Brainstem Glioma Research Articles

Shall we treat hydrocephalus associated to brain stem glioma in children?

Brain stem glioma accounts for 6-9% of brain tumors in children. Tumor progression may lead to CSF pathway obstruction and development of hydrocephalus. We retrospectively reviewed charts of patients consecutively treated in our institution with diffuse intrinsic pontine glioma in order to assess incidence of hydrocephalus, its management, and its impact on overall survival. All patients had brain stem glioma not amenable to surgery. Cases with exophytic brain stem glioma were excluded. Fifty-one children were treated from January 2005 to December 2010 for brain stem glioma in the Pediatric Neurosurgery Department of Necker Enfants Malades, Paris, France. Hydrocephalus occurred in 11 of them (22%). They were six boys and five girls; the average and median time from tumor diagnosis to onset of hydrocephalus were 5.3 and 3.2months, respectively, while average and median time from onset of hydrocephalus to death were 5.3 and 2.8months, respectively. Hydrocephalus was treated in nine patients by a ventriculoperitoneal (VP) shunt and in two patients by an endoscopic third ventriculostomy. Because of early failure, a VP shunt was implanted in one child. The overall 1-year survival rate was 33%. Survival rate of patients with such obstructive hydrocephalus was not significantly different from patients harboring brain stem glioma who did not develop hydrocephalus. Furthermore, hydrocephalus was not related to terminal tumor progression. Considering both risks and benefit of treatment, VP shunt could be proposed, on the base of our experience, as the first option in spite of the apparently obstructive nature of the hydrocephalus associated to a brain stem tumor.

Cavernous Malformations: A Paradigm for Progress

Cavernous Malformations: A Paradigm for Progress

Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study

To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1). MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.

Sparing of the hippocampus, limbic circuit and neural stem cell compartment during partial brain radiotherapy for glioma: A dosimetric feasibility study

The aim of this study was to assess the feasibility of sparing contralateral or bilateral neural stem cell (NSC) compartment, hippocampus and limbic circuit during partial brain radiotherapy (PBRT). Treatment plans were generated for five hemispheric high-grade gliomas, five hemispheric low-grade gliomas and two brainstem gliomas (12 patients). For each, standard intensity-modulated radiotherapy (IMRT) plans were generated, as well as IMRT plans which spared contralateral (hemispheric cases) or bilateral (brainstem cases) limbic circuit, hippocampus, and NSC. Biologically equivalent dose for late effects (BED(late effects)) was generated for limbic circuit, hippocampus and NSC. Per cent relative reduction in mean physical dose and BED was calculated for each plan (standard vs. sparing). We were able to reduce physical dose and BED(late effects) to these critical structures by 23.5-56.8% and 23.6-66%, respectively. It is possible to spare contralateral limbic circuit, NSC and hippocampus during PBRT for both high- and low-grade gliomas using IMRT, and to spare the hippocampus bilaterally during PBRT for brainstem low-grade gliomas. This approach may reduce late cognitive sequelae of cranial radiotherapy.

Use of Positron Emission Tomography in the Evaluation of Diffuse Intrinsic Brainstem Gliomas in Children

Diffuse intrinsic brainstem gliomas (DIBSGs) in children remain difficult tumors to treat and have a very poor prognosis. Intensifying both chemotherapy and radiation programs have been attempted without success. Positron emission tomography (PET) has been used to differentiate benign from malignant tumors and may predict outcome. To determine whether PET can characterize a specific metabolic pattern of DIBSGs and correlate this with patient survival. We conducted a retrospective review of patients with DIBSGs and PET scans at diagnosis. Data for ¹⁸[F] fluorodeoxyglucose (FDG) and ¹¹C-methionine (CMET) PET scans were collected. Treatment and survival were reviewed. We identified 30 patients with DIBSGs, 25 of whom had FDG and/or CMET PET scans. Scans showed both focal and generalized metabolic activity, and the patterns showed no correlation with survival. Patients with both FDG and CMET positive scans had a mean survival of 380 days, whereas those negative for both isotopes had a mean survival of 446 days. There was no specific PET pattern identified in this DIBSG cohort but a trend toward improved survival was noted with absence of FDG and CMET metabolism. Metabolically active areas may suggest potential sites for biopsy. We believe that biopsy is essential for improving therapy for this patient population.

