Faculty Bibliography

BACKGROUND: Psoriasis adversely affects health-related quality of life (HRQoL) in adults; however, little information exists about its impact on children and adolescents. OBJECTIVE: The effect of etanercept therapy on HRQoL compared with placebo was evaluated in children and adolescents with moderate to severe plaque psoriasis. METHODS: HRQoL data were collected from patients 4 to 17 years of age in a randomized, double-blind, placebo-controlled, North American, phase III study of etanercept. Instruments for assessing HRQoL included the Children's Dermatology Life Quality Index (CDLQI), Pediatric Quality of Life Inventory (PedsQL), Stein Impact on Family Scale, and Harter Self-Perception Profile for Children. RESULTS: Baseline CDLQI and PedsQL scores revealed reduced HRQoL in patients with psoriasis relative to comparative populations. Patients treated with etanercept demonstrated significantly higher mean percentage improvement in total CDLQI scores from baseline to week 12 compared with those treated with placebo (52.3% etanercept vs 17.5% placebo [P = .0001]). At week 12, patients who achieved 75% improvement in their Psoriasis Area and Severity Index score had higher percentage improvements from baseline in total CDLQI scores than those who did not have 75% improvement in Psoriasis Area and Severity Index score. LIMITATIONS: The PedsQL, Stein scale, and Harter profile demonstrated limited improvement in patients' HRQoL, suggesting that these scales may not be sensitive to issues that are relevant to children with psoriasis and their families. CONCLUSION: Etanercept therapy had a clinically and statistically meaningful impact on disease-specific quality of life (CDLQI) and a clinically meaningful impact on general quality of life (PedsQL) in children and adolescents with moderate to severe plaque psoriasis

Most metastatic melanomas are refractory to current available therapy, underscoring the need to identify new effective treatments. Sorafenib, a multikinase inhibitor of the mitogen-activated protein kinase signaling pathway, showed promise in earlier stages of clinical development, but ultimately failed to demonstrate efficacy as a single agent in the treatment of melanoma. In order to enhance the efficacy of sorafenib in the treatment of melanoma, we tested over 2,000 naturally occurring compounds and marketed drugs in the presence of sorafenib in chemoresistant human melanoma cell lines also resistant to sorafenib-induced apoptosis. Of the 9 compounds identified as sorafenib sensitizers, we prioritized the cholesterol-lowering agent fluvastatin, based on its favorable pharmacokinetics and safety profile. Our results demonstrate that fluvastatin at 1 muM, a level safely achieved through oral administration, dramatically enhances the growth-inhibitory activity of clinically achievable concentrations of sorafenib in M14 and SKM-173 melanoma cells, with a 3.2- and 3.6-fold reduction in sorafenib 50% growth inhibition (GI50), respectively. Similar effects were observed for other melanoma cell lines. Combination indices analysis revealed a synergistic relationship between the two agents. Fluvastatin enhances sorafenib-mediated apoptosis as revealed through enhanced cleavage of poly (ADP-ribose) polymerase. In combination with sorafenib, fluvastatin treatment results in reduced levels of activated murine thymoma viral oncogene homolog along with enhanced levels of activated c-Jun N-terminal kinase. Sensitization to sorafenib is unique to fluvastatin, as other statins (pravastatin and simvastatin) do not enhance sorafenib-mediated growth inhibition. These promising results warrant further investigation into the clinical applicability of fluvastatin as an agent for enhancing the efficacy of sorafenib in the treatment of melanoma

Although clearly effective in acute promyelocytic leukemia (APL), arsenic trioxide (ATO) demonstrates little clinical benefit as a single agent in the treatment of non-APL hematological malignancies. We screened a library of 2000 marketed drugs and naturally occurring compounds to identify agents that potentiate the cytotoxic effects of ATO in leukemic cells. Here, we report the identification of three isothiocyanates (sulforaphane, erysolin and erucin) found in cruciferous vegetables as enhancers of ATO cytotoxicity. Both erysolin and sulforaphane significantly enhanced ATO-mediated cytotoxicity and apoptosis in a panel of leukemic cell lines; erucin activity was variable among cell types. Cellular exposure to sulforaphane in combination with ATO resulted in a dramatic increase in levels of reactive oxygen species (ROS) compared to treatment with either agent alone. Sulforaphane, alone or with ATO, decreased intracellular glutathione (GSH) content. Furthermore, addition of the free radical scavenger N-acetyl-l-cysteine (NAC) rescued cells from ATO/isothiocyanate-mediated cytotoxicity. Our data suggest that isothiocyanates enhance the cytotoxic effects of ATO through a ROS-dependent mechanism. Combinatorial treatment with isothiocyanates and ATO might provide a promising therapeutic approach for a variety of myeloid malignancies

