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.

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.

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.