Human adipose tissue-derived mesenchymal stem cells: Characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas

Human mesenchymal stem cells (hMSCs) have emerged as attractive cellular vehicles for gene therapy against brain malignancy because of their targeted tropism for cancer and the intrinsic attribute of autologous transplantation. We evaluated the characteristics and therapeutic potential of human adipose tissue-derived MSCs (hAT-MSCs) and prodrug gene therapy against diffuse pontine gliomas. The hAT-MSCs were isolated from human adipose tissue and characterised for morphology, surface markers and potential to differentiate into mesenchymal and neuronal lineages. We genetically modified hAT-MSCs to express rabbit carboxylesterase (rCE) enzyme, which can efficiently convert the prodrug CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin), into the active drug SN-38 (7-ethyl-10-hydroxycamptothecin). The migratory capacity of hAT-MSCs expressing rCE (hAT-MSC.rCE), their ability to convert CPT-11 to SN-38 and cytotoxic effect on F98 cells were evaluated in vitro. The therapeutic potential of hAT-MSC.rCE was confirmed using a rat brainstem glioma model. The hAT-MSCs showed fibroblast-like morphology and expressed hMSC-specific markers including CD73, CD90 and CD105. The hAT-MSCs could differentiate into a mesenchymal lineage and transdifferentiate into a neuronal lineage under optimum culture conditions. The hAT-MSC.rCE converted CPT-11 to SN-38 and preserved the tumour tropism of hAT-MSCs. Brainstem glioma-bearing rats treated with hAT-MSC.rCE and CPT-11 survived 5 d more than rats treated with CPT-11 only ( p = 0.0018). Our study demonstrates that hAT-MSCs can be easily prepared and genetically modified as cellular vehicles for prodrug gene therapy and that they have therapeutic potential against brainstem gliomas.

Magnetic resonance spectroscopic detection of lactate is predictive of a poor prognosis in patients with diffuse intrinsic pontine glioma

Diffuse brainstem glioma has a poor prognosis, and there are few long-term survivors. We looked for clinical, conventional magnetic resonance (MR), and MR spectroscopic (MRS) findings predictive of the prognosis of patients with brainstem glioma. Our institutional review board approved this retrospective study of 23 patients with diffuse intrinsic pontine or diffuse medullary brainstem glioma treated during the period 2000-2009. To evaluate prognostic values, we performed a Kaplan-Meier survival analysis (log-rank test) that incorporated the patients' age and sex, symptom duration, the presence or absence of cranial nerve palsy, long tract sign, ataxia, and cysts, the chemotherapeutic regimen, Gd enhancement, longitudinal and cerebellar extension, basilar artery encasement, and MRS parameters. Of the 23 diffuse brainstem gliomas, 19 were located at the pons (ratio of male to female patients, 1.1:1). The mean age of the 23 patients was 15.9 years (range, 4-50 years); 16 were aged <20 years. The duration of overall survival was 19.7 months; in patients with diffuse intrinsic pontine glioma, it was 16.6 months, and in patients aged <20 years, it was 11.8 months. Clinical and conventional MR findings at presentation were not predictive of the prognosis in children with diffuse intrinsic pontine glioma. In addition, a patient age <20 years and the detection of lactate by MRS were poor prognostic factors. The MRS detection of lactate is a prognostic factor in patients with diffuse intrinsic pontine glioma. Additional studies of larger patient populations using other imaging modalities are needed.

A comparative study of pediatric CNS tumor activity as assessed by [18F]-FDG PET imaging and proton magnetic resonance spectroscopic imaging.

