Malignant melanoma.

CONTEXT: The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches. OBJECTIVES: To present the most current concepts on the etiology and pathogenesis of melanoma and to introduce the recent diagnostic techniques and the potential therapeutic approaches. METHODS: Data sources were reports on melanoma published in the English language literature and observations made using specimens available at Harvard University, Johns Hopkins Medical Center, Albany Medical College, Loyola University Medical Center, and University of Tennessee Health Science Center. RESULTS: Studies on melanoma containing chromosomal or genetic evaluation were selected for further analysis. Current clinical and pathologic categories with the reported genetic abnormalities were related to the latest information on pigment biology. The data extracted were used to develop a conceptual framework on the pathogenesis of melanoma; the generated model was then evaluated and used to suggest potential therapeutic approaches. CONCLUSIONS: (1) Melanoma is not genetically homogeneous, and the existing differences between the pathologic categories, particularly in areas such as type of growth phase (radial vs vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications. (2) Chromosomal aberrations and gene mutations are found in sporadic and familial melanomas; among the most important are those affecting the 9p21, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior. (3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen. (4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly entering the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.

Decreased bioavailability of vitamin D in obesity.

BACKGROUND: Obesity is associated with vitamin D insufficiency and secondary hyperparathyroidism. OBJECTIVE: This study assessed whether obesity alters the cutaneous production of vitamin D(3) (cholecalciferol) or the intestinal absorption of vitamin D(2) (ergocalciferol). DESIGN: Healthy, white, obese [body mass index (BMI; in kg/m(2)) > or = 30] and matched lean control subjects (BMI

Immunological responses to ultraviolet light B radiation in Black individuals.

Immunological factors are important participants in the pathogenesis of experimental skin tumors. We therefore studied cutaneous immune responses in subjects with either low natural incidence (Black individuals), or a high frequency rate (White individuals) of skin cancer. We performed whole body irradiation with a low dose of ultraviolet light B (UV-B) and evaluated peripheral lymphocytes. UV-B irradiation was associated with small but significant changes in lymphocyte phenotype frequency. In White subjects this consisted of an increased number of CD19 (B cells) and CD 4/29 (inducer of helper T cells); Black subjects had a slight decrease in CD3 (T cells). Natural killer activity, not affected by UV-B in White subjects, increased significantly in Black subjects. UV-B was devoid of immunological effects in vitro for any of the parameters tested. As expected, the low UV-B dose used in this study induced increases of serum vitamin D3 concentrations in White subjects, with lack of response in the Black subjects. We conclude that Black individuals selectively exhibit an increase in Natural Killer activity in response to irradiation with low dose UV-B. This race group-specific immune response to ultraviolet radiation appears to require mediation by the skin. Enhanced Natural Killer activity could underlie at least partly the resistance in Black individuals to the development of photodependent skin cancer.

Compensation for the interracial variance in the cutaneous synthesis of vitamin D.

We investigated the homeostatic compensation for the lower cutaneous synthesis of vitamin D in heavily melanized persons. Vitamin D2 (50,000 IU) was administered in a single oral dose to 24 young adults, 12 blacks and 12 whites, matched for age, gender, and socioeconomic status. We also included a group of eight healthy elderly white adults as representatives of a population with a nonracial mechanism for decreased cutaneous vitamin D synthesis. Plasma determinants were performed under basal conditions and at 6, 10, and 24 hours after vitamin D intake. Basal 25-hydroxyvitamin D (25-OH-D) levels were significantly lower in blacks (12.5 +/- 2.2 ng/ml (mean +/- SEM)) and in elderly whites (19.2 +/- 1.9 ng/ml), compared with young whites (30.2 +/- 3.0 ng/ml (p < 0.0001)); levels of basal 1,25-dihydroxyvitamin D (1,25(OH)2 -D) did not differ between groups. The vitamin D blood curve was similar between groups after the oral vitamin D2 load. Increases in 25-OH-D were 91.7 +/- 15.9% in blacks, 18.8 +/- 5.2% in young whites, and 28.6 +/- 6.9 in elderly whites; 1,25(OH)2-D levels increased slightly and did not differ between groups, although in blacks the change over time was significant (p < 0.05). As a whole, the study populations exhibited a strong relation between basal and peak 25-OH-D (r = -0.80; p < 0.001). Levels of intact parathyroid hormone and serum calcium of blacks and young whites did not differ within or between groups throughout the test.(ABSTRACT TRUNCATED AT 250 WORDS)

Neoplastic erythema nodosum.

