Diffuse Intrinsic Brainstem Gliomas Research Articles

DIPG-42. Diffuse midline gliomas, H3K27-altered as an interdisciplinary challenge

INTRODUCTION: Diffuse midline gliomas represent a particular challenge in treatment. DIPG behave like highly malignant glioma with extremely poor prognosis due to location and inoperability. Molecular genetic studies, complementary to classical histopathology, have found an entity for midline gliomas, newly described ten years ago and entered the WHO classification in 2016. This group of childhood tumor with DMG’s, H3K27-altered will be demonstrated in the following with 14 case reports from our clinic. METHODS: Clinical data of four patients with tectum/thalamic gliomas, six with diffuse intrinsic brainstem glioma, two with cerebellar, one with suprasellar, one with spinal glioma were retrospectively studied. MRI data, volume increase, contrast behavior was also analyzed. Tumor tissue was obtained by various surgical procedures and diagnostic workup included histopathology as well as genetics and epigenetics. RESULTS: 14 pediatric patients were treated from 2012 to 2021, median age 7,5 years. Leading symptoms were hydrocephalus, movement disorders, cranial nerve disorders. Four patients (29%) were partially resected, two (14%) received extended biopsy, seven (50%) were (stereo tactically) biopsied, one diagnosed by liquid biopsy (7%). Histological results revealed the presence of GBM in four cases (29 %). Subsequent methylome analyses confirmed that the tumors belonged to the group of diffuse midline gliomas, H3K27-altered. The other ten tumors (71%) were primarily assigned to this H3K27 group. CONCLUSION: The pediatric tumors of the brainstem, the further midline structures, including intraspinal manifestation show different MRI findings, histology, and clinical course. Complementary molecular genetic diagnosis is essential and a meaningful addition to the histological assignment. It is considered proven that the exclusivity of H3K27 – altered tumors of children and adolescents differs from that of IDH mutated gliomas and glioblastomas by their localization of hemispheric processes. Possible therapeutic approaches using targeted therapy require understanding of these oncological mechanisms.

IMG-01. Quantitative Direct Sodium (23Na) MRI in Pediatric Gliomas

BACKGROUND: The treatment of pediatric gliomas is typically assessed with proton (1H) MRI, which can have limitations. 23Na MRI has been shown in adult brain tumors to measure intra-tumoral total sodium concentration as a correlate of tumor proliferation. 23Na MRI sodium studies in pediatric patients are lacking. PURPOSE: (1) To compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) Compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. MATERIALS AND METHODS: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas [diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)] on sodium MRI images co-registered with proton MRI. In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed for tissue conspicuity using voxel-based parametric maps. RESULTS: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9 – 23.3 years) were scanned with 23Na MRI. Uninvolved tissues demonstrated a range of TSC values similar to published adult values. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (P<0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (P<0.002 for LGG, and P<0.02 for HGG). The dual echo 23Na MRI suppresses the sodium signal within both CSF and necrotic foci, resulting in improved conspicuity of both non-neoplastic and neoplastic, compared to serial TSC imaging. CONCLUSION: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging. Future studies are needed to determine the value of 23Na MRI in delineating therapeutic responses in pediatric gliomas.

Quantitative Sodium (23Na) MRI in Pediatric Gliomas: Initial Experience.

Background: 23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking. The purpose of the study: (1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. Methods: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed. Results: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9–23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci. Conclusion: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging.

Very long-term of survival, 5 years and more in diffuse intrinsic pontine brainstem gliomas in children and adolescents treated with Radiotherapy and Nimotuzumab