2101 Background: Magnetic resonance spectroscopic imaging (MRSI) allows in vivo analysis of tumor metabolism in discrete areas of the tumor. Changes in the ratio of two metabolites, choline and N-acetyl aspartate, (Cho:NAA) have been associated with tumor grade, treatment response and outcome. Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is the current standard of care to assess tumor metabolism, and FDG uptake has correlated with tumor grade and proliferative status. The relationship between tumor metabolic activity on MRSI and FDG-PET is unclear. The objective of this study was to compare the determination of metabolically active tissue between MRSI and FDG-PET in pediatric brain tumors. Methods: Children with a brain tumor or residual lesion after therapy underwent FDG-PET and a standard MRI with MRSI within a two-week period. FDG uptake and maximum Cho:NAA were each used to classify tumors as inactive, active, and highly active. The agreement between the two measures was determined using the percent agreement and the kappa statistic (K). Results: FDG-PET and MRSI were acquired in 37 patients (15M/22F) with a median age of 12.3 years. Tumor diagnoses included 20 brainstem gliomas, 8 high-grade, 8 low-grade gliomas and 1 patient with Lhermitte-Duclos disease. Four studies were excluded. Increased metabolic activity was identified in the majority of both PET and MRSI studies (Table), but overall agreement between MRSI and PET was weak (K=0.16), with only 14 of 33 studies yielding the same classification. The percent agreement between PET and MRSI was 42% (95% CI = 25 – 61%, p = 0.49). Patients continue to accrue to see if the results are applicable in a larger population. Conclusions: Pediatric brain tumors have a heterogeneous metabolic expression pattern on MRSI and FDG-PET. There was little agreement between maximum Cho:NAA values and maximum FDG-PET activity. MRSI classification PET classification Inactive (n=14) Active (n=9) Highly active (n=10) Inactive (n=8) 6 2 0 Active (n=23) 7 7 9 Highly active (n=2) 1 0 1

Cerebellar Mutism After Pineal Tumour Excision: A Case Report

Cerebellar mutism syndrome (CMS) was first described by Rekate et al in 1985. This syndrome is a common complication of posterior fossa surgery in children with range of 11-29% and usually manifests as diminished speech, hypotonia, and ataxia. The cause is due to bilateral pertubation of the dentate nuclei and their efferent pathways by edema, perfusional defects, axonal damage or metabolic disturbances. Other rare causes of CMS like acute subdural hematoma of the posterior fossa, head injury, brainstem glioma surgery, meningitis and basilar artery occlusion have also been reported. CMS after supracerebellar resection of the pineal tumor is a very rare with very few cases reported. We report such a case in a 10- year old boy who underwent excision of a pineal tumor through the infratentorial supracerebellar route. Key Words: Cerebellar mutism; hydrocephalus; pineal tumor; posterior fossa. DOI: 10.3126/jnps.v31i2.4167 J Nep Paedtr Soc 2010;31(2):124-126

Diffuse intrinsic pontine glioma—current status and future strategies

Diffuse intrinsic pontine gliomas which constitute 15% of all childhood brain tumors are inoperable and response to radiation and chemotherapy has not improved long-term survival. Due to lack of newer effective therapies, mean survival after diagnosis has remained less than 12 months. Trials investigating chemotherapy and/or radiation have proven disappointing. As biopsy of these tumors are rarely performed due to the high eloquence of the brain stem, information about the pathology and biology remains elusive hindering development of novel biologic agents. Poor access of most chemotherapeutic agents to these tumors due to the blood-brain barrier continues to undermine therapeutic efficacy. Thus, to date, we remain at a virtual standstill in our attempts to improve the prognosis of children with these tumors. An extensive review of the literature was performed concerning children with diffuse brain stem gliomas including clinical trials, evolving molecular biology, and newer therapeutic endeavors. A pivotal approach in improving the prognosis of these tumors should include the initiation of biopsy and encouraging families to consider autopsy to study the molecular biology. This will help in redefining this tumor by its molecular signature and profiling targeted therapy. Continued advances should be pursued in neuroimaging technology including identifying surrogate markers of early disease progression. Defining strategies to enhance local delivery of drugs into tumors with the help of newer surgical techniques are important. Exhaustive research in all these aspects as a multidisciplinary approach could provide hope to children with these fatal tumors.