We performed immunohistologic studies on a 75-year-old white woman with erythema nodosum (EN) and a systemic lymphoma. A skin biopsy specimen from an EN lesion showed lobular and septal pannicular infiltration by atypical lymphocytes. The cutaneous lymphocytic infiltrate was composed of a monoclonal population of B cells with lambda light chains. Atypical lymphocytes were also seen in the peripheral blood, and flow cytometry showed a predominance of the same phenotype of B cells with lambda light chains. Chemotherapy for systemic B-cell lymphoma resulted in the simultaneous resolution of EN and the lymphoma. This is the first documentation of EN representing direct cutaneous invasion by a B-cell lymphoma.

Kinetic and thermodynamic studies of the conversion of previtamin D3 to vitamin D3 in human skin.

The thermoisomerization of previtamin D3 to vitamin D3 is the last step in the synthesis of vitamin D3 in human skin. Kinetic and thermodynamic studies of this reaction in human skin and an organic solvent revealed that not only the equilibrium of the reaction was shifted in favor of vitamin D3 formation in human skin (equilibrium constant K at 37 degrees C = 11.44) compared to hexane (K = 6.15), but also the rate of the reaction was increased by more than 10-fold in human skin (T1/2 at 37 degrees C = 2.5 h) when compared to hexane (T1/2 = 30 30 h). This extraordinarily fast reaction rate was also confirmed in vitro in chicken skin and in vivo in human subjects. The enthalpy change for the reaction determined by the van't Hoff plot was delta H degree = -21.58 kJ mol-1 in human skin and delta H degree = -15.60 kJ mol-1 in hexane. Arrhenius plots showed that the activation energies for both the forward and the reverse reactions were lower in human skin (Ea1 = 71.05 kJ mol-1 and Ea2 = 92.63 kJ mol-1) than in hexane (Ea1 = 84.90 kJ mol-1 and Ea2 = 100.5 kJ mol-1). Activation parameters for the reaction in human skin and in hexane were also reported. Subcellular fractionation of human epidermal tissue revealed that most epidermal 7-dehydrocholesterol and previtamin D3 were in the membrane fraction, while only 20% were in the cytosol. The interaction of previtamin D3 with intracellular lipids and/or proteins in skin may be responsible for the increased vitamin D3 formation rate in the skin.

Human plasma transport of vitamin D after its endogenous synthesis.

Transport of vitamin D3 from its sites of cutaneous synthesis into the circulation has been assumed to be via the plasma vitamin D binding protein (DBP). We studied vitamin D transport from the skin in seven healthy volunteers who received whole body irradiation with 27 mJ/cm2 dosage of ultraviolet B light (290-320 nm). Samples of venous blood were collected serially in EDTA and immediately chilled. In KBr, plasma samples were ultracentrifuged to provide a rapid separation of proteins of density < and > 1.3 g/ml. Upper and lower phases and serial fractions were analyzed for vitamin D3 (extraction, HPLC), cholesterol (enzyme assay), and human DBP (hDBP) (radial immunodiffusion). Total plasma vitamin D (basal level < 1 ng/ml) increased by 10 h and peaked at 24 h (9 +/- 1 ng/ml). 98% of the D3 remained at the density > 1.3 layers for up to 7 d, whereas cholesterol (> 85%) was detected at density < 1.3 and all of the hDBP was at density > 1.3. In three volunteers who each ingested 1.25 mg of vitamin D2, the total plasma D2 increased to 90 +/- 32 ng/ml by 4 h, and the D2 was evenly distributed between the upper and lower layers at 4, 8, and 24 h after the dose, indicating a continuing association of the vitamin with chylomicrons and lipoproteins, as well as with hDBP. Actin affinity chromatography removed D3 from plasma of irradiated subjects, indicating the association of the D3 with DBP. These findings indicate that endogenously synthesized vitamin D3 travels in plasma almost exclusively on DBP, providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol observed after depot, parenteral administration of vitamin D. In contrast, the association of orally administered vitamin D with chylomicrons and lipoproteins allows for receptor-mediated, rapid hepatic delivery of vitamin D, and the reported rapid but less-sustained increases in plasma 25-hydroxycholecalciferol.

The association of potentially lethal neurologic syndromes with scleromyxedema (papular mucinosis).

