Phenotypic and histologic characteristics of cutaneous melanoma in patients with melanocortin-1 receptor polymorphisms

BackgroundThe melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure.ObjectivesTo analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma.Material and methodsA total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction.ResultsAt least one of the following MC1R variants was present in 58% of the patients: V60L, V92 M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P = .018) and melanomas located on areas with intermittent sun exposure (P = .019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P = .028).ConclusionsThe results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.     

Mental training during pregnancy. Feelings and experiences during pregnancy and birth and parental stress 1 year after birth – A pilot study

Background: Parental stress has been recognized as a problem despite governmental support of parent education programs aiming to prepare parents for parenthood.Aim: to compare parents who underwent a mental training program during pregnancy with a control group to measure feelings and experiences during pregnancy and birth and perceived parental stress.Methods: A comparative pilot study of 46 self-selected parents who underwent a mental training program during pregnancy, and 1408 parents living in the same catchment area (control group). Data was collected in mid-pregnancy, 2 months and 1 year after birth. The main outcome was parental stress.Results: Parents in the mental training group were more often expecting their first baby and had a higher level of education compared to parents in the control group. Parents participating in the mental training program had less positive feelings about expecting a baby (OR 14.0; 6.7–29.3), the upcoming birth (OR 2.0; 1.1–3.8) and the newborn baby (OR 3.1; 1.6–6.2). Parents who attended the mental training program attended an antenatal parent education to a higher degree (OR 2.0; 1.6–2.4) and were more likely to stay in contact with other participants in the antenatal education (OR 4.1; 1.9–8.6). Mothers in the mental training program used psycho prophylaxis to a higher extent (OR 3.0; 1.2–7.1) There was no difference in the birth experience or the perceived parental stress.Conclusion: Participating in a mental training program for birth and parenthood was not associated with the birth experience or the assessment of parental stress 1 year after birth.     

Regla «1-2-3» para la reconstrucción de defectos de mediano tamaño del cuero cabelludo

Background and objectiveExcision of cutaneous scalp tumors results in surgical defects that are difficult to repair because of poor distensibility in this area of the body. The main aim of this study was to develop a structured algorithm to help choose the best technique for reconstructing scalp defects.Material and methodsRetrospective study of patients who required surgical reconstruction following excision of a cutaneous scalp tumor. We excluded patients with defects that could be closed by simple direct suture and defects for which it was initially decided to use a skin graft or healing by secondary intention. The defects were classified into 5 groups according to the minimum distance between edges. The different reconstruction techniques used were evaluated in each group. The outcomes analyzed were complete defect closure, intraoperative and postoperative complications, and final aesthetic result.ResultsWe included 119 patients (102 men and 17 women) with a mean age of 71 years (range, 32–93 years). Mean follow-up was 42 months (range, 6–120 months). Sixty-eight patients had a moderate-sized defect with a distance between edges of 1 to 4 cm. Reconstructions started with relaxation incisions in 43 defects and resulted in the successful closure of 22 of them. Defects with a distance of 1 to 2 cm required a single relaxation incision. Two incisions were required for defects with a distance of 2 to 3 cm, while 3 incisions were required for those with a distance of 3 to 4 cm. In the 21 cases in which relaxation incisions were insufficient to close the defect, the incisions were extended to mobilize the flap to achieve closure. Relaxation incisions alone were insufficient for closing defects with a distance greater than 4 cm.ConclusionsThe 1-2-3 rule can help in choosing the best reconstruction technique for moderate-sized defects based on the principle that 1, 2, or 3 initial relaxation incisions are needed depending on the minimum distance between edges (1-2 cm, 2-3 cm, or 3-4 cm). In all cases, incision extension to mobilize the corresponding flaps remains an option.     

Modeling clinical efficacy of the S1P receptor modulator ponesimod in psoriasis

Background

Ponesimod is currently the only S1P receptor modulator studied in psoriasis. In a dose-finding study, the active doses showed similar efficacy.