Diffuse intrinsic brainstem gliomas have a bad prognosis, and short-term survival time. Radiotherapy has been the principal treatment, and chemotherapy has not improved outcome. The anti –EGFR monoclonal antibody Nimotuzumab combined with Radiotherapy was tested in a series of 41 children and adolescents with diffuse intrinsic pontine gliomas (DIPG) included between January 2008 and December 2015 and a follow-up till January 2021.They were irradiated in the Instituto Nacional de Oncologia y Radiobiologia, Havana, Cuba with a median dose of 54 Gy. Nimotuzumab was applied at a dose of 150 mg/m2, weekly during the period of irradiation, then every 2 weeks by 8 doses, and them monthly for 1,2 or more years. A response was observed in 87.8% of patients. Prolonged use of Nimotuzumab was feasible and well tolerated. Median age at diagnosis was 7 years old, median survival was 18.8 months. There were minor toxicities, only Grade I or II. Survival rate at 5 years was 34.1%, stablished till years or more. Two relapsing patients were re-irradiated. The combination of irradiation and Nimotuzumab is an option to increase survival in DIPG.

Tails of a Super Histone

Diffuse intrinsic brain stem gliomas (DIPGs) with characteristic K27M mutation of H3.3 are lethal and poorly understood childhood cancers. In this issue of Cancer Cell, Larson etal. exploit a unique murine DIPG model with inducible, endogenous K27M expression to reveal insights into mechanisms of K27M-mediated transformation in DIPG.

EPIG-17HUMAN ES CELLS AS A MODEL FOR MODELING BRAINSTEM GLIOMAS

Recent sequencing data demonstrate the presence of novel mutations in the H3.3. histone gene variant in diffuse intrinsic brainstem gliomas of childhood, DIPG. Surgical access to these tumors presents high risks, leading to a paucity of patient specimens and poor understanding of this tumor's biology. We used human embryonic stem cells differentiated into early neural precursors as a system to model the H3.3K27M tumors. We demonstrate in vitro and in vivo the neoplastic transformation of these cells, following expression of the H3.3K27M gene, as well as a combination of PDGFRA and p53. The tumors reproduced the major features of DIPG, and genome-wide analyses indicated a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Gene expression data from the transformed precursors clustered tightly with patient samples of H3.3K27M mutated gliomas rather than wild type or H3.3G34R/V gliomas. In addition, the tumors formed in animals upon grafting the transformed cells into the pons of immunocompromised mice, demonstrated key histological features of DIPG, including infiltration of the pons, leptomeningeal spread and encasement of the basilar artery. We established a drug screening system based on a competitive assay between the transformed precursors and normal neural precursors. Assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice. The drug was validated in cell lines established from DIPG samples. Ongoing work aims to establish efficacy of the drug in a large series as well as its pharmacokinetics and blood brain barrier permeability. In addition, we are investigating the role of menin in enhancing the tumorigenic potential of DIPG. These data highlight a considerable potential for human embryonic stem cell systems as a platform for developing cancer models.

HG-14 * CLINICAL, RADIOGRAPHIC, AND HISTOLOGIC CHARACTERISTICS OF LONG-TERM SURVIVORS OF DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY

Children with diffuse intrinsic brainstem glioma (DIPG) have a median survival of less than 1 year despite radiation ± chemotherapy. The International DIPG Registry, a collaborative effort among researchers in North America and Australia has enrolled 395 patients with data for over 900 patients committed from 35 institutions. Among the 395 patients, 32 long-term survivors (LTS) (overall survival [OS] ≥2 years) have been identified. Preliminarily, we report clinical, radiographic, and histologic data for 75 of 395 patients, including the 32 LTS and 43 in the comparison (C) group. On central radiographic review, 5 were deemed not to represent DIPG (3 LTS and 2 C). Median age at diagnosis for LTS and C groups was 5.5 and 6.1 years, respectively. Fifty-seven percent of LTS had >6 weeks between onset of symptoms and diagnosis versus 28% for the comparison group (p < 0.05). Incidence of signs and symptoms at diagnosis (cranial nerve, cerebellar, or pyramidal) was similar in both groups. All patients, except 3 LTS, underwent radiation at diagnosis; all but 6 received adjunct chemotherapy. Median OS was 28.4 and 10.8 months for the LTS and C groups, respectively. Two patients (1 LTS) had an H3.3K27M mutation and 2 (1 LTS) had an H3.1K27M mutation. Biology data from 25 other patients from autopsy (n = 12) or biopsy (n = 13) are under analysis. Presence of enhancement on diagnostic imaging was associated with poorer survival (p = 0.02). There was no significant difference in radiographic evidence of hemorrhage, necrosis, diffusion restriction, or tumor size between LTS and C groups. Preliminary data in children with DIPG suggest that LTS have a longer duration of presenting signs and symptoms and less often display radiographic evidence of enhancement at diagnosis. Complete clinical, radiographic, and biology (where available) data on all 395 patients enrolled are currently being analyzed and will be presented.