Two patients with scleromyxedema who had progressive neurologic impairment are described. One patient died, and one required prolonged mechanical ventilation. A review of the literature has produced 24 other cases of scleromyxedema in which neurologic changes were prominent.

Acne and related disorders.

Acne vulgaris is the clinical expression of inflammation of the pilosebaceous unit. Factors known to predispose to the development of acne include increased sebum, which is acted on by Propionobacterium acnes to generate inflammatory substances, and retention hyperkeratosis, which causes obstruction of the sebaceous follicle. Therapeutic modalities for acne include topical and systemic antibiotics, comedolytic agents (such as benzoyl peroxide and topical retinoids) and systemic retinoids. Acne scars may be treated surgically using procedures such as dermabrasion and dermal injections of bovine collagen or simple scar excision, scar punch elevation, or punch grafting.

Papular mucinosis (scleromyxoedema) complicating diffuse systemic sclerosis: clinical features and electron microscope observations.

Papular mucinosis (scleromyxoedema) is an uncommon disorder characterized by generalized papular eruption and cutaneous induration, which may be associated with a variety of extracutaneous manifestations. Although scleroderma and papular mucinosis share many features, they are clinically and histologically distinct entities. We report here a patient with diffuse scleroderma who developed superimposed papular mucinosis. Degranulating mast cells were a prominent ultrastructural finding in the involved skin. The occurrence of scleroderma and papular mucinosis, two uncommon cutaneous indurative diseases, in the same patient has not been described previously.

Elevation of blood vitamin D2 levels does not impede the release of vitamin D3 from the skin.

The mechanism for the transfer of fat-soluble vitamin D3 from the avascular basal cellular layers of the epidermis to dermal capillaries and peripheral circulation is unknown, although vitamin D-binding protein (DBP) is thought to mediate this process. To evaluate the effect of increased occupancy of vitamin D carrier(s) on vitamin D3 removal from the skin, serial serum vitamin D2 and D3 concentrations were determined in three groups of six healthy volunteers given combinations of an oral dose of vitamin D2 (50,000 IU) and a fixed dose of UVB radiation (27 mJ/cm2). Serum vitamin D3 levels increased significantly following UVB (time effect, P < .01 by ANOVA), but the response remained unchanged after pretreatment with vitamin D2, increasing from 3 +/- 1 to 14 +/- 5 ng/mL (mean +/- SEM), versus UVB alone, 5 +/- 1 to 16 +/- 5 ng/mL. Elevation of serum vitamin D2 levels was also similar in the groups given vitamin D2 alone (< 1 to 64 +/- 8 ng/mL) and vitamin D2 + UVB (< 1 to 45 +/- 8 ng/mL). There was no time or treatment effect for changes in serum levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, or (DBP) levels (P > .1). We conclude that vitamin D3 egress from the skin is not affected by elevated circulating vitamin D concentrations; thus, the cutaneous release of vitamin D is probably mediated by a protein such as DBP with a high carrying capacity for the vitamin.

Clothing prevents ultraviolet-B radiation-dependent photosynthesis of vitamin D3.

Photoprotection of the skin is mainly a function of clothing, although the effectiveness of the latter against UV-B solar radiation (wavelengths 290-320 nm) has not been measured in vivo. Since UV-B mediates the cutaneous formation of vitamin D3, we examined the attenuation of that photosynthetic reaction by the commonly used fabrics cotton, wool, and polyester in black and white colors. Direct transmission of UV-B was attenuated the most by black wool (98.6% of incident irradiance) and the least by white cotton (47.7%). None of the fabrics allowed the photoproduction of previtamin D3 from 7-dehydrocholesterol irradiated in vitro with up to 40 min of simulated sunlight or the elevation of serum vitamin D3 after irradiation with approximately one minimal erythema dose (MED) of UV-B in volunteers wearing jogging garments made of these fabrics. Increasing the whole body irradiation dose to six MEDs still failed to produce a serum vitamin D3 response in garment-clad subjects. Regular (seasonal) street clothing also prevented an elevation of the vitamin D3 in response to UV-B radiation. We conclude that clothing prevents or significantly impairs the formation of vitamin D3 after photostimulation with up to six MEDs of UV-B.

Cutaneous vitamin D3 formation in progressive systemic sclerosis.

