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.

B-cell and complement signature in severe hidradenitis suppurativa that does not respond to adalimumab.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder with significant morbidity. The pathogenesis remains incompletely understood although immune dysregulation plays an important role. It is challenging to treat and approximately 50% of patients respond clinically to adalimumab, the only licensed treatment. OBJECTIVES: To examine differences between lesional and nonlesional HS skin at baseline using bulk RNA sequencing, and to compare the transcriptome in the skin before and after 12 weeks of treatment with adalimumab. To examine transcriptomic differences between adalimumab responders and nonresponders using Hidradenitis Suppurativa Clinical Response and the International Hidradenitis Suppurativa Severity Score System (IHS4); and to compare transcriptomic differences based on disease severity (Hurley stage and IHS4). METHODS: We completed bulk RNA sequencing on lesional and nonlesional skin samples of patients before and after 12 weeks of treatment with adalimumab. RESULTS: Baseline differentially expressed genes and pathways between lesional and nonlesional skin highlighted chemokines and antimicrobial peptides produced by keratinocytes; B-cell function; T-cell-receptor, interleukin-17 and nuclear factor-κB signalling; and T-helper-cell differentiation. Transcriptomic differences were identified in lesional skin at baseline, between subsequent responders and nonresponders. Patients with severe HS who did not respond to adalimumab had enriched complement and B-cell activation pathways at baseline. In addition, logistic regression identified CCL28 in baseline lesional HS skin as a potential biomarker of treatment response. CONCLUSIONS: This highlights the potential for targeting B-cell and complement pathways in HS treatment and the potential of stratifying patients at baseline to the most suitable treatment based on the skin transcriptome. CCL28 has not previously been identified in HS skin and has potential clinical relevance due to its antimicrobial function and homing of B and T cells at epithelial surfaces. Our results provide data to inform future translational and clinical studies on therapeutics in HS.

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.

Metastatic melanoma in the Mid-West of Ireland: a retrospective review.

BACKGROUND: Melanoma is the fifth most common invasive cancer in Ireland, and incidence is increasing. Metastatic melanoma has been associated with poor overall survival historically. New systemic anti-cancer treatment (SACT) options for advanced melanoma have emerged in the last decade, and outcomes are improving. AIMS: The aim of our study was to assess the incidence and clinicopathological features of metastatic melanoma in our centre, and subsequent treatment with SACT. METHODS: We analysed retrospectively patients with metastatic melanoma in the Mid-West of Ireland, over a 6-year period (2014-2019). RESULTS: In 6 years, a total of 620 patients were diagnosed with melanoma, 28 (5%) had metastatic or unresectable disease at diagnosis. Mean age at primary diagnosis was 64.5 years (range 24-90 years) and 20 (71%) were male. Median Breslow depth was 4.3 mm (mean 5.5 mm, SD ± 4.4 mm). Thirteen patients (46%) had metastases at initial presentation. Fifteen (53%) received systemic treatment in the regional cancer centre. Of 13 who did not have systemic treatment, 8 had radiological and clinical surveillance, 3 declined further treatment or surveillance and 2 were lost to follow-up. Eleven patients died from the disease with median overall survival of 1.5 years (SD ± 1.3 years). CONCLUSION: Patients with metastatic melanoma commonly had metastases at the time of first presentation. Just over half of patients with metastatic melanoma received SACT. Early detection of melanoma is key. Further research on factors involved in late presentation, and those precluding systemic treatment, may contribute to improved outcomes in advanced melanoma.

Explaining the fall in Coronary Heart Disease mortality in the Republic of Ireland between 2000 and 2015 - IMPACT modelling study.

BACKGROUND: To investigate the contribution of individual and population factors to Coronary Heart Disease (CHD) mortality rates in Ireland between 2000 and 2015. METHODS: The Irish IMPACT CHD model was utilized with CHD Deaths Prevented or Postponed (DPPs) as outcome. RESULTS: CHD mortality rates in Ireland in those aged 25-84 years fell by 56% (63% in women vs. men 53%), with 4060 fewer deaths than expected in 2015. Improvements in CHD risk factors explained ~30% of the decline (785 DPPs in men; 425 in women): [population systolic blood pressure (+25% DPPs), mean cholesterol serum levels (+11%) and smoking prevalence (+5%)]. Additional deaths attributable to rises in diabetes prevalence (-6%), BMI (-4%) and physical inactivity (-2%) negatively impacted DPPs. Increased uptake of cardiology treatments explained ~60% of the decline (1620 DPPs in men; 825 in women), particularly secondary prevention and heart failure treatments. Some 10% was unexplained. CONCLUSION: CHD mortality declined in Ireland between 2000 and 2015, with two-thirds attributable to increased uptake in cardiology treatments and only one-third to improvements in population risk factors, partly reflecting adverse trends in obesity, diabetes and physical inactivity. Additional investments in prevention policies and treatments will be necessary to reduce future CHD deaths.

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.

Inverse Association Between Atopy and Melanoma: A Case-control Study.

Heightened cutaneous immune surveillance in atopic patients may inhibit development of melanoma. The aim of this study was to analyse the association between atopy and melanoma (development and outcome). A total of 188 cases of melanoma and 596 healthy controls were interviewed by telephone with a standardized questionnaire on atopic, demographic and melanoma characteristics. Cases were matched with controls on important confounders (age, sex, sunburn sensitivity, hair colour, number of moles, sunburn as juvenile, ever solarium, familial melanoma). Melanoma outcome data (disease relapse and death) within cases were retrieved. Analysis showed a general inverse association between atopy and melanoma development, but this was statistically significant only for a history of personal atopy (odds ratio 0.53, 95% confidence interval: 0.30-0.96, p-value = 0.04). Among melanoma patients, atopy did not affect survival or progression. In conclusion, this study suggests an inverse association between a history of atopy and melanoma development, but not with disease progression.