Purpose: Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas.We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT. Experimental Design: A total of 85 melanomas arising from sun-protected (n = 23) and sunexposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-function mutations in BRAF, NRAS, and KIT. Results: GAB2 amplifications were found in 9% of the cases and were associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2, 13% for KIT, 30% for BRAF, and 4% for NRAS. Importantly, the majority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT. Conclusions: GAB2 amplification is critical for melanomas arising from sun-protected sites. Genetic alterations in GAB2 will help refine the molecular classification of melanomas.Several melanoma subtypes are recognized based on anatomic site, sun exposure characteristics, and histopathologic features. In recent years, the identification of distinct genetic aberrations among melanoma subtypes has resulted in improved classification (1), with the ultimate goal of developing treatment strategies based on molecular characteristics. However, the identification of additional genetic events is necessary to refine the current melanoma classification and develop novel therapeutic agents.The mitogen-activated protein kinase pathway is a key regulator of melanoma cell proliferation with extracellular signalregulated kinase activation seen in majority of melanomas (2). BRAF and NRAS mutations, leading to constitutive activation of this pathway, occur in f50% and f15% of melanomas, respectively (3), and have been associated with melanomas arising from nonchronically sun-exposed sites, most of which are located on trunk and extremities (1, 4). Mutations in these genes are mutually exclusive in melanoma. In contrast, BRAF and NRAS mutations are rare in melanomas arising from sun-protected areas, such as acral, mucosal, and uveal melanomas, suggesting genetic events or mechanisms other than oncogenic mutations in BRAF and NRAS leading to extracellular signal-regulated kinase activation in these melanoma subtypes (4, 5). Amplification of the KIT locus on 4q12 and activating mutations in the KIT gene have recently been identifi...
SUMMARYA 51-year-old woman with dermatomyositis (DM) on chronic immunosuppressive therapy was hospitalised for evaluation of haematuria. Surprisingly, abdominal imaging demonstrated pneumoperitoneum and pneumatosis intestinalis (PI). Her abdominal examination and white cell count were normal, but she subsequently developed nausea and fever. Owing to concern for perforation, a hemicolectomy was performed. Pathology revealed PI without inflammatory, ischaemic or neoplastic features, and she recovered uneventfully. Her immunosuppressive therapy was discontinued. Six months later, a follow-up CT of the abdomen revealed recurrence of PI. As she was asymptomatic, she was managed conservatively with resolution of PI on subsequent imaging. PI is characterised by the presence of gas within the wall of the intestine. Its aetiology is often unclear but this case highlights the association between PI and both immunosuppressive therapy and DM. A review of PI in patients with DM suggests that clinically stable patients may be observed, while avoiding surgical intervention. BACKGROUND
Orlistat is a United States Food and Drug Administration (FDA) approved medication indicated for the management of obesity. The FDA has issued a warning of rare, but severe, reports of liver injury following orlistat use. We report the case of a 40 year old female, with no prior medical history, who experienced fulminant liver failure following orlistat use. She presented to our center with severe cholestasis and coagulopathy. Liver ultrasound, serologies for viral hepatitis, and autoimmune markers were unremarkable. Early cessation of the
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