N -cadherin, E- cadherin and β- catenin expressions in human brainstem gliomas

Objective To explore the expression and significance of N - cadhefin,E - cadherin and β - catenin in human brainstem gliomas.Methods N - cadherin,E - cadherin and β - catenin proteins and mRNA were detected in 38 cases of brainstem gliomas using immunohistochemistry and RT - PCR Methods.Results There was no significant difference in the expression of N - cadherin between grades Ⅰ ～ Ⅱ and grade Ⅲ ～ Ⅳ ( P ＞ 0.05 ).The expression of N - cadherin mRNA in human brainstem gliomas of grade Ⅰ ～ Ⅱ was significantly lower than that in grade Ⅲ ～ Ⅳ ( t =2.711,P ＜ 0.05 ).There was no significant difference in the expression of E - cadherin and E - cadherin mRNA between grade Ⅰ ～ Ⅱ and grade Ⅲ～ Ⅳ ( P ＞ 0.05 ).The expression of β - catenin in human brainstem gliomas of grade Ⅰ ～ Ⅱ was significantly lower than that in grade Ⅲ ～ Ⅳ ( P ＜ 0.05 ).As regard to β - catenin mRNA,there was no significant difference between grade Ⅰ ～ Ⅱ and grade Ⅲ ～ Ⅳ ( P ＞ 0.05 ).Conclusions The over -expressionof N -cadherin and β -catenin may play an important role in the invasion and malignant progression of human brainstem gliomas. Key words: Brainstem ; Glioma ; N - cadherin ; E - cadherin ; β - catenin ;

Abstract 4307: Establishment of a patient-derived diffuse infiltrative pontine glioma primary cell line and animal model: Implications for future investigations and treatment

Abstract Diffuse infiltrating brainstem glioma arises almost exclusively in children and despite advances in imaging, neurosurgery and radiotherapy, the majority of patients die within 2 years after initial diagnosis. Because of the infiltrative nature and anatomic location in an eloquent area of the brain, most brainstem gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and biochemical abnormalities associated with these tumors, and is a substantial obstacle for the development of animal model designed specifically for the preclinical testing of specific molecular target of brainstem gliomas. We established a brainstem glioma cells originated from human biopsy sample of a low grade brainstem glioma. The brainstem glioma cells were subsequently modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase) to immortalize the cells and analyzed genetic and biochemical abnomalities of the cells. The established human brainstem glioma cells were tumorgenic in athymic rodents and the developed brainstem tumor was recapitulated the infiltrative growth of diffuse infiltrating brainstem glioma in patients, and can be monitored for tumor growth noninvasively by bioluminescence imaging (BLI). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4307. doi:10.1158/1538-7445.AM2011-4307

Abstract 3455: Comparison of expression profiles of pediatric high and low grade brainstem gliomas to pediatric supratentorial high grade astrocytomas