Características clínicas de los pacientes con melanoma cutáneo en función de las variaciones en el gen del receptor 1 de la melanocortina (MC1R)

IntroductionPatients with cutaneous melanoma who are carriers of polymorphisms in the melanocortin 1 receptor gene (MC1R) have distinctive clinical characteristics. The objective of this study was to determine the clinical characteristics associated with differing degrees of functional impairment of the melanocortin 1 receptor, as determined by the number and type (R and r) of MC1R polymorphisms.Material and methodsIn total, 1044 consecutive patients with melanoma diagnosed in our hospital after January 2000 were selected from the melanoma database. These patients were divided into 3 groups according to a score based on nonsynonymous MC1R polymorphisms. The frequencies of epidemiologic, phenotypic, and histologic variables and personal and family history of cancer were compared.ResultsPatients with a score of 3 or more were more likely to develop melanoma before the age of 50 years (odds ratio [OR] = 1.47), have a tumor on the head or neck (OR = 3.04), have a history of basal cell carcinoma or cutaneous squamous cell carcinoma (OR = 1.70), have atypical nevi (OR = 1.74), and have nevi associated with the melanoma (OR = 1.87).ConclusionsThe use of a scoring system for MC1R polymorphisms allowed us to identify associations between the degree of functional impairment of the melanogenesis pathway and the clinical characteristics of the patients and melanoma presentation.     

«Baby Merkel»: tumor de Merkel incipiente; a propósito de 2 casos

Merkel cell carcinoma is a malignant skin tumor with a poor prognosis that primarily affects photoexposed areas of elderly patients. Tumor size is a very strong prognostic factor, with much better outcomes associated with small lesions, measuring less than 1 cm. However, such lesions are rarely seen in the clinic in view of the rapid growth of this tumor.We report 2 cases of incipient Merkel cell carcinoma. Both cases of incipient Merkel cell carcinoma measured approximately 5 mm in diameter. One tumor was confined to the epidermis and papillary dermis on the nose of a 79-year-old man and the other was located in the deep dermis, almost in the hypodermis, on the buttock of an 82-year-old woman. In both cases, the lesions had appeared weeks earlier. The first tumor seemed to originate in the dermoepidermal junction whereas the second originated almost in the hypodermis. Although the lesions were at a similar disease stage and had a similar size, their different locations within the dermis highlight once again the controversy about which cells give rise to Merkel cell carcinoma. The precursor cells could feasibly be Merkel cells in the first case but not in the second.     

A novel mutation of the tyrosinase gene causing oculocutaneous albinism type 1 (OCA1)

Tyrosinase is a rate-limiting enzyme in the melanin biosynthetic pathway and a complete defect of the enzyme activity caused by homozygous mutations of the tyrosinase gene is well known to result in tyrosinase-negative oculocutaneous albinism (OCA1A) patients who never develop any melanin pigment in the skin, hair and eyes throughout life. In this paper, we report a novel missense substitution, R239W(CGG --> TGG) of the tyrosinase gene in a patient with tyrosinase-negative OCA.     

Neurofibromatosis type 1 associated with Charcot–Marie–Tooth type 1A

Neurofibromatosis and Charcot–Marie-Tooth are genetic disorders of the nervous system affecting the development and growth of nerve cells and demyelination of peripheral neurons, respectively. We report a 22-year-old man who presented clinical manifestations of both neurofibromatosis type 1 (NF1) and Charcot–Marie–Tooth type 1A. The simultaneous occurrence of neurofibromatosis and Charcot–Marie–Tooth disease has rarely been reported. More extensive reports and further investigations of this combination will certainly provide a better understanding of this linkage in the near future.     

The use of digital dermoscopy in the surveillance of melanocytic skin lesions: A real-life retrospective study comparing university hospital and private practices

BackgroundFew studies have evaluated the role of digital dermoscopy (DD) in the surveillance of pigmented lesions in real-life practice.Patients and methodsPatients followed with DD by 4 hospital dermatologists (group 1) and 4 private dermatologists (group 2) were retrospectively included if they had had at least 2 DD examinations for a minimum of 4 pigmented lesions. Their characteristics, risk factors, history of excision of benign nevi and melanomas prior to and during the DD follow-up, and characteristics of detected melanomas, were recorded.ResultsOne hundred and ninety-six patients were included in group 1 and 205 in groups 2. A family history of melanoma (25% vs. 12%, p < 0.01), a personal history of melanoma before DD follow-up (47% vs. 15%, p < 0.01), and a family (3% vs. 0%, p = 0.01) and personal (8% vs. 1%, p < 0.01) germline CDKN2a mutation were more frequent in group 1 than in group 2. In both groups, the number of excisions of benign lesions was higher before DD follow-up (380 and 347, respectively) than during DD follow-up (194 and 132). During follow-up, 29 melanomas were detected in group 1, with a median Breslow thickness of 0.4 mm, versus 1.3 mm for melanomas diagnosed before DD follow-up (p < 0.02). In group 2, 4 melanoma and 5 superficial atypical melanocytic proliferations of unknown significance were detected. The median Breslow thickness of newly diagnosed melanomas was 0.35 mm vs. 0.6 mm before DD follow-up (p = 0.1).ConclusionIn both populations in real-life practice, DD seemed to allow the detection of thin melanomas and to decrease the rate of “futile” resections.     

