Kellie Nazemi

Emergency Department Presentation of Childhood Cancer

Cancer is the second leading cause of death in children in the United States and is the most common cause of death due to disease. Although the signs and symptoms of these patients can be vague and can mimic other more common childhood illnesses, there are often specific elements of the cancer patients history, examination, and laboratory evaluation that can lead the provider to the correct diagnosis. The manifestations of certain types of cancer constitute medical emergencies that require acute intervention. This article reviews the most common presentations of childhood cancer and the appropriate initial management in the Emergency Department.

High Incidence of Veno‐Occlusive Disease With Myeloablative Chemotherapy Following Craniospinal Irradiation in Children With Newly Diagnosed High‐Risk CNS Embryonal Tumors: A Report From the Children's Oncology Group (CCG‐99702)

The outcomes with high‐risk central nervous system (CNS) embryonal tumors remain relatively poor despite aggressive treatment. The purposes of this study using postirradiation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (ASCR) were to document feasibility and describe toxicities of the regimen, establish the appropriate dose of thiotepa, and estimate the overall survival (OS) and event‐free survival (EFS).

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.

Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma

Background Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%). Conclusions Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Abstract A08: IGF1R as a key target in high risk, metastatic medulloblastoma

The risk or presence of metastasis in childhood medulloblastoma represents a substantial cause of morbidity and mortality. Relatively little has been known about the molecular mechanisms of medulloblastoma dissemination throughout the cerebrospinal axis. To determine potential interventions that address both metastasis and tumor growth, we examined the expression of cytokines and growth factors in the CSF of metastatic medulloblastoma patients that were also present in the conditioned media of metastatic, MYC amplified medulloblastoma cell lines and/or cell culture models of the leptomeninges. The presence of IGF1, the IGF-sequestering protein Igfbp3, which can be cleaved by metal metalloproteases (MMP) and the serine protease tPA, and the presence of corresponding protease modulators TIMP1 and SerpinE1/PAI-1, led us to explore the bioactivity of IGF1 in medulloblastoma. IGF1 led not only to receptor phosphorylation but also increased migration and increased relative cell growth. A tumor cell viability screen of 60 clinically-related compounds prioritized IGF1R inhibitors. Our findings support a model whereby medulloblastoma tumor cells actively migrate, rather than arrive passively, to the leptomeningeal cell surface and provide a rationale for exploring IGF1R as a target for therapeutics in future clinical trials. Citation Format: Matthew N. Svalina, Ken Kikuchi, Jinu Abraham, Sangeet Lal, Monika A. Davare, Jennifer L. Peckham, Yoon-Jae Cho, Melanie Jackson, Daniel J. Guillaume, Nathan R. Selden, Darell D. Bigner, Kellie J. Nazemi, Sarah C. Green, Christopher L. Corless, Sakir Gultekin, Brian P. Rubin, Randall Woltjer, Charles Keller. IGF1R as a key target in high risk, metastatic medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A08.