTS: At baseline, psoriasis patients had higher median amplitude and AUC compared with HC (p < 0.0001). After correction for possible confounders (BMI, smoking behavior, psoriatic arthritis, arterial hypertension, diabetes and coronary artery disease), the increased amplitude in psoriasis patients compared to HC remained significant. Successful anti-inflammatory treatment resulted in a significant decrease in amplitude (p = 0.0365). CONCLUSION: This is the first prospective study comparing the CLP of psoriasis patients with that of HC. A significant increase in both amplitude and area under the curve, indicative of a hypercoagulable CLP, was observed in psoriasis patients compared to HC. After successful anti-inflammatory treatment, amplitude significantly decreased.

Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Clinical and genetic determinants of vitamin D receptor expression in cutaneous melanoma patients.

Decrease of vitamin D receptor (VDR) expression is observed in melanocytic naevi and melanoma compared to normal skin. Little is known about factors influencing VDR expression in cutaneous melanoma (CM). We investigated the correlation of VDR expression in CM with 25-hydroxy vitamin D (25OHD) levels, demographic/clinical parameters, genetic variants of VDR and pathology of the primary tumor. Demographic/clinical parameters were recorded in 407 prospectively recruited CM patients of a multi-center controlled study (ViDMe trial). We determined VDR expression both in the nucleus and in the cytoplasm by semi-quantitative assessment in CM tissue using histochemistry in 279 patients, expressed in percentages and histoscore (H-score). Genomic DNA from 332 patients was extracted to genotype thirteen VDR single nucleotide polymorphisms (SNPs) using TaqMan. VDR expression in CM tissue from 279 patients was correlated with clinical/demographic parameters and 25OHD levels (univariable and multivariable analysis), VDR SNPs (univariable analysis) and pathology parameters of primary CM tissue (univariable analysis). Cytoplasmic VDR expression was increased in patients who stated to have a high sun exposure during their life compared to patients with low sun exposure (p H-score,univariable : 0.001, p H-score,multivariable : 0.004). The A allele of the genetic VDR polymorphism Fok1 was associated with a higher expression of the VDR in the cytoplasm (p cytoplasmic, univariable : 0.001 and p H-score, univariable : 0.02). In the primary tumor, presence of mitosis (p nucleus,%, univariable : 0.002) and perineural invasion (p nucleus,%,univariable : 0.03) were significantly associated with low nuclear VDR expression. ClinicalTrials.gov Identifier: NCT01748448.

Impact of the COVID-19 Pandemic on the Incidence and Thickness of Cutaneous Melanoma in Belgium.

(1) Background: COVID-19 had a major impact on cancer diagnostics and treatment. Delays in diagnosis of cutaneous melanoma were particularly feared, given the impact on survival and morbidity that comes with advanced stages. Moreover, its incidence in Belgium has been rapidly increasing in recent decades. This Belgian population-level study quantifies the pandemic effect on the number of melanoma diagnoses and Breslow thickness in 2020 and 2021. (2) Methods: In using an automated algorithm, the number of cutaneous melanoma diagnoses and Breslow thickness were extracted from all pathology protocols from 2017-2021 by the Belgian Cancer Registry. Monthly variations, as well as year-to-year differences, were studied. (3) Results: Annual incidence of cutaneous melanoma fell by 1% in 2020, compared to 2019, mainly due to a diagnostic deficit in March, April, and May 2020. An 8% incidence increase occurred in 2021, primarily reflecting an increase in the number of the thinnest melanomas (≤1 mm). Both the mean and median Breslow thicknesses were higher in spring 2020, resulting from an underrepresentation of thinner tumors. However, no particulars stood out on a full-year basis in either 2020 or 2021. (4) Conclusions: Considering the expected incidence increase, we estimate almost 210 melanoma diagnoses were missed in Belgium in 2020, corresponding to 6% of the expected number. This deficit occurred mainly during the first COVID-19 wave. Despite some rebound, the 2021 total was still 3% short of the expected number, leaving around 325 diagnoses remaining pending in 2020 and 2021, corresponding to a two-year deficit of 4.35%. Fortunately, mainly thin melanomas were missed, without any detectable shift toward thicker tumors later in 2020 and or 2021.

Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy.

BACKGROUND: One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance. METHODS: Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity. RESULTS: We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity. CONCLUSIONS: We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.

Can Multispectral Dermoscopy Help In Distinguishing Blue Color?