Gangliosides inhibit urokinase-type plasminogen activator (uPA)-dependent squamous carcinoma cell migration by preventing uPA receptor/alphabeta integrin/epidermal growth factor receptor interactions

The interaction of the urokinase-type plasminogen activator (uPA) receptor (uPAR) with integrins plays a critical role in the regulation of cell adhesion and migration. However, the molecular events underlying the modulation of the interaction of uPAR and integrin are poorly understood. Gangliosides are thought to regulate epithelial cell adhesion and migration by inhibiting alpha(5)beta(1) integrin and epidermal growth factor receptor (EGFR) signaling. We report here that increases in the expression of ganglioside NeuAcalpha2-->3Galbeta1-->3GalNAcbeta1-->4(NeuAcalpha2-->8NeuAcalpha2-->3)Galbeta1-->4Glcbeta1-Cer (GT1b) or NeuAcalpha2-->3Galbeta1-->4Glcbeta1-Cer (GM3) inhibit uPA-dependent cell migration by preventing the association of uPAR with alpha(5)beta(1) integrin or uPAR/alpha(5)beta(1) integrin with the EGFR, respectively. As a result, uPA-dependent focal adhesion kinase (FAK) and integrin-mediated EGFR signaling are suppressed. Both gangliosides inhibit uPAR signaling-stimulated migration; however, GM3 inhibits uPA-induced EGFR phosphorylation by blocking the crosstalk between integrin and EGFR, whereas GT1b suppresses both uPA-induced FAK and EGFR activation by preventing the activation of integrin alpha(5)beta(1).     

High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TYRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X, L668P, 532insC, 1691delA). An IVS5+5G --> A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melan-ep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.     

Cyclin D1 promoter -56 and -54 bp CpG un-methylation predicts invasive progression in arsenic-induced Bowen’s disease

Background

Patients with arsenic-induced Bowen’s disease (As-BD) are at risk of developing invasive cancers in the skin, lung, and urinary bladder. However, a longitudinal follow-up study on the association between As-BD and invasive cancers is still lacking.

The effect of 4-hydroxypanduratin A on the mitogen-activated protein kinase-dependent activation of matrix metalloproteinase-1 expression in human skin fibroblasts

BackgroundExposure of ultraviolet (UV) light on the skin induces photoaging associated with up-regulated matrix metalloproteinases (MMPs) activities. The MMP-1 expression due to UV irradiation can be mediated by mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), Jun-N-terminal kinase (JNK) and p38 kinase activation.ObjectiveWe investigated the effects of 4-hydroxypanduratin A, isolated from Kaempferia pandurata Roxb., on the expression of MMP-1 and activation of MAPKs signal pathways in UV-irradiated human skin fibroblasts.MethodsThe fibroblasts were treated with 4-hydroxypanduratin A for indicated times and the cells were irradiated with UVB. MMP-1 protein expression and phosphorylation of MAPKs were determined by Western blot. Activator protein-1 (AP-1) DNA binding activity was investigated using electrophoretic mobility shift assay (EMSA).Results4-Hydroxypanduratin A in the range of 0.001–0.1 μM significantly reduced the expression of MMP-1 levels and inhibited UV-induced MAPKs activation. Moreover, inhibition of MAPKs by 4-hydroxypanduratin A resulted in decreasing c-Fos expression and c-Jun phosphorylation induced by UV, which led to inhibiting AP-1 DNA binding activity.ConclusionsThe results suggest that 4-hydroxypanduratin A can be a potential candidate for the prevention and treatment of skin aging brought about by UV.     

