CASE REPORT J Neurosurg Pediatr 19:319–324, 2017 B rain tumors are the most common solid tumor in childhood, and astrocytomas account for the larg- est proportion of these tumors. The low-grade as- trocytoma classifcation encompasses pilocytic astrocy- tomas (WHO Grade I), pilomyxoid astrocytomas (Grade II), infltrating astrocytomas (Grade II), and pleomorphic xanthroastrocytoma (Grade I), and ganglioglioma (Grade I). Pilocytic astrocytomas are a group of heterogeneous tumors with various locations, radiological features, his- tological atypia, and clinical behavior. They can occur anywhere within the central nervous system (CNS); most are found in an infratentorial location. For some tumors, especially those in the hypothalamic and/or chiasmatic re- gion, complete resection is impossible without signifcant defcit, and treatment must include adjuvant therapy given the less favorable progression-free and overall survival in patients with these lesions. Within the past decade, signifcant breakthroughs have been made regarding the genetics of low-grade as- trocytomas. Previously, few aberrations had been identi- fed, but little was known regarding their tumorigenesis. The mitogen-activating protein kinase (MAPK) pathway transduces extracellular signals such as stress, hormones, cytokines, and growth factors to the nucleus via a series of consecutive phosphorylations. The result is a variety of physiological responses, including cell proliferation, dif- ferentiation, and apoptosis. Abnormalities in this pathway have been found in a high proportion (80%) of pilocytic astrocytomas, with a smaller incidence (13%) in Grade II tumors. 9 Multiple mutations within BRAF have been dis- covered, including the BRAF V600E point mutation and duplication of BRAF at 7q34. 2–4,6,11 Recently, multiple published articles have reported the 2-Mb duplication of 7q34 causing the fusion of 2 genes. The N-terminus of KIAA1549 replaces the regulatory re- gion of BRAF , resulting in a constitutively activated pro- tein. The fusion product is expressed at higher levels than the wild-type BRAF because the inhibitory domain that normally regulates BRAF activity was lost. The deregulat- ed BRAF activity leads to increased downstream signaling (MEK/ERK) and subsequent increased cell proliferation. There are several other fusion variants that have been rec- ognized; however, they are less common. 1,7,8,10 We present 2 cases of hypothalamic optic pathway pediatric astrocytomas that progressed despite multiple chemotherapy treatments. Each tumor was found to have ABBREVIATIONS CNS = central nervous system; MAPK = mitogen-activating protein kinase. SUBMITTED July 9, 2016. ACCEPTED September 27, 2016. INCLUDE WHEN CITING Published online December 23, 2016; DOI: 10.3171/2016.9.PEDS16328. Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response Catherine Miller, MD, 1 Daniel Guillaume, MD, 1 Kathryn Dusenbery, MD, 2 H. Brent Clark, MD, PhD, 3 and Christopher Moertel, MD 4 Departments of 1 Neurosurgery, 2 Radiation Oncology, 3 Pathology, and 4 Pediatric Hematology/Oncology, University of Minnesota, Minneapolis, Minnesota Brain tumors are the most common solid tumor in childhood, and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specifc mutations within tumor subtypes that may represent targets for individualized tumor treatment. The mitogen-activating protein kinase (MAPK) pathway and, more specifcally, BRAF mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and may represent one such area to target. Herein, the authors describe 2 cases of inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a documented response to trametinib, an MAPK pathway inhibitor. While these cas- es were not treated in the setting of a clinical trial, their data support further ongoing clinical trial investigation to evaluate the safety and ef fcacy of this agent in pediatric low-grade gliomas. https://thejns.org/doi/abs/10.3171/2016.9.PEDS16328 KEY WORDS pediatric; astrocytoma; MAPK pathway; BRAF mutation; trametinib; oncology ©AANS, 2017 J Neurosurg Pediatr Volume 19 • March 2017 319 Unauthenticated | Downloaded 05/04/21 03:56 AM UTC