INTRODUCTION: The interpretation of colors is essential in the dermoscopic evaluation of skin lesions. The same blue color on white dermoscopy may indicate blood or pigment deep in the dermis. Contrary to white dermoscopy, multispectral dermoscopy uses different wavelengths of light to illuminate a lesion and is able to decompose the dermoscopic image into individual maps that allow to more clearly visualize specific skin structures such as pigment distribution (pigment map) and vasculature (blood map). These maps are called skin parameter maps. OBJECTIVES: The aim of this research is to investigate whether skin parameter maps can be used to objectively identify and distinguish the presence of pigment and blood, by using blue naevi and angiomas as models for respectively pigment and blood. METHODS: We retrospectively analyzed 24 blue naevi and 79 angiomas. The skin parameter maps of each of the lesions were independently reviewed by 3 expert dermoscopists, in the absence of the regular white-light dermoscopic image. RESULTS: All the observers provided high levels of diagnostic accuracy for blue naevus and angioma based on skin parameter maps alone, and the dermoscopic diagnosis was considered substantially reliable because of the 79% of diagnostic K agreement. Percentages of blue naevi and angiomas that showed respectively deep pigment and blood were very high at 95.8% and 97.5%. There was a percentage of lesions that counterintuitively showed blood in blue naevi (37.5%) and deep pigment in angiomas (28.8%). CONCLUSIONS: Skin parameter maps based on multispectral images can help to objectify the presence of deep pigment or blood in blue naevi and angiomas. The application of these skin parameter maps could help in the differential diagnosis between pigmented and vascular lesions.

Senescence Induced by UVB in Keratinocytes Impairs Amino Acids Balance.

Skin is one of the most exposed organs to external stress. Namely, UV rays are the most harmful stress that could induce important damage leading to skin aging and cancers. At the cellular level, senescence is observed in several skin cell types and contributes to skin aging. However, the origin of skin senescent cells is still unclear but is probably related to exposure to stresses. In this work, we developed an in vitro model of UVB-induced premature senescence in normal human epidermal keratinocytes. UVB-induced senescent keratinocytes display a common senescent phenotype resulting in an irreversible cell cycle arrest, an increase in the proportion of senescence-associated ß-galactosidase‒positive cells, unrepaired DNA damage, and a long-term DNA damage response activation. Moreover, UVB-induced senescent keratinocytes secrete senescence-associated secretory phenotype factors that influence cutaneous squamous cell carcinoma cell migration. Finally, a global transcriptomic study highlighted that senescent keratinocytes present a decrease in the expression of several amino acid transporters, which is associated with reduced intracellular levels of glycine, alanine, and leucine. Interestingly, the chemical inhibition of the glycine transporter SLC6A9/Glyt1 triggers senescence features.

Preoperative assessment of cutaneous melanoma thickness by multispectral dermoscopy.

Preoperative assessment of Breslow thickness by means of sonography and clinical and dermoscopic criteria in white light dermoscopy has been reported, but up until now, the use of multispectral dermoscopy has not been investigated. Aim of this research is to determine whether multispectral dermoscopy and more specifically pigment maps can be used as a predictive marker for Breslow thickness in melanoma. Pigment maps are generated in real time from multispectral dermoscopic images and help to visualize the presence of pigment in a lesion. Multispectral images of 110 melanomas were collected, using a digital handheld multispectral dermatoscope, and assessed independently by five observers for the presence or absence of deep pigment compared with the surrounding skin. According to histopathological examination, the mean Breslow thickness of all 110 melanomas was 1.04 mm (ranging from 0.1 to 14 mm). The group of melanomas where deep pigment was visualized on the multispectral image (n = 78) had a significantly higher Breslow thickness (1.19 mm) than the group where no deep pigment was observed (n = 32, mean Breslow 0.68 mm) (P = 0.025). This study is unique in preoperative assessment of tumour thickness by means of multispectral dermoscopy. Our data indicate that the presence of deep pigment as visualized in digital dermoscopic skin parameter maps identifies a group of thicker melanomas. Further prospective research is needed to validate these pigment maps, generated by multispectral dermoscopy as a measure to predict invasiveness in melanoma.

Determinants of 25-hydroxyvitamin D Status in a Cutaneous Melanoma Population.