Demographic characteristics and health-related quality of life of patients with moderate-to-severe psoriasis: The VACAP study

BackgroundPsoriasis is associated with a deterioration in the health-related quality of life (HRQoL) of affected patients. The aim of this study was to assess the HRQoL of patients with moderate-to-severe psoriasis.MethodsA prospective observational study (the VACAP Study) was carried out in 123 centers in Spain with 1217 patients. Patients were evaluated at baseline (visit 1 [V1]) and again four months later (visit 2 [V2]). The severity of psoriasis was determined using the following indices: (i) Psoriasis Area and Severity Index (PASI) (score range 0–72, higher score indicates more severe disease), (ii) the body surface area (BSA) affected, and (iii) the Physicians Global Assessment (PGA) (range 1–7, higher score indicates more severe disease). Four questionnaires were used for the assessment of the HRQoL: (i) the Short-Form 36 quality-of-life questionnaire (SF-36) (score range 0–100, higher score indicates better HRQoL); (ii) Euroqol (EQ-5D) (range from 1 to 3, lower score indicates better HRQoL); (iii) Dermatology Life Quality Index (DLQI) (ranges 0–30; from best to worst HRQoL); and (iv) Psoriasis Disability Index (PDI) (ranges 0–45; higher score indicates better HRQoL).ResultsThe mean (SD) age of the patients was 45.11 (13.92) years at V1. The mean age at the onset of psoriasis was 26.08 (14.19) years. The majority of patients were female (61%) and were employed (68%). The mean PASI score was 13.24 (9.50) at V1 and 5.07 (6.03) at V2 (P < .001). Scores from the generic HRQoL questionnaires (EQ-5D, SF-36) showed significant improvement between visits in all dimensions measured (P < .001). The disease-specific questionnaires also revealed overall improvements in quality of life over time: the DLQI mean total score was 8.97 (7.28) at V1 and 4.76 (5.72) at V2 (P < .001), and the PDI mean total score was 9.24 (8.76) V1 and 4.88 (6.65) at V2 (P < .001). Multivariate analysis using PDI as the dependent variable showed that the principal factors related to HRQoL were severity of psoriasis as measured by PASI (P < .001), and gender (P = .048).ConclusionsThe principal factor related to HRQoL in patients with psoriasis is the severity of the disease.     

Vulvar Fordyce adenitis: A cohort of 45 women

BackgroundRecurrent episodes of painful papules and nodules, mostly located on the labia minora, have been reported under the denominations of vulvar sebaceous adenitis (14 published cases) and vulvar acne (16 published cases).ObjectivesThe primary aim of this study was to delve further into the clinical and pathological features of this condition. The secondary aim was to collect therapeutic data.MethodsIn this retrospective cohort study, files and photographs of patients with papules or nodules on the labia minora or the inner labia majora were extracted from a vulvar clinic database. Clinical, pathological and therapeutic data were analysed.ResultsForty-five women were included from 2002 to 2018. The median age at the time of diagnosis was 36 years (range: 16–60). The median time to diagnosis was 6.5 years. Clinical features included recurrent painful papules, pustules or nodules, suppuration (n = 22), and pitted scars (n = 10) on the labia minora (n = 41), the inner labia majora (n = 19), the outer labia majora (n = 1), and the clitoral hood (n = 1). Associated acne vulgaris was seen in 17 out of 26 patients for whom data were available. Hidradenitis suppurativa, androgenic alopecia and hirsutism were observed in 3, 1 and 1 cases respectively. Neutrophilic infiltrates were observed in the 4 available biopsies within or around the Fordyce sebaceous glands in 2 patients. Treatment with tetracyclines and oral zinc was not consistently effective. Isotretinoin led to complete remission in 4 patients unresponsive to tetracyclines.DiscussionVulvar sebaceous adenitis/vulvar acne is a clinically identifiable cause of painful recurrent inflammatory lesions affecting the labia minora and the inner labia majora, which are coincidentally sites of Fordyce granules. We therefore suggest a more specific denomination: “vulvar Fordyce adenitis”. The relationship with acne vulgaris and hidradenitis suppurativa requires further investigation. We suggest use of an oral anti-acne therapeutic strategy to reduce inflammation and to decrease the secretion of the sebaceous glands.     

BAP1‐deficient and VE1‐negative atypical Spitz tumor

Atypical Spitz tumor with loss of BAP1 or Wiesner nevus is a peculiar variant of intradermal spitzoid melanocytic neoplasm composed of epithelioid melanocytes with a sheet‐like growth pattern, abundant infiltrating lymphocytes and rare or absent mitotic activity. This subset of atypical spitzoid tumors is characterized by the BRAF^V600E mutation and loss of BAP1 expression. Recognition of these lesions is important because they can be a marker for a hereditary BAP1‐associated cancer syndrome. We present an unusual case of sporadic Wiesner nevus that had typical histopathologic features and a BAP1 but not a BRAF mutation. The biological significance of Wiesner nevus is controversial, and little is known about prognosis, particularly in atypical cases like this one.