R. Steven Padilla

ULTRAVIOLET RADIATION - INDUCED MALIGNANT MELANOMA IN Monodelphis domestica

Several lines of evidence support the hypothesis that ultraviolet radiation (UVR) is involved in the etiology of cutaneous melanoma in humans. However, progress in understanding the mechanisms involved in induction of melanotic tumors by UVR has been hindered by lack of a suitable animal model. During the course of multiple exposures (3 times/wk for 70 wk) of the South American opossum, Monodelphis domestica, to UVR, we first observed the appearance of areas of dermal melanocytic hyperplasia (MH) on the exposed skin. Post‐UVR exposure to photoreactivating light (320–500 nm) suppressed the occurrence of MH. We also observed at 100 weeks from first exposure that 10 of 46 surviving animals had developed melanotic tumors which arose, presumably, from areas of MH. Tumors on three of the 10 animals have been classified as malignant melanomas based on metastasis to lymph nodes. We conclude from these results that UVR can act as a complete carcinogen for melanoma induction and, based on the photoreactivation of MH induction, that DNA damage is involved in melanoma formation.

Effect of High-Dose Intravenous Immunoglobulin Therapy in Stevens-Johnson Syndrome: A Retrospective, Multicenter Study

Background:Stevens-Johnson syndrome (SJS) is a severe cutaneous drug reaction associated with considerable morbidity, possible transition to toxic epidermal necrolysis (TEN) and death in certain cases. Objective: To determine whether treatment with high-dose IVIG in SJS patients may improve outcome. Methods: Data from 12 patients (collected between January 1997 and November 2000 from7 university dermatology centers in Europe and North America) diagnosed with SJS according to a recent consensus definition was analyzed retrospectively. All patients had progressive ongoing epidermal detachment at the time of treatment initiation. Patients with overlap syndromes and TEN were excluded. Tolerance, survival at 45 days after onset and total healing time were assessed. Results: Twelve SJS patients (mean age 44 years) were treated with IVIG at a mean dose of 0.6g/kg/day for an average of 4 days. An objective response to IVIG infusion was observed in all patients within a mean of 2 days, and the overall survival rate was 100%. Total skin healing occurred, on average, within 8.3 days. Time to total healing was shorter in a group of patients with fewer severe underlying diseases who had received IVIG infusion rapidly after the onset of skin lesions. Conclusion: High-dose IVIG may be effective in blocking the progression of SJS and reducing the time to complete skin healing.

Gene Expression Patterns of Normal Human Skin, Actinic Keratosis, and Squamous Cell Carcinoma: A Spectrum of Disease Progression

OBJECTIVES To identify and compare the gene expression profiles of actinic keratosis (AK) and squamous cell carcinoma (SCC) and to further clarify critical genetic alterations in the evolution of SCC from normal sun-damaged human skin. DESIGN Observational study. SETTING University practice. PATIENTS Skin biopsy specimens were obtained from 16 patients. The specimens included 14 normal non-sun-exposed skin samples, 14 normal sun-exposed skin samples, 5 AKs, and 15 cutaneous SCCs. MAIN OUTCOME MEASURES Gene expression profiles from normal non-sun-exposed skin, normal sun-exposed skin, AKs, and SCCs. RESULTS Using a highly astringent shrunken centroid threshold of 6.52 and the prediction analysis of microarrays, we identified 89 unique genes that most likely contribute to the molecular evolution of SCC. Our model was cross-validated using data from a separate study and clearly distinguishes between skin tumors (AK and SCC) and normal skin independent of sun exposure. Genes that were upregulated in AK and SCC were downregulated in normal skin, and genes that were downregulated in AK and SCC were upregulated in normal skin. CONCLUSIONS The finding of similar differentially expressed genes in AK and SCC confirms that AK is a precursor lesion of SCC and indicates that they are closely related genetically. Clear elucidation of these relationships will be critical to improving therapeutic approaches.