Melanoma is the most aggressive and deadly form of skin cancer. The current standard of care produces response rates of less than 20%, underscoring the critical need for identification of new effective, nontoxic therapies. Disulfiram (DSF) was identified using a drug screen as one of the several compounds that preferentially decreased proliferation in multiple melanoma subtypes compared with benign melanocytes. DSF, a member of the dithiocarbamate family, is a copper (Cu) chelator, and Cu has been shown previously to enhance DSF-mediated growth inhibition and apoptosis in cancer cells. Here, we report that in the presence of free Cu, DSF inhibits cellular proliferation and induces apoptosis in a panel of cell lines representing primary and metastatic nodular and superficial spreading melanoma. Both decreased cellular proliferation and increased apoptosis were seen at 50-500 nmol/l DSF concentrations that are achievable through oral dosing of the medication. In the presence of Cu, DSF caused activation of the extrinsic pathway of apoptosis as measured by caspase-8 cleavage. The addition of Z-IETD-FMK, a selective caspase-8 inhibitor, was protective against DSF-Cu-induced apoptosis. Production of reactive oxygen species (ROS) in response to DSF-Cu treatment preceded the induction of apoptosis. Both ROS production and apoptosis were prevented by coincubation of N-acetyl cysteine, a free radical scavenger. Our study shows that DSF might be used to target both nodular and superficial spreading melanoma through ROS production and activation of the extrinsic pathway of apoptosis

Summary Accumulation of proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), comprising three signaling pathways initiated by Ire1, Perk and Atf6 respectively. Unfolded protein response activation was compared in chemically stressed murine wildtype melanocytes and mutant melanocytes that retain tyrosinase in the ER. Thapsigargin, an ER stressor, activated all pathways in wildtype melanocytes, triggering Caspase 12-mediated apoptosis at toxic doses. Albino melanocytes expressing mutant tyrosinase showed evidence of ER stress with increased Ire1 expression, but the downstream effector, Xbp1, was not activated even following thapsigargin treatment. Attenuation of Ire1 signaling was recapitulated in wildtype melanocytes treated with thapsigargin for 8 days, with diminished Xbp1 activation observed after 4 days. Atf6 was also activated in albino melanocytes, with no response to thapsigargin, while the Perk pathway was not activated and thapsigargin treatment elicited robust expression of the downstream effector CCAAT-enhancer-binding protein homologous protein. Thus, melanocytes adapt to ER stress by attenuating two UPR pathways

Summary Background Hair loss is an unwelcome event at any age, but it can be particularly distressing for adolescents and their families. While androgenetic alopecia (AGA) is the most common form of hair loss in adults, little is known about its prevalence, clinical features and response to treatments in the paediatric population. Objectives To better characterize the causes of alopecia in a paediatric population. Methods We performed a retrospective chart review to identify all patients with hair loss seen in an academic paediatric dermatology practice at New York University over a 12-year period to better characterize the causes of alopecia in this population. We review the clinical and histological features, natural progression and associated laboratory abnormalities of AGA in 57 paediatric patients. Results AGA was identified as the most frequent cause of hair loss in adolescents and the second most common diagnosis overall. The male to female ratio was 2 : 1 and the average age at initial presentation with AGA was 14.8 years. Adolescent girls had diffuse thinning or thinning at the crown, and boys frequently presented with female pattern hair loss. When biopsies were performed, perifollicular inflammation was a common finding. A family history of AGA was reported in 83% of patients. Laboratory evaluation for androgens revealed polycystic ovarian syndrome in three girls and late-onset congenital adrenal hyperplasia in one boy. Conclusions AGA is the most common form of hair loss in adolescents, and can be the presenting sign of an underlying endocrine disorder. An accurate and timely diagnosis is essential for appropriate medical and psychosocial intervention when warranted