Purpose: Children with unresectable cervico-medullary low-grade glial tumors (CMTs) have poor progression-free survival when treated with conventional chemotherapy and radiation. The BRAFV600E mutation occurs in many low-grade glial tumors that are amenable for targeted therapy using mutation-specific kinase inhibitors. However, these inhibitors’ effectiveness and best treatment duration in these tumors setting are not defined. Method: Retrospective description of three cases of childhood cervico-medullary low-grade tumor with BRAFV600E mutation and their response to BRAF inhibitor therapy with Dabrafenib. Results: Dabrafenib therapy was provided as first line for two patients and second line for one patient with CMTs. All patients experienced rapid tumor regression and significant and durable clinical and radiological improvement. The targeted therapy was tolerated well in two patients despite the long-term use of 3-5 years, while one patient stopped therapy after 1 year due to serious adverse event that was reversible upon discontinuing therapy. Conclusion: Dabrafenib was effective and well-tolerated in two of the three patients. We observed clinical and radiological response that demonstrates the role of targeted therapy as alternative for adjuvant chemotherapy and radiation in BRAFV600E unresectable tumors. These cases indicate the need to re-evaluate the therapeutic approach in children with CMT, the early use of Dabrafenib and the treatment duration and to explore the possible adverse and late effects of this promising therapy.

Encephalopathy following Ifosfamide treatment is a well-described phenomenon that is commonly treated with Methylene Blue (MB). The course of encephalopathy and MB therapy has not been described in the literature as lasting longer than 30 days following treatment cessation. We present the case of an 11-year-old female with recurrent episodes of severe somnolence for five months following Ifosfamide-containing chemotherapy for her germ cell tumor. Administration of MB gave immediate but limited response. Our novel case continued to require treatment for 5 months following cessation of therapy. We hypothesize that a genetic component confers increased susceptibility to Ifosfamide-induced encephalopathy.

Background The MAPK pathway, is a signal transduction pathway involved in the oncogenesis of a variety of pediatric tumors. The clinical use of BRAF inhibitors and MEK inhibitors is increasingly used in oncology practice. The toxicity profile of these drugs in the pediatric population, particularly in relation to development, growth and sexual maturation remains insufficiently studied. Procedure This study includes 22 pediatric patients with molecularly confirmed MAPK pathway driven tumors treated with MEK or BRAF between August 2014 and March 2020. Throughout treatment they underwent regular laboratory, endocrine, cardiac, ophthalmic and dermatologic evaluation. Toxicity was recorded and evaluated according to CTCA v4. Results Overall an adverse event frequency of 86% was encountered. Dermatological disorders accounted for 68% of the adverse events. Overall 8 patients suffered from severe adverse events including Erythema Nodosum, PLEVA-like rash, osteoporosis, Sarcoid-like massive lymphadenopathy, retinal toxicity and elevated liver enzymes & CPK. Four patients discontinued treatment as a result of adverse events. In this cohort we did not encounter any treatment-related abnormalities of sexual maturation or gonadal function nor statistically significant growth retardation, however a slower than expected growth rate was observed in one patient. In addition dose-dependent, non-symptomatic and within normal range for age decreased cardiac SF% was noted in two patients treated with MEK inhibitor. Conclusion Treatment with BRAF and MEK inhibitors was shown to be generally safe, we report drug tolerability of 82%. However, further prospective studies should be preformed to are characterize the full scope of side effects in the pediatric population.