Linear focal elastosis (elastotic striae)

Three patients are described who had a distinctive clinical and histologic presentation of dermal elastosis. Sunlight apparently played little role in the development of this elastotic change. To the best of our knowledge, this is the first report of this form of elastosis.

Evaluation of a novel Arg-Gly-Asp-conjugated α-melanocyte stimulating hormone hybrid peptide for potential melanoma therapy.

UNLABELLED The purpose of this study was to determine whether Arg-Gly-Asp (RGD)-conjugated α-melanocyte stimulating hormone (α-MSH) hybrid peptide could be employed to target melanocortin-1 (MC1) receptor for potential melanoma therapy. METHODS The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), DPhe(7), Arg(11)]α-MSH(3-13) {(Arg(11))CCMSH} to generate RGD-Lys-(Arg(11))CCMSH hybrid peptide. The MC1 receptor binding affinity of RGD-Lys-(Arg(11))CCMSH was determined in B16/F1 melanoma cells. The internalization and efflux, melanoma targeting and pharmacokinetic properties and single photon emission computed tomography/CT (SPECT/CT) imaging of (99m)Tc-RGD-Lys-(Arg(11))CCMSH were determined in B16/F1 melanoma cells and melanoma-bearing C57 mice. Clonogenic cytotoxic effect of RGD-Lys-(Arg(11))CCMSH was examined in B16/F1 melanoma cells. RESULTS RGD-Lys-(Arg(11))CCMSH displayed 2.1 nM MC1 receptor binding affinity. (99m)Tc-RGD-Lys-(Arg(11))CCMSH showed rapid internalization and extended retention in B16/F1 cells. The cellular uptake of (99m)Tc-RGD-Lys-(Arg(11))CCMSH was MC1 receptor-mediated. (99m)Tc-RGD-Lys-(Arg(11))CCMSH exhibited high tumor uptake (14.83 ± 2.94% ID/g 2 h postinjection) and prolonged tumor retention (7.59 ± 2.04% ID/g 24 h postinjection) in B16/F1 melanoma-bearing mice. Nontarget organ uptakes were generally low except for the kidneys. Whole-body clearance of (99m)Tc-RGD-Lys-(Arg(11))CCMSH was rapid, with approximately 62% of the injected radioactivity cleared through the urinary system by 2 h postinjection. Flank melanoma tumors were clearly imaged by small animal SPECT/CT using (99m)Tc-RGD-Lys-(Arg(11))CCMSH as an imaging probe 2 h postinjection. Single treatment (3 h incubation) with 100 nM of RGD-Lys-(Arg(11))CCMSH significantly (p < 0.05) decreased the clonogenic survival of B16/F1 cells by 65% compared to the untreated control cells. CONCLUSION Favorable melanoma targeting property of (99m)Tc-RGD-Lys-(Arg(11))CCMSH and remarkable cytotoxic effect of RGD-Lys-(Arg(11))CCMSH in B16/F1 cells warranted the further evaluation of (188)Re-labeled α-MSH hybrid peptides as novel therapeutic peptides for melanoma treatment once the strategies of amino acid coinjection or structural modification of peptide sequence substantially reduce the renal uptake.

Pigmented basal cell carcinoma in Hispanics

BACKGROUND Pigmented basal cell carcinoma (PBCC) may occasionally be misdiagnosed as melanoma. In the Hispanic population, PBCC is common. OBJECTIVE We attempted to determine the prevalence of PBCC in a Hispanic population. METHODS A randomized, blinded, retrospective study was designed to assess histologic slides for the presence of microscopic pigment. Basal cell carcinoma (BCCs) from 30 patients with a Hispanic surname were compared histologically with BCCs from 30 patients with a northern European surname. In the prospective phase of the study, 15 Hispanic and 44 non-Hispanic patients with clinically suspected BCC or PBCC completed a questionnaire about their ethnic background and skin type to determine whether PBCC is more common in Hispanics. RESULTS Pigment was identified twice as frequently in BCCs from patients with a Hispanic surname than in BCCs from patients with a northern European surname. In the prospective clinical study, 66% of clinically diagnosed PBCCs were found in Hispanic patients, whereas only 11% of nonpigmented BCCs came from Hispanic patients (p < 0.01). CONCLUSION In patients with a BCC, PBCCs are more common in Hispanics than non-Hispanics. This may reflect an increased incidence of PBCCs in the Hispanic population.

