Léa Trémezaygues

Vitamin D analogs in the treatment of psoriasis: Where are we standing and where will we be going?

Vitamin D and analogs exert in the skin and other tissues potent effects on cellular differentiation and proliferation. Moreover, these compounds regulate apoptosis and exert immunomodulatory effects. During the last decades, it has convincingly been shown that vitamin D compounds are effective and safe in the topical treatment of psoriasis, where they nowadays represent a standard therapy. This review summarizes laboratory and clinical investigations related to the treatment of psoriasis with calcitriol or analogs. Additionally, promising concepts for the development of new vitamin D analogs are discussed. As a matter of fact, the final goal to create strong antiproliferative or antiinflammatory acting vitamin D analogs that exert only minor calcemic activity has not been reached until today. New agents that may activate selective vitamin D signalling pathways but may exert only negligible calcemic activity would declare a new era in dermatologic therapy and may also be effective in the topical or systemic treatment of various inflammatory skin diseases including atopic dermatitis and in various cutaneous malignancies, including lymphomas, squamous cell carcinoma or basal cell carcinoma.

1,25-dihydroxyvitamin D3 protects human keratinocytes against UV-B-induced damage: in vitro analysis of cell viability/proliferation, DNA-damage and repair

The skin is the only organ that has the capacity to photosynthesize the biological active vitamin D metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] from 7-dehydocholesterol (7-DHC), following exposure to ultraviolet (UV)-B irradiation. The aim of the present work was to investigate the capacity of 1,25(OH)2D3 to protect human keratinocytes (HaCaT) and squamous cell carcinoma cell lines (SCL-1) against the hazardous effects of UV-B irradiation. Human keratinocytes (HaCaT) and squamous cell carcinoma cell lines (SCL-1) were pretreated with 1,25(OH)2D3 over 48 hours and then irradiated once with UVB-radiation. We evaluated the results of several assays (colony-forming-unit-culture assay, WST-1-assay and crystal violet assay), comparing viability/proliferation in 1,25(OH)2D3-pretreated cells with controls that were pretreated with the carrier substance ethanol alone. Additionally, we analyzed the effects of 1,25(OH)2D3 on UV-induced DNA damage in HaCaT-keratinocytes by detection of cyclobutane pyrimidine dimers (CPDs) via dot blot analysis. We prove that 1,25(OH)2D3, in a concentration of 10-7M, protects human keratinocytes (HaCaT) as well as squamous cell carcinoma cell lines (SCL-1) against the hazardous effects of UV-B-radiation (100J/cm2-1000J/cm2) in vitro. Moreover, we demonstrate that the number of CPDs induced in HaCaT-keratinocytes after irradiation with UV-B (100J/cm2-1000J/cm2) was decreased after pretreatment with 1,25(OH)2D3, as compared to carrier-treated controls. Analysis of the time course revealed that the elimination of UV-B-induced DNA-damage in HaCaT-keratinocytes occurs quicker when cells are pretreated with 1,25(OH)2D3 (as compared to controls). To put it in a nutshell, our data support the hypothesis that 1,25(OH)2D3 protects cultured human keratinocytes against the hazardous effects of UV-B radiation.

The spectrum of reticulate pigment disorders of the skin revisited

Within the group of classical reticulate pigment disorders of the skin, Galli-Galli disease (GGD), Dowling-Degos disease (DDD), Kitamuras disease (RPK), Habers syndrome (HS), and reticulate acropigmentation of Dohi (RAD) are included and distinguished clinically and histopathologically. The clinical appearance of the reticulate pigment disorders of the skin is similar, with slight differences in age of onset and associated disorders. The histopathologic features of reticulate pigment disorders of the skin are comparable, with the exception of the unique hallmark of suprabasal acantholysis, which can be observed exclusively in GGD. Based on a critical discussion, we recommend using major and minor defining criteria for diagnosing skin lesions compatible with the reticulate pigment dermatoses of the skin. Herein we discuss a unifying nosological concept to provide straightforward diagnoses of the reticulate pigment disorders of the skin with a therapeutic impact.

From the bench to emerging new clinical concepts: Our present understanding of the importance of the vitamin D endocrine system (VDES) for skin cancer.

It is well accepted that growth and differentiation of keratinocytes and other cell types are regulated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D. Moreover, growing evidence now indicates that the UV-B-mediated cutaneous photosynthesis of vitamin D (and the consecutive cutaneous production of 1,25(OH)2D3) represents an evolutionary highly-conserved endocrine system that protects the skin against environmental hazards that may promote skin cancerogenesis, including ultraviolet and ionizing radiation. It is the aim of this review to summarize our present understanding of the cutaneous vitamin D endocrine system (VDES) and its importance for the prevention of skin cancerogenesis.

1,25-Dihydroxyvitamin D3 modulates effects of ionizing radiation (IR) on human keratinocytes: In vitro analysis of cell viability/proliferation, DNA-damage and -repair ☆

We investigated the capacity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to protect spontaneously immortalized human keratinocytes (HaCaT) and cutaneous squamous cell carcinoma cells (SCL-1) against the hazardous effects of ionizing radiation (IR). We pretreated HaCaT and SCL-1 cells in vitro with 1,25(OH)2D3 (10(-7) M) over 48 h and then irradiated them once with IR (1 Gy, 2 Gy, and 5 Gy). Using WST-1-assay and crystal violet (CV) assay, we compared viability/proliferation in 1,25(OH)2D3-pretreated cells with controls that were pretreated with the carrier substance ethanol alone. Additionally, we analyzed the effects of 1,25(OH)2D3 on the presence of IR-induced DNA-damage by immunocytochemical detection of gamma-H2AX-foci in HaCaT-keratinocytes. We demonstrate that 1,25(OH)2D3 (10(-7) M) inhibits proliferation of human keratinocytes and that IR (1-5 Gy) has no significant effect on proliferation and viability of HaCaT-keratinocytes and SCL-1 cells. Moreover, we show that IR modulates dose-dependently the number of gammaH2AX-foci in HaCaT-keratinocytes. Pretreatment of the cells with 1,25(OH)2D3 reduces the number of IR-induced gammaH2AX-foci after irradiation with 1 Gy and 2 Gy and increases it after irradiation with 5 Gy. To put it in a nutshell, our data support the hypothesis that 1,25(OH)2D3 modulates the effects of low-dose IR (1-5 Gy) on cultured human keratinocytes.

Factor-XI-deficiency: perioperative coagulation management in a patient with an extensive squamous cell carcinoma of the shin

Factor XI (FXI) deficiency is an autosomal bleeding disorder with a worldwide prevalence of approximately 1/100.000. The bleeding tendency in patients with FXI deficiency is variable and except for menorrhagia spontaneous bleeding is rare [1]. Most commonly, prolonged bleeding is observed after surgery or injuries [2]. No specific bleeding score has been established for FXI deficiency [3]. The bleeding intensity neither correlates with the type of genetic defect nor with FXI activity. Therefore, medical history is essential to estimate the bleeding risk in those patients. Compared to other surgical procedures, surgery of skin tumors is usually associated with a low bleeding risk, albeit depending on the kind of defect repair (highest risk for partial repair, OR = 43.13) [4].

Faktor‐XI‐Mangel: Perioperatives Gerinnungsmanagement bei einer Patientin mit ausgedehntem Plattenepithelkarzinom des Unterschenkels

Der Faktor-XI (FXI)-Mangel ist eine autosomale Blutgerinnungsstörung mit einer weltweiten Prävalenz von etwa 1/100 000. Die Blutungsneigung bei Patienten mit FXI-Mangel ist variabel und Spontanblutungen treten mit Ausnahme der Menorrhagie selten auf [1]. Am häufigsten werden protrahierte Blutungen nach operativen Eingriffen oder Traumata beobachtet [2]. Ein spezifischer Blutungsscore für den FXI-Mangel existiert nicht [3]. Die Intensität der Blutungen korreliert weder mit der Art des genetischen Defekts noch mit der FXI-Aktivität. Und so ist eine Anamnese unerlässlich, um das Blutungsrisiko dieser Patienten abschätzen zu können. Verglichen mit anderen chirurgischen Eingriffen sind Operationen bei Hauttumoren für gewöhnlich mit einem niedrigen Blutungsrisiko assoziiert, allerdings ist das Risiko abhängig von der Art des Defektverschlusses (höchstes Risiko bei zweizeitigem Defektverschluss, OR = 43,13) [4].

Relevance of the Cutaneous Vitamin D Endocrine System for Skin Physiology and Treatment of Skin Diseases

Vitamin D can be absorbed from the diet or synthesized in the skin from 7-dehydrocholesterol (7-DHC) under the influence of ultraviolet B (UVB) radiation. The keratinocyte is the only cell type known today that is able to synthesize the biologically active vitamin D metabolite 1,25(OH)2D3 from 7-dehydrocholesterol. Numerous in vitro and in vivo studies have demonstrated dose-dependent effects of vitamin D analogues on cell proliferation and differentiation as well as immunomodulatory effects, effects on apoptosis, and antioxidative and cytoprotective effects. 1,25(OH)2D3 and numerous of its analogues are used in the treatment of psoriasis and other skin diseases.

Differential considerations of skin tumours with florid vascularisation: report of a solitary giant vascular eccrine spiradenoma.

The authors report the case of an 81-year-old male who presented with a 3-year-history of a bluish, nodular tumour located on the extensor side of his right forearm. Subjective symptoms included tenderness upon palpation and spontaneous haemorrhage. In order to exclude malignant neoplasms, for example, nodular melanoma, metastatic melanoma or angiosarcoma, the tumour was surgically removed and tissue submitted for microscopic examination. Histologically, the authors diagnosed this as giant vascular eccrine spiradenoma, a rare variant of eccrine spiradenoma, which can easily be mistaken for angiomatous lesions due to the haemorrhagic features and florid vascularisation. It is our aim to help clarify the diagnosis and differentiate giant vascular eccrine spiradenoma from other painful cutaneous tumours exhibiting a high degree of vascularisation, for example, angiosarcoma or venous thrombosis, as this case represents one of only seven found in published literature.