Abstract Diffuse intrinsic pontine gliomas (DIPG) are one of the most devastating pediatric malignancies and currently the number one cause of brain tumor related death in children with a 10-12 month median survival. Despite this very little is understood about the biology of these tumors. We have already shown potential novel therapeutic targets for DIPG using high-resolution SNP-based analysis. We performed high resolution genetic analysis using whole-genome single-nucleotide polymorphism (SNP) arrays (Affymetrix 500K and 6.0) on post mortem tumor with matched normal brain samples (n=9) and surgical samples (n=2) for a series of DIPG patients as well as pediatric supratentorial high grade astrocytomas (sHGA, n=20). Here we extend our initial study to include expression array analysis, amalgamating the datasets to generate a more complete understanding of the genetic alterations underlying brainstem gliomas. Expression profiling using Illumina HumanHT-12 arrays was conducted on 26 high grade brainstem gliomas, including 23 DIPGs, 51 low grade brainstem gliomas and 30 supratentorial high grade astrocytomas. Expression profiles highlighted the distinctiveness of DIPGs when compared to high grade supratentorial astrocytomas. Analysis resulted in two groups of DIPGs when clustering based on most significant differentially expressed genes (p &amp;lt; 0.005) with one group being more similar to pediatric low grade brainstem gliomas and the other distinct from both the supratentorial high grade tumors and other brainstem gliomas. This data will increase our understanding of brainstem glioma biology, information crucial to the development of agents targeted more specifically towards this devastating disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3455. doi:10.1158/1538-7445.AM2011-3455

Diffuse Intrinsic Brainstem Tumor in an Infant

Brainstem gliomas constitute 10% to 20% of all pediatric tumors of the central nervous system, and diffusely infiltrative brainstem gliomas are the most common brainstem tumors associated with a poor prognosis. A small subset of these tumors is benign, showing low-grade features on histology. The role of chemotherapy in the management of these tumors is ill defined, especially in the neonates. There are anecdotal reports of spontaneous remission, but the natural history of these tumors does not support a wait-and-see approach. Thus, we report a successful experience of chemotherapy in a 4-month-old girl with a diffuse brainstem fibrillary astrocytoma, treated with vinorelbine (30 mg/m/d on days 0, 8, and 22), a vinca alkaloid that has shown activity against glioma. Our experience suggests that vinorelbine may be effective in pediatric low-grade gliomas as this patient showed significant clinical improvement over a short period of time.

Hydrocephalus in Patients with Neurofibromatosis Type 1: MR Imaging Findings and the Outcome of Endoscopic Third Ventriculostomy

Although hydrocephalus associated with NF-1 is not rare, up to now the MR imaging findings in these patients and the role of ETV in the treatment of hydrocephalus associated with NF-1 have not been investigated thoroughly. We present the MR imaging findings of hydrocephalus associated with NF-1 in 7 of 54 patients with NF-1. Although the types of obstruction were various, including aqueductal web, superior velum medullary synechia, periaqueductal/tectal hamartomas, cerebellar and pontine tegmentum hamartomas, brain stem glioma, or a combination, the presence of hamartomas was a consistent finding in patients with NF-1 with hydrocephalus. In 5 cases, 8 ETV procedures were performed and followed for up to 53 months. All children treated with ETV were shunt-free at their most recent examinations. ETV may be the primary procedure for the treatment of hydrocephalus associated with NF-1, regardless of the cause and the level of the obstruction.

MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC)

We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on these variables. MRI (including diffusion and perfusion) was done before treatment, every 8 weeks (first year), every 12 weeks (thereafter), and at the end of treatment or disease progression. Reduced tumor volume (P < .0001) and tumor diffusion values (P <.0001) were apparent on the first post-RT/drug studies. Decreases in tumor volume correlated with pre-RT volume (P < .0001) and pre-RT diffusion values (P < .0001); larger decreases were noted for tumors with higher volumes and diffusion values. Patients with larger pre-RT tumors had longer progression-free survival (P < .0001). Patients with ≥ 25% decrease in tumor volume and diffusion values after RT had longer progression-free survival (P = .028) and overall survival (P = .0009). Enhancement at baseline and over time was significantly associated with shorter survival. Tumor diffusion values with baseline enhancement were significantly lower than those without (P = .0002). RT of BSG is associated with decreased tumor volume and intralesional diffusion values; patients with ≥ 25% decrease in values post-RT had relatively longer survival intervals, apparently providing an early imaging-based surrogate for relative outcomes. Patients with larger tumors and greater decreases in tumor volume and diffusion values had longer survival intervals. Tumor enhancement was associated with shorter survival, lower tumor diffusion values (increased cellularity), and a smaller drop in diffusion values after RT (P = .006). These associations justify continued investigation in other large clinical trials of brainstem glioma patients.