Vitamin D status is influenced by well-known determinants, but factors associated with low 25-hydroxyvitamin D levels in the cutaneous melanoma population are not well defined. The aim of this study was to confirm the well-known determinants and to assess new determinants for 25-hydroxyvitamin D levels in a cutaneous melanoma population. In a prospectively included cohort of 387 patients with cutaneous melanoma the association of 25-hydroxyvitamin D levels with sex, age, body mass index, time of blood withdrawal, Fitzpatrick phototype, vitamin D supplementation, score for intensity of lifetime sun exposure, smoking, education level, hair and skin colour, eye colour, total number of benign naevi, freckles and parameters of chronic sun damage was investigated. In addition, 25-hydroxyvitamin D levels were correlated with pathological parameters of the primary tumour and melanoma stage (8th edition of the American Joint Committee on Cancer (AJCC). Univariate and multivariate logistic regressions were performed using R software. The following factors had a significant effect on vitamin D status: body mass index, seasonal time of blood sampling, vitamin D supplementation, and a subtype of skin, and hair colour.

Contact allergy in a paediatric population observed in a tertiary referral centre in Belgium.

BACKGROUND: Contact allergy is increasingly recognized as being important in children with eczema. OBJECTIVES: To retrospectively analyse the patch test results in children over the past 10 years, aiming to (1) evaluate demographic characteristics and lesion locations, (2) describe frequencies of positive patch test reactions, and (3) investigate the relationship with atopic dermatitis (AD). METHODS: A total of 329 children were patch tested between January 2010 and December 2019 with the European (children) baseline series and/or other series, and the personal product(s) used. RESULTS: A total of 119 (36%) children presented with at least one positive reaction. Children with AD had a higher prevalence of positive reactions compared with the non-AD group (P = .002), but without statistically significant difference regarding sensitization to more than one hapten (P = .39). The face (20.2%), hands (19.3%), feet (16.8%), arms (12.6%), and body folds (10.9%) were the most common sites of primary localizations. The most frequent contact allergens were nickel sulfate and linalool hydroperoxide (both 16%), limonene hydroperoxide (13.5%), and para-phenylenediamine (10.9%). No statistically significant difference for nickel sulfate was found between the AD and non-AD group (P = .20). CONCLUSIONS: Contact allergy in children with eczema was frequently observed in our tertiary referral centre in Belgium as well, confirming the need for patch testing.

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.

Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their functional role in the progression of CMM. We conducted a systematic literature review to identify studies providing evidence of bona fide TSGs by cell line or animal experiments. We performed a broad first search and a gene-specific second search, supplemented by reference checking. We included studies describing bona fide TSGs in CMM with promoter CpG-island hypermethylation in which inactivating mechanisms were reported. We extracted data about protein role, pathway, experiments conducted to meet the bona fide criteria and hallmarks of cancer acquired by TSG inactivation. A total of 24 studies were included, describing 24 bona fide TSGs silenced by promoter CpG-island hypermethylation in CMM. Their effect on cell proliferation, apoptosis, growth, senescence, angiogenesis, migration, invasion or metastasis is also described. These data give further insight into the role of TSGs in the progression of CMM.

An update on congenital melanocytic nevus syndrome: A case report and literature review.

Congenital melanocytic nevus syndrome (CMNS) is a rare condition characterized by pigmented skin lesions that are usually present at birth and are associated with an increased risk of neurological abnormalities and malignant melanoma. It mostly results from a post-zygotic NRAS mutation of neural-derived crest cells, leading to uncontrolled cell growth. Because of the increased knowledge of the genetics underlying CMNS, targeted therapy becomes a promising treatment option. We present a case of CMNS in a newborn. Physical examination at birth showed a giant congenital melanocytic nevus, extending from the occipital to the lower lumbar region. A magnetic resonance imaging scan revealed multiple cerebral and cerebellar parenchymal lesions. Genetic analysis of the cutaneous lesions showed the presence of an NRAS Q61R mutation. The patient was treated with dermabrasion to reduce the color intensity of the nevus. However, this was complicated by recurrent wound infections and laborious wound healing. At the age of 1 year, the patient had an age-appropriate psychomotor development, without neurological deficits.