Progressive systemic sclerosis (PSS) is a predominantly dermal disorder which may be associated with epidermal atrophy. We investigated epidermal function in 8 patients with PSS and their healthy controls matched for age, sex and racial group. We measured the vitamin D3 photosynthetic response to whole body irradiation with ultraviolet light B (UVB). There were no significant differences in basal serum vitamin D3 levels (mean +/- SEM: PSS 1.2 +/- 0.2 ng/ml; controls 0.8 +/- 0.1 ng/ml; p greater than 0.1) or post UVB blood values (PSS 5.2 +/- 1.4 ng/ml; controls 6.9 +/- 1.1 ng/ml; p greater than 0.1); although the increases post-UVB were significant in both groups (p less than 0.01). In an additional group of 19 patients with PSS and their corresponding matched healthy controls, we performed determination of random levels of the active vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D [1,25-(OH)2-D]. Similar levels were observed in both groups: 25-OH-D PSS 28 +/- 3 ng/ml, controls 29 +/- 3 ng/ml; 1,25-(OH)2-D PSS 27 +/- 2 pg/ml, controls 31 +/- 2 pg/ml (p greater than 0.1). None of the correlations between skin area involved and vitamin D3 formation or active circulating metabolites reached statistical significance (p greater than 0.1). We conclude that global epidermal synthesis of vitamin D is retained in PSS and, that the hepatic and renal vitamin D hydroxylating mechanisms function normally in that condition.

Racial pigmentation and the cutaneous synthesis of vitamin D.

The varying epidermal melanin content that produces racial pigmentation determines the number of photons that reach the lower (malpighian) cellular layers, where vitamin D3 synthesis takes place. We investigated the effect of racial pigmentation on vitamin D3 formation, stimulating the process with a fixed dose of UVB radiation (wavelengths, 290 to 320 nm). Vitamin D nutritional status was further assessed measuring serum 25-hydroxyvitamin D and the most active serum metabolite, 1,25-dihydroxyvitamin D. Experimental subjects were young (third decade of life) and healthy, representing the white, Oriental (East Asian), Indian (South Asian), and black races. Basal serum vitamin D3 levels were similar among groups, ranging from 2.3 +/- 0.6 nmol/L (mean +/- SEM) for blacks to 3.4 +/- 1.0 nmol/L for Indians. Following whole-body exposure to 27 mJ/cm2 of UVB, there was a significant racial group effect on serum vitamin D3 levels. Post-UVB levels were significantly higher in whites (31.4 +/- 4.4 nmol/L) than in Indians or blacks (12.8 +/- 2.9 and 9.1 +/- 2.1 nmol/L, respectively), while the levels in Orientals (27.8 +/- 4.4 nmol/L) differed significantly from those in blacks and Indians but not in whites. Race had only a marginal effect on serum 25-hydroxyvitamin D, with higher levels in whites than in blacks (69.9 +/- 12.7 vs 29.7 +/- 6.2 nmol/L). Serum 1,25-dihydroxyvitamin D and vitamin D binding protein levels were similar in all groups. We conclude that while racial pigmentation has a photoprotective effect, it does not prevent the generation of normal levels of active vitamin D metabolites.

Elastase inhibitory activity in serum of patients with thyroid dysfunction.

Dermal elastic fiber fragmentation and decreased fiber density are characteristic cutaneous abnormalities in myxedema. We therefore evaluated elastase inhibitory activity in serum in thyroid dysfunctional states by measuring the protease inhibitor alpha 1-antitrypsin (A-1-AT), as well as by directly determining the inhibition of porcine pancreatic elastase activity. Overall there was a strong correlation between A-1-AT concentration and elastase inhibitory activity in serum (r = 0.95, P less than 0.001). Mean (+/- SE) A-1-AT concentrations were greatest in hyperthyroidism (39 +/- 3 mumol/L, n = 13), followed by normal controls (29 +/- 1, n = 11), subclinical hypothyroidism (27 +/- 2, n = 7), and hypothyroidism (25 +/- 1, n = 12). Concentrations of both A-1-AT and porcine pancreatic elastase inhibitory activity were significantly greater in subjects with hyperthyroidism than in the other groups (P less than 0.01). The correlations (r) between the overall free thyroxin (T4) index and A-1-AT and elastase inhibitory activity were 0.68 and 0.61, respectively (P less than 0.01), implying that free T4 variations account for 46% of the variance in A-1-AT concentrations and 37% of the variance in elastase inhibitory activity. We conclude that serum elastase inhibitory activity is increased in hyperthyroid patients.