Oral etoposide therapy for diffuse intrinsic brain stem glioma regrowth after local radiation therapy

Oral etoposide therapy for diffuse intrinsic brain stem glioma regrowth after local radiation therapy

Molecular analysis of diffuse intrinsic brainstem gliomas in adults

Diffuse intrinsic brainstem gliomas (DIBG) account for 1-2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9-65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p < 0.01). IDH1 sequencing revealed two mutations (IDH1 (R132G) , IDH1 (R132C) ) out of 7 DIBG whereas the R132H IDH1 enzyme was detected in 1/17 DIBG, suggesting that IDH1 mutations are mostly non R132H in DIBG (2/2), in contrast to supratentorial gliomas (31/313; p = 0.01). Mutations in histone genes H3F3A (encoding H3.3) and HIST1H3B (encoding H3.1) were found in 3/8 (37.5 %) of the DIBG (two H3F3A (K27M) and one HIST1H3B (K27M) ) versus 6/205 (2.9 %) of the supratentorial high-grade gliomas (four H3F3A (G34R) and two H3F3A (K27M) ) (p = 0.002). The CGH array showed a higher frequency of chromosome arm 1q gain, 9q gain and 11q loss in DIBG compared to the supratentorial high-grade gliomas, which had a less frequent chromosome 7 gain, and a less frequent chromosome 10 loss. No EGFR amplification was found. These data suggest that adult DIBG differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare.

Abstract 5004: NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma.

Abstract Introduction: Pediatric brainstem glioma (BSG) is one of the most difficult cancers to treat accounting for 10-20% of all pediatric central nervous system (CNS) tumors. BSGs may occur throughout the brainstem and are categorized into two main groups: diffuse intrinsic pontine gliomas (DIPGs) and focal brainstem gliomas. DIPGs represent about 80% of BSG and have a peak onset of six to nine years of age. DIPGs invade throughout the pons and may spread to other portions of brainstem. To better understand the pathophysiology of the disease, a genetically engineered (PDGFα-expressing) BSG mouse and a xenograft model have been established. Results: We recently reported proteome profiling of DIPG CSF and formalin fixed specimens. To expand our molecular studies of the disease, we generated complete protein profiles of specimens obtained from BSG mouse tumor and aged-matched healthy controls. Neuroglia 2 (NG2), also known as chondroitine sulfate proteoglycan 4 (CSPG4) was selected for further analysis based on its exclusive expression in BSG specimens. Although NG2 has been previously implicated in adult gliomas, its role in pediatric gliomas has not been investigated and currently there are no publications on the role of NG2 in DIPGs. Recently, NG2 expression has been shown to play a significant role in neoplastic transformation of glioma precursor cells. Gliomas are thought to originate from cells including astrocytes, stem cells, and glioma progenitor cells. Glial progenitor cells are specifically important since several groups have reported detection of oligodendrocyte markers including NG2, PDGFRα, and Olig-2 in gliomas. Our preliminary data shows high expression of NG2 in murine model of brainstem glioma as well as 80% of pediatric DIPG specimens tested. We show that shRNA-mediated knockdown of NG2 reduces cellular migration in vitro. NG2 expression is defective (symmetric) in dividing cells in vitro and in vivo. The defective NG2 expression is consistent with a recent observation in adult high grade gliomas. Injection of NG2 expressing neurospheres (NS) into brainstems of 2 day old mice (P2) results in highly aggressive brainstem tumors resulting in death within 3-7 weeks post-injection. Therefore the NS injected mouse model of brainstem glioma provides a solid model for testing therapeutics and evaluating interventions. Furthermore, we show selective delivery of liposomal nanoparticles to brainstem of our robust BSG mouse model. We also show that nanoparticle-mediated delivery of doxorubicin will induce apoptosis in tumor and not the adjacent normal region. Conclusion: We introduce a robust murine model of brainstem glioma that is developed using NG2 expressing cells. High expression of NG2 in a subset of DIPGs and its defective expression may provide novel approaches for treating DIPGs and BSGs. Citation Format: Sridevi Yadavilli, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Paker, Javad Nazarian. NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5004. doi:10.1158/1538-7445.AM2013-5004

