Faculty Bibliography

To address the therapeutic challenges in childhood relapsed ALL, a phase 1 study combining a survivin mRNA antagonist, EZN-3042, with reinduction chemotherapy was developed for pediatric patients with second or greater bone marrow relapses of B-lymphoblastic leukemia. EZN-3042 was administered as a single agent on days -5 and -2 and then in combination with a 4-drug reinduction platform on days 8, 15, 22, and 29. Toxicity and the biological activity of EZN-3042 were assessed. Six patients were enrolled at dose level 1 (EZN-3042 2.5 mg/kg/dose). Two dose-limiting toxicities were observed: 1 patient developed a grade 3 gamma-glutamyl transferase elevation and another patient developed a grade 3 gastrointestinal bleeding. Downmodulation of survivin mRNA and protein were assessed after single-agent dosing and decreased expression was observed in 2 of 5 patients with sufficient material for analysis. Although some biological activity was observed, the combination of EZN-3042 with intensive reinduction chemotherapy was not tolerated at a dose that led to consistent downregulation of survivin expression. The trial was terminated following the completion of dose level 1, after further clinical development of this agent was halted.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a rare embryonal neoplasm of early childhood with dismal outcome and no current uniformly accepted treatment. Given its highly aggressive nature and predilection for dissemination at diagnosis, intensive multimodal therapy is required. MATERIALS AND METHODS: Nineteen children with newly diagnosed CNS AT/RT were treated on the head start (HS) III protocol. Treatment consisted of surgical resection, 5 cycles of induction chemotherapy, followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on patient age, disease extent at diagnosis, and treatment response to induction. RESULTS: Nineteen children (median age of 14 months) were treated on HS III between 2003 and 2009. Only four finished induction and three proceeded to consolidation. There are presently four survivors at 40, 42, 46, and 79 months from study enrollment. Eleven patients experienced tumor progression at a median time to progression of 4.1 months of whom 10 died with a median time from progression to death of 2.6 months. Five toxic deaths occurred, three of them while on the study. The 3-year event-free survival (EFS) and overall survival (OS) for the whole group was 21 +/- 9% and 26 +/- 10%, respectively. Five patients received irradiation at progression with only one long-term survivor. CONCLUSION: A minority of children with CNS AT/RT treated on HS III may be long-term survivors without irradiation. More effective therapies are desperately needed. Pediatr Blood Cancer 2014;61:95-101. (c) 2013 Wiley Periodicals, Inc.

BACKGROUND: We analyzed the long-term survival of children under 6 years of age (<6 years) enrolled upon the Children's Cancer Group (CCG)-945 high-grade glioma (HGG) study to determine the impact of intrinsic biological characteristics as well as treatment upon both survival and quality of life (QOL) in this younger age population. PROCEDURE: Analyses were undertaken on patients <6 years with institutionally diagnosed HGG enrolled on the CCG-945 trial. Comparisons of survival were performed for patients <3 years of age (<3 years) (treated with intent to avoid irradiation) versus those between 3 and 6 years of age (3-6 years) (treated with irradiation and chemotherapy) at diagnosis. Discordance between the institutional diagnoses of HGG and consensus-reviewed diagnoses led us to perform further survival analyses for both groups. We compared the two groups of patients for biological markers, and evaluated the neuropsychological and QOL outcomes of long-term survivors. RESULTS: Patients <3 years (n = 49, 19.5% of all enrolled patients) at diagnosis had a 10-year EFS and OS of 29 +/- 6.5% and 37.5 +/- 7%, respectively, while for patients 3-6 years (n = 34, 13.5% of all enrolled patients) 10-year EFS and OS were 35 +/- 8% and 36 +/- 8%, respectively. Molecular marker analysis showed that a smaller proportion of patients <3 years harbored TP53 mutations (P = 0.05). Analysis of QOL outcomes with a median length of follow-up of 15.1 years (9.5-19.2) showed comparable results. CONCLUSIONS: QOL and survival data were similar for the two groups. A larger prospective study is justified to study the efficacy of chemotherapy only regimens in younger children. Pediatr Blood Cancer (c) 2013 Wiley Periodicals, Inc.

PURPOSE/OBJECTIVE:Diffuse intrinsic pontine gliomas (DIPGs) are rapidly progressive and aggressive tumors that usually arise in children. Their anatomic location makes gross total surgical resection impossible, and fewer than 10% of patients survive more than 2 years after diagnosis. Often, these lesions are treated based on imaging characteristics alone. However, despite aggressive chemotherapy and radiation treatments available, prognosis remains poor. There is therefore a need for new therapies directed by biologic profiling. This necessitates a tissue diagnosis and, therefore, surgical biopsy. We have reviewed the results of biopsy for DIPGs in children at a single institution and compared our results to those available in the literature to elucidate the utility of biopsy for DIPGs. METHODS:A historical cohort study was performed using medical records of patients under the age of 18 who underwent surgical biopsy of a DIPG at a single institution. RESULTS:Nine patients were included, four males and five females. Age at presentation ranged from 8 months to 10 years (average 5.7 years). Pathologic diagnoses included five high grade (WHO grade III or IV) gliomas and four low grade (WHO grade II) astrocytomas. There were no intraoperative complications, and only one patient developed a new postoperative neurologic deficit. CONCLUSIONS:Stereotactic biopsy of DIPGs is essential to obtain a pathologic diagnosis and is associated with low morbidity. This technique is important to elucidate biological characteristics of these tumors in order to direct multidisciplinary treatment plans possibly involving chemotherapy, radiation therapy, or other future clinical trial interventions for children with DIPGs.

The purpose of this study is to determine the accuracy with which a non-Gaussian measure of diffusion, mean kurtosis (MK), predicts the histologic grade of pediatric brain tumors. After institutional review board approval, 21 World Health Organization (WHO) grade I, 7 WHO grade II, and 7 WHO grade IV pathologically-proven intracranial pediatric malignancies were retrospectively reviewed for preoperative diffusional kurtosis imaging. Multiple diffusion metrics of the tumors including MK, mean diffusivity (MD) and fractional anisotropy (FA) were determined. Comparisons between groups were performed using the Mann-Whitney test (p < .05). Receiver operating characteristics analysis was done to assess accuracy of each metric in predicting histologic grade. MK was significantly higher for grade IV neoplasms (0.97, p < 0.0004) than grade I (0.62) or grade II (0.67) tumors. MD was significantly higher for grade I (1.43) compared with grade IV neoplasms (1.07, p < 0.018), however not for grade II (1.43) compared with grade IV (p < 0.08) tumors. FA did not differ significantly between grades. Area under the receiver operating characteristic curve was highest for MK (0.94) and lower for MD (0.89). FA performed only slightly better than chance (0.54). MK is an accurate diffusion metric for predicting histologic grade of pediatric brain tumors, consistent with conclusions from prior studies demonstrating similar results in adult populations

OBJECTIVES: To investigate the concordance of blood count indices measured locally and at a central laboratory. DESIGN AND METHODS: In a multi-center clinical trial of hydroxyurea therapy in infants with sickle cell anemia (BABY HUG), the concordance between blood count indices measured locally and at a central laboratory was investigated. RESULTS: Local laboratory measurements of neutrophil and monocyte counts were significantly higher (44% and 37%, respectively) compared to the central measurements (p<0.0001), and mean corpuscular volume (MCV) was higher centrally. CONCLUSION: Overnight shipping with processing delay causes spurious reductions in absolute neutrophil count (ANC) and absolute monocyte count (AMC) that may result in incorrect monitoring decisions in multicenter clinical trials.

Treatment of high-grade gliomas with selective intra-arterial (IA) administration of chemotherapies has been proposed, and utilized as a therapeutic modality. This approach offers the conceptual benefit of providing maximal delivery of the agent to the tumor bed, while potentially reducing systemic exposure to the agent. This retrospective study was designed to determine the vascular distribution of glioblastoma multiforme (GBM) at the time of diagnosis in an effort to determine what proportion of patients would likely be candidates for this approach. The preoperative MRI scans of 50 patients with GBM were analyzed and compared to published normative data of intracranial vascular distribution. Vascular distribution was determined by analyzing post-gadolinium axial and coronal T1 images, axial T2 images, and axial T2 images with an additional 1 cm margin (T2 + 1 cm) added in all dimensions. T1 analysis demonstrated 60% of tumors in a single vascular distribution. T2 analysis of these tumors reduced that number to 34%. When the T2 + 1 cm margin was utilized, only 6% of tumors were in a single vascular distribution. 66% of tumors were limited to the anterior circulation on T1 imaging but only 34% on T2 + 1 cm imaging. 30% of tumors were also within the distribution of the anterior choroidal artery. These findings suggest that the use of selective IA administration of agents is necessarily limited to a fraction of presenting patients or will require administration via multiple cerebral arteries.