Microarray analysis of cutaneous squamous cell carcinomas reveals enhanced expression of epidermal differentiation complex genes.

Gene expression profiles were determined for 12 cutaneous squamous cell carcinomas (SCC) removed from sun‐exposed sites on nonimmunosuppressed patients. Gene expression in each SCC was compared to that in sun‐exposed skin from the same patient using the Affymetrix HGU133 2.0 PlusGeneChip. We identified 440 genes with increased expression in SCC and 738 with decreased expression; overall we identified a large number of small changes in gene expression rather than a few marked changes that distinguished SCC from sun‐exposed skin. Analyzing this robust data set according to biofunctional pathways using DAVID, transcriptional control elements using oPOSSUM, and chromosomal location using GSEA suggested genetic and epigenetic mechanisms of gene expression regulation in SCC. Some altered patterns of gene expression in SCC were consistent with regulation of spatially separated genes by a number of developmentally important transcription factors (forkhead, HMG, and homeo factors) that negatively regulated gene expression and to a few factors that positively regulated expression (Creb‐1, NFκB, RelA, and Sp‐1). We also found that coordinately enhanced expression of epidermal differentiation complex genes on chromosome 1q21 was a hallmark of SCC. A novel finding in our study was enhanced expression of keratin 13 in SCC, a result validated by immunohistochemical staining of an SCC tumor tissue array.

Topical Tetracycline Hydrochloride vs. Topical Clindamycin Phosphate in the Treatment of Acne.: A Comparative Study

ABSTRACT: In a comparative study of topical antibiotic solutions, clindamycin phosphate vs. tetracycline hydrochloride for the treatment of mild to moderate inflammatory facial acne, clindamycin phosphate solution proved to be a superior agent in the reduction of papules and pustule. Both preparations had minimal side effects.

Giant dermatofibroma with monster cells.

We report a case of a 64-year-old woman with a giant dermatofibroma on her back with the unusual histologic feature of monster cells. The firm, exophytic, 3-cm nodule had purple and yellow components with surface telangiectasia. Histologic examination demonstrated characteristic findings of a dermatofibroma, including rete ridge flattening and bridging; a stroma containing scattered, large, round, eosinophilic collagen bundles; and a polymorphous dermal infiltrate of spindle and xanthomatous cells with scattered siderophages. Some xanthomatous cells demonstrated features consistent with monster cells, including huge bizarre nuclei and one or more nucleoli. Immunohistochemical staining for factor XIIIa was positive. A diagnosis of giant dermatofibroma with monster cells (DFMC) was made. Giant dermatofibromas are rare, with monster cells being an uncommon finding in dermatofibroma. To our knowledge, this is the first report of DFMC.

Malignant melanoma arising in a giant congenital melanocytic nevus: A case report with cytogenetic and histopathologic analyses

A malignant melanoma developed in a 2‐year‐old Hispanic girl with a giant congenital melanocytic nevus (bathing‐trunk type). Histopathologic evaluation showed a deep‐seated tumor arising from a nonepidermal origin. Cytogenetic analysis demonstrated multiple chromosomal abnormalities in hyperdiploid cells (chromosome range, 56 to 61). No two karyotypes were identical, but many abnormalities were common to all analyzed cells, suggesting both karyotypic instability and evolution. The metaphases were monosomic for 3, 12, and 16, trisomic for 1, 2, 8, 19, 20, and 21, and included structural aberrations deletion 1 and derivatives 3 and 16. Eight markers were identified, including one ring. The extra 19 was possibly an isochromosome. No abnormalities of 6 or 10 were identified.