Faculty Bibliography

IMPORTANCE: Controversy exists regarding strategies for diagnosis and management of Spitz nevi, a type of melanocytic neoplasm that most often develops in children. OBJECTIVE: To determine the beliefs, behaviors, and experiences of pediatric dermatologists with regard to Spitz nevi. DESIGN: Anonymous web-based survey. SETTING: Private and academic dermatology practices. PARTICIPANTS: Respondents included 175 pediatric dermatologists from the United States and around the world, representing a 51.1% response rate (175 of 342). Analyses were limited to the 144 respondents whose practices included at least 50% children (younger than 18 years). MAIN OUTCOME MEASURES: Assessment of the following with regard to Spitz nevi: frequency of diagnosis, general beliefs, techniques used for evaluation (eg, dermoscopy and biopsy), management strategies, and observed outcomes. RESULTS: Collectively, respondents had seen approximately 20 000 Spitz nevi; 67.6% (96 of 142) had diagnosed at least 6 Spitz nevi yearly, whereas 90.1% (128 of 142) had diagnosed no more than 2 prepubertal melanomas in the past 5 years. Ninety-six percent of respondents (95.8%; 136 of 142) categorized typical Spitz nevi as benign. Eighty percent of respondents (79.6%; 113 of 142) used dermatoscopy, and 96.5% (137 of 142) avoided partial biopsies of Spitz nevi. In children with a suspected Spitz nevus, clinical follow-up was chosen by 49.3% (69 of 140) of respondents for a small, stable nonpigmented lesion and by 29.7% (41 of 138) for a pigmented lesion with a typical starburst pattern seen via dermatoscopy. Predictors of clinical follow-up of the latter lesion included believing that Spitz nevi are not melanoma precursors (P = .04). Forty-seven percent (62 of 132) of respondents had observed involution of Spitz nevi. No deaths had resulted from the approximately 10 000 Spitz nevi or atypical spitzoid neoplasms seen by the 91 respondents with academic or hospital-based practices. CONCLUSIONS AND RELEVANCE: The results of our survey support conservative management of Spitz nevi in children, with clinical follow-up representing an option for typical lesions. This represents an important difference from strategies used for management of these lesions in adults.

Mebendazole (MBZ) was identified as a promising therapeutic on the basis of its ability to induce apoptosis in melanoma cell lines through a B-cell lymphoma 2 (BCL2)-dependent mechanism. We now show that in a human xenograft melanoma model, oral MBZ is as effective as the current standard of care temozolomide in reducing tumor growth. Inhibition of melanoma growth in vivo is accompanied by phosphorylation of BCL2 and decreased levels of X-linked inhibitor of apoptosis (XIAP). Reduced expression of XIAP on treatment with MBZ is partially mediated by its proteasomal degradation. Furthermore, exposure of melanoma cells to MBZ promotes the interaction of SMAC/DIABLO with XIAP, thereby alleviating XIAP's inhibition on apoptosis. XIAP expression on exposure to MBZ is indicative of sensitivity to MBZ as MBZ-resistant cells do not show reduced levels of XIAP after treatment. Resistance to MBZ can be reversed partially by siRNA knockdown of cellular levels of XIAP. Our data indicate that MBZ is a promising antimelanoma agent on the basis of its effects on key antiapoptotic proteins.

Persistent paraprotein production in plasma cells necessitates a highly developed rough endoplasmic reticulum (ER) that is unusually susceptible to perturbations in protein synthesis. This biology is believed to account for the exquisite sensitivity of multiple myeloma (MM) to the proteasomal inhibitor bortezomib (BTZ). Despite remarkable response rates to BTZ in MM, BTZ carries the potential for serious side-effects and development of resistance. We, therefore, sought to identify therapeutic combinations that effectively disrupt proteostasis in order to provide new potential treatments for MM. We found that sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, inhibits TNFalpha-induced Ikappabeta proteasomal degradation in a manner similar to BTZ. Like BTZ, sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide (ATO), an agent with clinical activity in MM. ATO and sulforaphane co-treatment augmented apoptotic induction as demonstrated by cleavage of caspase-3, -4 and PARP. The enhanced apoptotic response was dependent upon production of reactive oxygen species (ROS) as demonstrated by glutathione depletion and partial inhibition of the apoptotic cascade after pretreatment with the radical scavenger N-acetyl-cysteine (NAC). Combination treatment resulted in enhanced ER stress signaling and activation of the unfolded protein response (UPR), indicative of perturbation of proteostasis. Specifically, combination treatment caused elevated expression of the molecular chaperone HSP90 (heat shock protein 90) along with increased PERK (protein kinase RNA-like endoplasmic reticulum kinase) and eIF2alpha phosphorylation and XBP1 (X-box binding protein 1) splicing, key indicators of UPR activation. Moreover, increased splicing of XBP1 was apparent upon combination treatment compared to treatment with either agent alone. Sulforaphane in combination with ATO effectively disrupts protein homeostasis through ROS generation and induction of ER stress to culminate in inhibition of protein secretion and apoptotic induction in MM. Our results suggest that sulforaphane deserves further investigation in combination with ATO in the treatment of MM.

Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.Journal of Investigative Dermatology advance online publication, 14 June 2012; doi:10.1038/jid.2012.181.

OBJECTIVE To investigate the frequency, epidemiology, clinical features, and prognostic significance of inflamed molluscum contagiosum (MC) lesions, molluscum dermatitis, reactive papular eruptions resembling Gianotti-Crosti syndrome, and atopic dermatitis in patients with MC. DESIGN Retrospective medical chart review. SETTING University-based pediatric dermatology practice. PATIENTS A total of 696 patients (mean age, 5.5 years) with molluscum. MAIN OUTCOME MEASURES Frequencies, characteristics, and associated features of inflammatory reactions to MC in patients with and without atopic dermatitis. RESULTS Molluscum dermatitis, inflamed MC lesions, and Gianotti-Crosti syndrome-like reactions (GCLRs) occurred in 270 (38.8%), 155 (22.3%), and 34 (4.9%) of the patients, respectively. A total of 259 patients (37.2%) had a history of atopic dermatitis. Individuals with atopic dermatitis had higher numbers of MC lesions (P < .001) and an increased likelihood of molluscum dermatitis (50.6% vs 31.8%; P < .001). In patients with molluscum dermatitis, numbers of MC lesions increased during the next 3 months in 23.4% of those treated with a topical corticosteroid and 33.3% of those not treated with a topical corticosteroid, compared with 16.8% of patients without dermatitis. Patients with inflamed MC lesions were less likely to have an increased number of MC lesions over the next 3 months than patients without inflamed MC lesions or dermatitis (5.2% vs 18.4%; P < .03). The GCLRs were associated with inflamed MC lesion (P < .001), favored the elbows and knees, tended to be pruritic, and often heralded resolution of MC. Two patients developed unilateral laterothoracic exanthem-like eruptions. CONCLUSIONS Inflammatory reactions to MC, including the previously underrecognized GCLR, are common. Treatment of molluscum dermatitis can reduce spread of MC via autoinoculation from scratching, whereas inflamed MC lesions and GCLRs reflect cell-mediated immune responses that may lead to viral clearance.

The pathobiology of vitiligo, characterized by the spread of depigmented skin patches due to localized melanocyte loss, is not fully understood. Oxidative stress is thought to play a role in disease onset with a subsequent autoimmune response underlying progression. We therefore sought to identify mechanisms that linked oxidative stress and autoimmune responses. Melanocytes at the periphery of vitiligo lesions have distended endoplasmic reticuli (ER). We hypothesized that oxidative stress disrupted homeostasis of the ER where oxidation/reduction reactions facilitate disulfide bond formation. As a result, misfolded peptides would accumulate, dilating the ER and activating the unfolded protein response (UPR). The UPR is a stress response pathway, initiated by three regulators (IRE1, PERK and ATF6). It first promotes cell survival, however sustained activation induces apoptosis. In order to identify a potential role for the UPR in vitiligo we dosed melanocytes with 4-tertiary butyl phenol (4- TBP) and monobenzyl ether of hydroquinone (MBEH), phenols known to trigger vitiligo. The phenols caused an increase in expression of IRE1 and PERK. PERK activation leads to enhancement of the antioxidant response by recruitment of the transcription factor NRF2 to the nucleus and increased expression of the antioxidant HMOX1. The IRE1 effector, X-box binding protein-1 (XBP1) was also activated by phenol treatment which led to increased production of interleukin-6 (IL6) and IL8, cytokines expressed at increased levels in perilesional skin in vitiligo. Treatment with XBP1 inhibitors reduced phenol-induced IL6 and IL8 production, while over-expression of active XBP1 increased their expression. Thus, chemicals known to cause vitiligo trigger a UPR-mediated increase in cytokine production. There are a number of potential roles for the UPR in vitiligo. The UPR may (i) induce apoptosis following sustained oxidative stress causing release of melanocyte specific antigens, (ii) be dysregulated resulting in a muted PERK-!

Although the precise mechanisms that trigger vitiligo remain elusive, autoimmune responses mediate its progression. The development of therapies has been impeded by a paucity of animal models, since mice lack interfollicular melanocytes, the primary targets in vitiligo. In this issue, Harris et al. describe a mouse model in which interfollicular melanocytes are retained by Kit ligand overexpression and an immune response is initiated by transplanting melanocyte-targeting CD8+ T cells.