Central Nervous System Xanthoma Disseminatum: Response to 2CdA in an Adolescent.

Xanthoma disseminatum is a normolipemic non-Langerhans cell histiocytosis characterized by red-brown rubbery papules of the skin which coalesce into plaque-like lesions with symmetric involvement of face, flexor, and intertriginous areas. Less commonly, xanthoma disseminatum may affect mucosal linings, abdominal organs, and the central nervous system, leading to endocrinopathies. We report a 12-year-old adolescent with mucosal, central nervous system, and painful cutaneous lesions, further complicated by diabetes insipidus and amenorrhea. Treatment with 2-chlorodeoxyadenosine led to relief of pain and significant improvement of mucosal, central nervous system, and cutaneous lesions, with subsequent restoration of menstrual cycles.

Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma.

Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with the features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic drivers of BCC and SCC development have been extensively characterized, BSC has not been well studied, and it remains unclear whether these tumors originally derive from BCC or SCC. In addition, it is unknown which molecular pathways mediate the reprogramming of tumor keratinocytes toward basaloid or squamatized phenotypes. We sought to characterize the genomic alterations underlying sporadic BSC to elucidate the derivation of these mixed tumors. We identifed frequent Hedgehog (Hh) pathway mutations in BSCs, implicating Hh deregulation as the primary driving event in BSC. Principal component analysis of BCC and SCC driver genes further demonstrate the genetic similarity between BCC and BSC. In addition, 45% of the BSCs harbor recurrent mutations in the SWI/SNF complex gene, ARID1A, and evolutionary analysis revealed that ARID1A mutations occur after PTCH1 but before SCC driver mutations, indicating that ARID1A mutations may bestow plasticity enabling squamatization. Finally, we demonstrate mitogen-activated protein kinase pathway activation and the loss of Hh signaling associated with the squamatization of BSCs. Overall, these results support the genetic derivation of BSCs from BCCs and highlight potential factors involved in modulating tumor reprogramming between basaloid and squamatized phenotypes.

Alopecia and Associated Toxic Agents: A Systematic Review.

IMPORTANCE/OBJECTIVE: There are a number of toxic agents that can cause alopecia. In this review we summarize the known substances that cause alopecia as one of the clinical signs of overdose or toxicity. EVIDENCE REVIEW: A search was conducted using PubMed, EMBASE, and Cochrane for studies describing hair loss of any type as a result of exposure to or ingestion of a toxic agent. The search yielded 856 articles, with 47 studies included in this review. FINDINGS: Agents with the strongest evidence of association to alopecia include thallium, mercury, selenium, and colchicine. Agents with described incidents include boric acid, arsenic, vitamin A, botulinum toxin, Podostroma cornu-damae, and the synthetic opioid MT-45. CONCLUSIONS AND RELEVANCE: Numerous toxic agents have been implicated in alopecia, and the strength of evidence behind each agent varies. Toxic levels of thallium and colchicine have long been established to cause alopecia, as compared to agents such as botulinum toxin A and synthetic recreational drugs which have less literature describing their links to alopecia and will need further investigation to characterize their relationships to hair loss. Knowledge of typical presentations of hair loss will aid in the development of a differential diagnosis for patients presenting with alopecia.

Genomic Stability in Syndromic Basal Cell Carcinoma.

Basal cell cancers (BCCs) are characterized by upregulation of Hedgehog pathway through loss of PTCH1 or activation of SMO, and SMO inhibitors, such as vismodegib, are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with basal cell nevus syndrome (BCNS) harbor germline defects in PTCH1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to SMO inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of UV mutagenesis, increased genomic stability, and harbor fewer functionally resistant SMO mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to SMO inhibitors. BCNS-BCCs appear to have reduced mutator phenotype compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.

Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption.

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short-term (30 min) SC reservoir predict long-term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate-limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright © 2015 John Wiley & Sons, Ltd.

Skin lesion metrics: role of photography in acne.

Accurate assessment of acne severity is essential for determining the appropriate treatment required. This paper reviews photographic methods for such assessment. Literature included met the following criteria: proposed photographic standards to assess acne, evaluated such standards, or offered photographic methods to improve visualization and assessment. Validity was evaluated by comparing given photographic grading methods to other methods, such as lesion counting. Many photographic standards were shown to be objective, time-efficient, and have intra-grader and inter-grader consistency. Photography also documents progress for retrospective verification. Drawbacks include not allowing determination of depth, minimization of small lesions and erythema, and difficulty in maintaining consistent settings. Fluorescence and polarized photography improve visualization beyond clinical observation alone. Advances such as computer alignment, imaging segmentation, and three-dimensional analysis methods track lesions and measure objective characteristics. The combined experience summarized here strongly promotes the use of a photographic standard in assessing acne severity. Cook's method can also be used to train and qualify graders. Photographic advancements improve accuracy of assessment by solving problems with consistent settings and depth visualization. Further advancements can improve image analysis through analysis of objective attributes.