Severe H1N1‐associated acute respiratory failure in immunocompromised children

Severe pandemic influenza A (H1N1) infection can lead to acute respiratory failure (ARF) with associated high mortality. Children with malignancy may be at higher risk of H1N1-associated ARF because of underlying primary disease or immunosuppression associated with chemotherapy. We describe the clinical course and outcome of critically ill pediatric oncology/hematology patients with H1N1-associated ARF. Five patients were admitted to the St. Jude Children's Research Hospital (SJCRH) ICU with H1N1 infection during the 2009-2010 influenza season. Underlying diagnoses included 2 patients with acute lymphoblastic leukemia and one each with neuroblastoma, brainstem glioma, and hemolytic anemia secondary to pyruvate kinase deficiency. All patients were mechanically ventilated secondary to ARF following unsuccessful trials of non-invasive ventilatory support. The majority of patients (4/5) required inotropic support, and none required dialysis. Further measures to support their ARF included high frequency oscillatory ventilation in 2 patients, nitric oxide in 3 patients, and surfactant in 1 patient. Three patients had bronchopleural air leak. All patients received oseltamivir; however, 2 were switched to intravenous zanamivir once resistance to oseltamivir was documented. Mean duration of mechanical ventilation was 24 ± 6.8 days and mean duration of ICU admission was 37 ± 12 days. All patients survived to hospital discharge. Our series suggests an overall favorable outcome in immunocompromised children with H1N1-related ARF. Our experience underscores the value of aggressive support during H1N1-related ARF, and early detection and management of oseltamivir-resistant H1N1 infection in this high-risk population.

A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: A report from the Pediatric Brain Tumor Consortium

This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m(2)/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents.

Harvey Cushing’s early experience with pediatric gliomas

Diagnosing and operating pediatric patients with intracranial lesions posed a greater diagnostic challenge for physicians during the early twentieth century. At the time, an intracranial neoplasm was indistinctively diagnosed as a glioma, encompassing a broad category of brain tumor pathologies. The treatment and surgical interventions followed for children diagnosed with gliomas is not well-described in the literature from this time. Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896-1912. Patients 18 years or younger, who underwent surgical intervention by Cushing for suspected intracranial tumors, were selected. Of the eight pediatric cases diagnosed with gliomas by Cushing, four cases were later diagnosed as medulloblastomas by Dr. Cushing in 1925. Of the remaining four pediatric cases, one was diagnosed as a brainstem glioma and another as a ventricular glioma. We describe the remaining two cases. These examples illustrate Cushing's approach to treating brain tumors diagnosed as gliomas in pediatric patients, focusing on an initial decompression and followed by a thorough surgical exploration for tumor. Furthermore, these cases demonstrate Cushing's early attempts to manage such lesions in children and highlight the challenges faced in diagnosing and localizing intracranial lesions within this group of patients.

Phase 1 Study of Valproic Acid in Pediatric Patients with Refractory Solid or CNS Tumors: A Children's Oncology Group Report

The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100 to 150 mcg/mL or 150 to 200 mcg/mL in children with refractory solid or central nervous system (CNS) tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics (PKs) and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state. Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100 to 150 mcg/mL. First-dose and steady-state PKs were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique. Twenty-six children, sixteen of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intratumoral hemorrhage were associated with VPA troughs of 100 to 150 mcg/mL. Therefore, the final cohort of six children received VPA to maintain troughs of 75 to 100 mcg/mL and did not experience any dose-limiting toxicity. First-dose and steady-state VPA PK parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed. VPA administered three times daily to maintain trough concentrations of 75 to 100 mcg/mL was well tolerated in children with refractory solid or CNS tumors. Histone hyperacetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors.