Faculty Bibliography

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 Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as >/=15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

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.

OBJECTIVE: The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG) clinical trials. METHODS: The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials. RESULTS: Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Children's Visual Function Questionnaire as a secondary endpoint is also proposed. CONCLUSIONS: The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.

BACKGROUND: There is increasing reliance on oncoprotein assays such as the beta-subunit of human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP) for diagnosis or confirmation of histology of central nervous system (CNS) germ cell tumors (GCT), but the relative diagnostic sensitivity and reliability of assays from serum (S), lumbar (L), and ventricular (V) cerebrospinal fluid (CSF) are uncertain. PROCEDURE: A total of 86 patients with CNS GCT were identified from our database. Fourteen patients had contemporaneous beta-hCG and/or AFP measurements from serum, ventricular, and lumbar CSF at diagnosis (n = 13) or relapse (n = 1), constituting the subjects for this report. Their primary tumor sites were: pineal (n = 8), suprasellar (n = 1), or both (n = 5). Their mean age at diagnosis was 16.0 years (range 9.1-25.9). The male:female sex ratio was 13:1. RESULTS: For the germinoma-treated patients (n = 8), the median (range) beta-hCG values (S, V, L) were 0 (0-6.9), 7.0 (0-57.4), 8.3 (0-34.0) mIU/ml. For patients managed as mixed malignant GCT (MMGCT) (n = 6), the median (range) beta-hCG values (S, V, L) were 3.9 (0-58.0), 3.6 (0-147.0), 61.8 (0-358.0) mIU/ml. The median (range) AFP values were 7.5 (0-27,400.0), 2.0 (0-2,981.0), 3.0 (0-14,015.0) ng/ml. Lumbar CSF beta-hCG values were equal or greater than those in ventricular CSF or serum in 12 of 13 cases (92.3%). All patients with MMGCT had lumbar AFP equal or greater than the ventricular CSF values, while serum AFP values remained highest. CONCLUSIONS: Ventricular CSF values cannot be considered a replacement for lumbar CSF. Lumbar CSF is the most reliable source of tumor markers to establish baseline and follow-up diagnostic endpoints. Pediatr Blood Cancer 2013;60:1647-1650. (c) 2013 Wiley Periodicals, Inc.

Background/Aims. Primary CNS germinoma is readily curable with relatively large volume/high dose radiotherapy with late neuroendocrine/neurocognitive risks. Preradiotherapy chemotherapy with response-based reduced volume/dose radiotherapy may decrease these late effects without compromising survival. We combined the results of two similar trials (NY Germinoma Consortium and COG ACNS0232 - Regimen B) which followed a similar treatment paradigm. Methods. Eligibility included newly diagnosed, histologically confirmed, completely staged CNS germinoma with serum and lumbar CSF H

This study investigates the outcome of children <10 years old with newly-diagnosed ependymoma treated on the prospective multinational "Head Start" III clinical trial. Between April 2004 and July 2009, 19 children with newly-diagnosed ependymoma were enrolled. All children were to receive five induction chemotherapy cycles followed by one consolidation cycle of myelo-ablative chemotherapy and autologous hematopoietic cell rescue. Children between 6 and 10 years of age or with residual tumor prior to consolidation were to receive irradiation thereafter. Median age of 19 children (8 female) was 20 months at diagnosis. Median follow up was 44 months. The primary site was infratentorial in 11 and supratentorial in 8 patients. Gross total resection was achieved in 10 patients. After induction chemotherapy, all three supratentorial ependymoma patients with residual disease achieved a complete response (CR), while only one of six infratentorial patients with residual disease achieved CR. Three infratentorial patients developed progressive disease during induction chemotherapy. All four infratentorial patients with residual disease who underwent autologous hematopoietic cell transplant, failed to achieve CR. Four patients received focal irradiation following chemotherapy. The 3-year event free survival (EFS) and overall survival (OS) for supratentorial ependymoma were 86 +/- 13 % and 100 % respectively. The 3-year EFS and OS for infratentorial ependymoma were 27 +/- 13 % and 73 +/- 13 % respectively. The role of intensive induction and consolidation chemotherapy in deferring irradiation should be investigated further in children with supratentorial ependymoma with residual disease following surgery. This approach appears ineffective in children with infratentorial ependymoma in the absence of irradiation.