Role of partition coefficients in determining the percutaneous penetration of salicylic acid and formaldehyde under varying occlusion durations.

CONTEXT: Occlusion is widely utilized to enhance the percutaneous penetration of applied drugs in clinical practice; however, occlusion does not increase the penetration of all chemicals. OBJECTIVE: This study determines: (1) whether occlusion enhances the percutaneous penetration of the lipophilic salicylic acid or the hydrophilic formaldehyde when compared to non-occlusion, (2) evaluate whether occlusion duration affects the penetration of compounds and (3) establish to what extent occlusive films in clinical practice interact with topically-applied chemicals and possibly hinder penetration. MATERIALS AND METHODS: Separately, single doses of [14C]-formaldehyde and [14C]-salicylic acid were applied onto human skin overlying diffusion cells under non-occlusion as well as various occlusive time periods (1, 4 and 8 h). The percent dose penetrating into each compartment as well the percent dose adhering to the plastic wrap were determined. RESULTS: The radioactivity recovery as percent of applied dose of [14C]-salicylic acid was significantly higher under occlusion versus non-occlusion in the epidermis, dermis and receptor fluid after 24 h (p < 0.05). For [14C]-formaldehyde, no significant statistical differences were observed between occlusion versus non-occlusion. The plastic wrap often used to enhance the penetration of topically applied drugs does not itself substantially adhere to the tested chemicals. CONCLUSION: Occlusion duration, previously undocumented for in vitro studies, impacted the percutaneous penetration of the lipophilic salicylic acid more so than the hydrophilic formaldehyde. A strong correlation between occlusion-enhanced penetration and partition coefficients was observed, but we do not wish to overgeneralize these results until more compounds of varying physical--chemical properties are studied.

Transungual delivery of ketoconazole using novel lacquer formulation.

Onychomycosis, a common fungal infection of the nail, can have a substantial impact on quality of life. The success of topical therapy for onychomycosis depends on effective penetration, which can be enhanced using an appropriate delivery method. This study evaluated the effectiveness of a novel topical lacquer on enhancing [(14)C]-ketoconazole penetration by comparing nail absorption, nail distribution, and nail penetration of [(14)C]-ketoconazole dissolved in the novel lacquer versus a commercial ketoconazole cream. Using the in vitro finite dose model, the formulations were applied daily to human nail plates for 7 days. Drug absorption was measured by monitoring rate of appearance in each nail layer and the supporting bed. After the multiple day treatment, cumulative concentrations of ketoconazole formulated in novel lacquer in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of commercial ketoconazole (p<0.05), as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of causative dermatophytic and yeast species. These results suggest that this novel ketoconazole lacquer has the potential to be an effective topical treatment for onychomycosis.

Towards a perfect vehicle(s) for diagnostic patch testing: an overview.

The correct selection of vehicles for patch testing is crucial in evaluating suspected allergic contact dermatitis. We reviewed literature by searching Pubmed and Embase for the years 1971-2011 utilizing the subjects "vehicle," "allergic contact dermatitis" and "patch test" for advances in knowledge of vehicles." A universal optimal vehicle more efficient than petrolatum remains undiscovered. Literature provides research supporting alternate vehicles for specific allergens and insights on vehicle characteristics, such as influence on bioavailability of chemicals and subsequent percutaneous absorption or interaction with allergens. These findings should accelerate our ability to define, and thus determine, the optimum vehicle(s).

Percutaneous absorption in diseased skin: an overview.

The stratum corneum's (SC) functions include protection from external hazardous environments, prevention of water loss and regulation of body temperature. While intact skin absorption studies are abundant, studies on compromised skin permeability are less common, although products are often used to treat affected skin. We reviewed literature on percutaneous absorption through abnormal skin models. Tape stripping is used to disrupt water barrier function. Studies demonstrated that physicochemical properties influence the stripping effect: water-soluble drugs are more affected. Abrasion did not affect absorption as much. Freezing is commonly used to preserve skin. It does not seem to modify water absorption, but still increases the penetration of compounds. Comparatively, heating the skin consistently increased percutaneous absorption. Removing SC lipids may increase percutaneous absorption of drugs. Many organic solvents are employed to delipidize. Delipidization with chloroform-methanol increased hydrophilic compound permeability, but not lipophilic. Acetone pre-treatment enhanced hydrophilic compound penetration. More data is needed to determine influence on highly lipophilic compound penetration. Sodium lauryl sulfate (SLS) induces irritant dermatitis and is frequently used as a model. Studies revealed that SLS increases hydrophilic compound absorption, but not lipophilic. However, skin irritation with other chemicals increases lipophilic penetration as much as hydrophilic. Animal studies show that UV exposure increases percutaneous absorption whereas human studies do not. Human studies show increased penetration in psoriatic and atopic dermatitis skin. The data summarized here begin to characterize flux alteration associated with damaged skin. Understanding the degree of alteration requires interpretation of involved conditions and the enlarging of our database to a more complete physicochemical spectrum.