Venous thrombotic events in psoriasis patients: a systematic review with meta-analysis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease associated with numerous comorbidities. Psoriasis has been linked to an increased risk of metabolic syndrome and atherosclerotic arterial disease. Inflammatory conditions are known to increase the risk of venous thromboembolism (VTE), a frequent cause of morbidity and mortality. However, the relationship between psoriasis and VTE has received little attention and existing studies have shown conflicting results. OBJECTIVES: This systematic review aims to perform a meta-analysis on VTE in psoriasis patients. METHODS: We conducted a systematic electronic search of the incidence of VTE (pulmonary embolism [PE], deep venous thrombosis [DVT] and/or retinal vein occlusion [RVO]) in psoriasis patients on PubMed, Web of Science, Embase and Cochrane (specifics: see Appendix 1 in Supporting information). Only English literature and full manuscripts were included; abstracts were excluded. Pooled risk ratio and 95% confidence interval were calculated using Review Manager. RESULTS: Seven articles were included. Each study separately indicated a correlation between psoriasis and VTE after adjustment for several clinical parameters. The confounders included in the adjustment differed between studies, but all included adjustment for age, gender and comorbidities. A meta-analysis of the unadjusted data of the five studies that reported raw data on number of VTE events and patient follow-up (person-years) showed a pooled risk ratio for VTE and psoriasis of 1.29 (95% CI: 0.92-1.81). The statistical heterogeneity was high with I2 of 97%. CONCLUSIONS: Published data adjusted for key confounders demonstrate in general a significantly increased prevalence of VTE in psoriasis patients. Both psoriasis severity and number of confounders assessed seem to have an impact on this correlation. In this review, we pooled unadjusted data of the studies and we found a non-significant increased risk for VTE in psoriasis patients compared to healthy controls. This discrepancy suggests that psoriasis severity, age, gender or comorbidities may influence the risk of VTE in subgroups of the psoriasis population. Future research to identify subgroups at risk for VTE is warranted.Key messagesThe included studies reported an increased risk of VTE, DVT, PE and RVO in psoriasis patients.A meta-analysis was performed on five studies that reported raw data and showed that the pooled risk ratio for VTE in psoriasis patients overall was increased, however not significantly, compared to healthy controls.Further research to pinpoint psoriasis subgroups at risk (e.g. severe psoriasis patients, younger age, associated comorbidities) of developing VTE is warranted.

A digital mRNA expression signature to classify challenging Spitzoid melanocytic neoplasms.

Spitzoid neoplasms are a challenging group of cutaneous melanocytic proliferations. They are characterized by epithelioid and/or spindle-shaped melanocytes and classified as benign Spitz nevi (SN), atypical Spitz tumors (AST), or malignant Spitz tumors (MST). The intermediate AST category represents a diagnostically challenging group since on purely histopathological grounds, their benign or malignant character remains unpredictable. This results in uncertainties in patient treatment and prognosis. The molecular properties of Spitzoid lesions, especially their transcriptomic landscape, remain poorly understood, and genomic alterations in melanoma-associated oncogenes are typically absent. The aim of this study was to characterize their transcriptome with digital mRNA expression profiling. Formalin-fixed paraffin-embedded samples (including 27 SN, 10 AST, and 14 MST) were analyzed using the NanoString nCounter PanCancer Pathways Panel. The number of significantly differentially expressed genes in SN vs. MST, SN vs. AST, and AST vs. MST was 68, 167, and 18, respectively. Gene set enrichment analysis revealed upregulation of pathways related to epithelial-mesenchymal transition and immunomodulatory-, angiogenesis-, hormonal-, and myogenesis-associated processes in AST and MST. A molecular signature of SN vs. MST was discovered based on the top-ranked most informative genes: NRAS, NF1, BMP2, EIF2B4, IFNA17, and FZD9. The AST samples showed intermediate levels of the identified signature. This implies that the gene signature can potentially be used to distinguish high-grade from low-grade AST with a larger study cohort in the future. This combined histopathological and transcriptomic methodology is promising for prospective diagnostics of Spitzoid neoplasms and patient management in dermatological oncology.

Enhanced visualization of blood and pigment in multispectral skin dermoscopy.

