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Bilateral infarction of the superior cerebellar arteries with sparing of the rest of the posterior circulation, particularly the posterior cerebral arteries, is an uncommon finding in neurological practice. Most commonly, the deficits of the superior cerebellar arteries and posterior cerebral arteries occur together due to the close proximity of their origins at the top of the basilar artery. A patient was transferred to the neurological intensive care unit with a history of recent-onset falls from standing, profound hypertension, dizziness, and headaches. The neurological exam revealed cerebellar signs, including dysmetria of the right upper extremity and a decreased level of consciousness. Computed tomography of the head and neck revealed decreased attenuation throughout most of the cerebellar hemispheres suggestive of ischemic injury with sparing of the rest of the brain. Further investigation with a computed tomography angiogram revealed a fetal-type posterior cerebral artery on the right side that was providing collateral circulation to the posterior brain. Due to this embryological anomaly, the patient was spared significant morbidity and mortality that would have likely occurred had the circulation been more typical of an adult male.

Atopic dermatitis (AD) is a chronic, pruritic skin disease often complicated by bacterial superinfection affecting 10.7% of American children. The pathogenesis involves a skin barrier breakdown in addition to dysfunctional innate and adaptive immune response, including an unbalanced increase in T-helper 2 cells and hyperimmunoglobulinemia E. The increased numbers of T-helper 2 cells are involved in stimulating the production of immunoglobulin E and eosinophilia by releasing interleukin-4, -5, and -13 as well as in decreasing protection against bacterial superinfection by releasing interleukin-10. The current Food and Drug Administration-approved symptomatic treatment for AD includes topical ointments, topical and systemic corticosteroids, topical immunomodulant therapy, antibiotics, and phototherapy, but there are not approved targeted therapies or cures. By presenting a case of an 8-year-old African-American boy, this case report supports novel therapy of moderate-to-severe AD with apremilast, a phosphodiesterase type 4 inhibitor. Apremilast has recently completed the phase 2 clinical trial (NCT02087943) for treatment of AD in adults. This case report illustrates the potential for apremilast as a treatment for AD in children, where there is a great need for safe and effective medications.

"Skin popping" is a method of injecting illicit drugs into the skin. There are numerous acute and chronic complications associated with skin popping. We present a case of a 48-year-old, African-American female patient with 40 - 60 hyperpigmented, fibrotic, depressed, round papules and plaques on the extremities, which were incidentally noticed during a clinic visit for her acne vulgaris. Skin popping scars are important clues for possible drug abuse. Healthcare practitioners should be aware of and recognize the lesions associated with this practice so further testing can be performed if clinically indicated. Recognition of the lesions and thus earlier treatment of the complications could prevent the complications of skin popping in the skin and other organs.

ACKNOWLEDGMENTS The Italian Melanoma Intergroup (IMI) includes the following additional members who participated as investigators in this study and should be considered as co-authors: Nicola Mozzillo (Istituto Nazionale Tumori, Napoli, Italy), Panagiotis Paliogiannis (Chirurgia, Microchirurgia e Scienze Mediche, Universita di Sassari, Italy), PaolaQueirolo (Oncologia, Azienda Ospedaliera, Genoa, Italy), Corrado Rubino (Chirurgia Plastica, Universita di Salerno, Italy), MariaCristina Sini (IstitutodiChimicaBiomolecolare,CNR, Sassari, Italy), Ignazio Stanganelli (Dermatologia, Universita di Parma—Skin Cancer Unit, IRST, Meldola, Italy), Francesco Tanda (Anatomia Patologica, Universita di Sassari, Italy). The authors are grateful to patients for their important contribution to this study. The work was supported by Ricerca Finalizzata Ministero Salute andSardinianRegionalGovernment (Regione Autonoma della Sardegna).

BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.

Purpose: While the prognosis of cutaneous squamous cell carcinoma (cuSCC) is excellent overall, advanced metastatic disease represents a substantial mortality burden for which no standard targeted therapy exists. Findings from genomic and proteomic studies and the observed induction of cuSCC by BRAF inhibitor driven MEK/ERK pathway engagement suggest that MEK/ERK activation is essential for cuSCC tumorigenesis and tumor proliferation. Most cuSCC arise from a clinically and histopathologically defined preneoplastic precursor, the actinic keratosis (AK). Molecular studies of early events in cuSCC pathogenesis strongly implicate MEK/ERK signaling at the proteomic and transcriptional level. This occurs at the earliest recognizable transitions from chronically UV-exposed skin to AK, with sharp elevation of ETS2/ELK1 transcriptional target expression. With these compelling rationales in mind, we tested whether MEK inhibitors (MEKi) are a clinically actionable treatment and chemoprevention approach for cuSCC. Given that several MEKi are approved, this is a readily translated strategy. Experimental Design: Preclinical testing was performed in 10 cuSCC cell lines and two mouse models of cuSCC using two distinct MEK inhibitors, trametinib and cobimetinib. We show that two MEKi, trametinib and cobimetinib are highly effective against cuSCC cell lines in culture, effectively engage MEK/ERK signaling in cells and in vivo, and potently induce cell cycle arrest and senescence. Both established and new tumors are powerfully inhibited in both xenograft and UV-driven autochthonous mouse models. This model, which utilizes immunocompetent SKH-1E mice exposed to chronic, low-dose, solar simulated UV light (12.5 kJ/m2 UVB weekly administered across three doses) more faithfully recapitulates human cuSCC molecularly than chemical carcinogenesis models. Lesions in this model exhibit heterogeneity in latency and responses to therapy, as do human tumors. Results: MEK inhibitor treatment of cuSCC lines strongly reduces proliferation and induces senescence markers in cells, including p21 and beta-galactosidase. This response was universal, but highly heterogeneous. Sensitivity to MEKi was determined, in part, by modulation of AKT activity, and combination MEKi and AKTi. In-vivo, an SRB1 xenograft model was exquisitely sensitive to oral trametinib treatment, and in our spontaneous UV-driven Hairless mouse model of cuSCC, treatment with the MEK inhibitors trametinib and cobimetinib strongly reduced tumor growth and almost completely abrogated tumor induction. We confirmed target engagement in-vivo showing that ERK signaling was significantly suppressed. Conclusions: Overall, we conclude MEK signaling is critical for cuSCC tumor induction and maintenance, and that MEK inhibition is an attractive approach for both advanced cuSCC treatment as well as chemoprevention. Citation Format: Charles H. Adelmann, Kimberly Truong, Roger Liang, Varun Bansal, Rachael Saporito, Woojin Lee, Lili Du, Courtney Nicholas, Marco Napoli, Elsa R. Flores, Kenneth Y. Tsai. MEK is a therapeutic and chemopreventative target in squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2613.