BACKGROUND AND OBJECTIVES: Dermoscopy has proven its value in the diagnosis of skin cancer and, therefore, is well established in daily dermatology practice. Up until now, analogue white light dermoscopy is the standard. Multispectral dermoscopy is based on illumination of the skin with narrowband light sources with different wavelengths. Each of these wavelengths is differently absorbed by skin chromophores, such as pigment or (de)oxygenated blood. Multispectral dermoscopy could be a way to enhance the visualization of vasculature and pigment. We illustrate possible additional information by such "skin parameter maps" in some cases of basal cell carcinoma and Bowen's disease. METHODS: Using a new digital multispectral dermatoscope, skin images at multiple wavelengths are collected from different types of skin lesions. These particular images together with the knowledge on skin absorption properties, result in so called "skin parameter maps". RESULTS: A "pigment contrast map," which shows the relative concentration of primarily pigment, and a "blood contrast map" which shows the relative concentration of primarily blood were created. Especially, the latter is of importance in diagnosing keratinocyte skin cancer hence vascular structures are a characteristic feature, as further illustrated in the study. CONCLUSIONS: Skin parameter maps based on multispectral images can give better insight in the inner structures of lesions, especially in lesions with characteristic blood vessels such as Bowen's disease and basal cell carcinoma. Skin parameter maps can be used complementary to regular dermoscopy and could potentially facilitate diagnosing skin lesions.

Solar Lentigines are Associated with Better Outcome in Cutaneous Melanoma.

The rising incidence of cutaneous melanoma and its stable high mortality rates despite innovative cancer care, require better prediction of the clinical outcome. In a large cutaneous melanoma population we explored whether the known clinical risk factors for melanoma susceptibility (nevus phenotype, phototype, family and personal history of melanoma and sun damage) affect melanoma outcomes. A total of 1,530 melanoma patients were included. Multivariable analysis adjusted for age, gender, melanoma stage, localization and subtype showed that familial melanoma, solar lentigines on head and neck, the back of hands, arms and shoulders were associated with a better relapse free survival. The presence of atypical naevi was associated with an increased risk of relapse. After Bonferroni correction, the correlation between presence of solar lentigines on the back of the hands and arms remained the most robust and significant prognostic factor for the relapse free survival in cutaneous melanoma patients.

Melanoma susceptibility variant rs869330 in the MTAP gene is associated with melanoma outcome.

The rising incidence of cutaneous melanoma (CM), an aggressive skin cancer, emphasizes the need for novel biomarkers to guide personalized care and better predict outcome. Genetic factors including germline risk variants are promising candidates for this aim. We explored the association between germline risk variants and melanoma outcome in a large genetically homogenous Belgian melanoma population, focusing on single nucleotide polymorphisms which generated the highest association with melanoma susceptibility. Between 2004 and 2014, blood samples of 1088 patients with histologically confirmed CM were collected and genotyped for nine variants. Cox proportional hazard models were used to assess the association between each single nucleotide polymorphism and relapse-free survival and overall survival, adjusted by age, sex, melanoma stage, site, and subtype. We identified significant associations for rs869330 (in the methylthioadenosine phosphorylase - MTAP gene) with overall survival (hazard ratio = 0.760, P = 0.048, 95% confidence interval: 0.580-0.998) and relapse-free survival (hazard ratio = 0.800, P = 0.020, 95% confidence interval: 0.650-0.970). This exploratory study is the first to show a significant association between the rs869330 variant (in the MTAP gene) and outcome in a large CM population.

Molecular profiling of Spitz nevi identified by digital RNA counting.

The molecular properties of benign melanocytic lesions are poorly understood. Only a few studies have been carried out on specific nevi subtypes, including common nevocellular nevi (NCN) or Spitz nevi (SN). Genomic alterations in melanoma-associated oncogenes are typically absent in SN. In the present study, mRNA expressions of 25 SN and 15 NCN were analyzed. Molecular profiling was performed using the RNA NanoString nCounter Gene Expression Platform (number of genes=770). Marker discovery was performed with a training set consisting of seven SN and seven NCN samples from the same patients, and validation was performed using a second set consisting of 18 SN and eight NCN samples. Using the training set, 197 differentially expressed genes were identified in SN versus NCN. Of these, 74 genes were validated in the validation set (false discovery rate q≤0.13). In addition, using random forest and least absolute shrinkage and selection operator feature selection, a molecular signature of SN versus NCN was identified including 15 top-ranked genes. The present study identified a distinct molecular expression profile in SN compared with NCN, even when lesions were obtained from the same patients. Gene set analysis showed upregulation of gene pathways with increased expression of transcripts related to immunomodulatory, inflammatory, and extracellular matrix interactions as well as angiogenesis-associated processes in SN. These findings strongly indicate that SN represent a distinct group of melanocytic neoplasms and evolve differentially and not sequentially from NCN.