Expression of β-catenin and E- and N-cadherin in human brainstem gliomas and clinicopathological correlations

Brainstem gliomas are usually associated with serious dysfunction and poor prognosis especially for diffuse intrinsic brainstem gliomas; however, the reasons are still unclear. Some clinical studies have suggested that the invasive ability may be different among brainstem gliomas, and the dysfunction of β-catenin and E- and N-cadherin appears to be connected with tumor invasion and progression. In this study, the expression of β-catenin and E- and N-cadherin was detected in 40 brainstem glioma samples using immunochemistry and was further analyzed in 18 samples using reverse transcription-polymerase chain reaction. The clinicopathological characteristics were also analyzed. The results show that there was no obvious staining for E-cadherin, but weak expression at the messenger RNA (mRNA) level could be seen in a few samples. The protein and mRNA expression levels of β-catenin and N-cadherin were significantly associated with the pathological grades of brainstem gliomas. No significant differences in the expression levels of β-catenin and N-cadherin were observed for age, sex, location or diffuse growing pattern. The overall survival of patients with low β-catenin expression was longer than that with high β-catenin expression, and there was a trend toward increased expression of N-cadherin with shorter survival; however, both of them had no statistical differences. These results demonstrate that expression of β-catenin and N-cadherin is associated with the malignant progression of brainstem gliomas but not correlated with the diffuse and invasive growing pattern. β-catenin and N-cadherin are potential therapeutic targets and prognostic markers for brainstem glioma, which need to be validated in a larger patient cohort.

The effects of temozolomide delivered by prolonged intracerebral microinfusion against the rat brainstem GBM allograft model

Diffuse intrinsic brainstem gliomas are considered to be inoperable. We report our initial experience of temozolomide (TMZ) administration into brainstem by intracerebral (i.c.) microinfusion using a rat brainstem glioblastoma allograft model. Forty-eight Fischer 344 female rats were used. In a feasibility study, various doses of i.c.-TMZ (1-10 mg) were administered into the brainstem using AlzetTM pumps in order to evaluate survival rates and neurotoxicity. For tumor implantation, rats received an injection of 10(5) 9 L gliosarcoma cells. For local therapy, 5 days after inoculation, a total amount of 1 mg of TMZ or saline was administered into the brainstem at 1 μl/h over 7 days (n = 8/group). For systemic therapy, rats were treated with an orally administered maximum daily dose of 50 mg/kg TMZ for 5 consecutive days. Survival time and neurological deficit were recorded as outcome parameters. In the neurotoxicity study, low dose TMZ (1 mg) was feasible to be administered into brainstem over 7 days without neurological deficit. Using high dose TMZ (5-10 mg), marked neurotoxic effect was observed. In the brainstem tumor study, survival was significantly prolonged in low dose i.c.-TMZ group compared to control rats (median survival 23.5 versus 29.5 days; p < 0.01). Systemic therapy with maximal oral-TMZ dose resulted in longer survival time compared to low dose i.c.-TMZ group (median survival 33.5 versus 29.5 days; p < 0.01). i.c.-TMZ is feasible and effective against rat brainstem glioblastoma allograft. However, we could not show superior potential of i.c.-TMZ compared to oral-TMZ administration. Modification of TMZ infusion with systemic therapy warrants future investigations.

Adult Brainstem Gliomas

Brainstem gliomas are uncommon in adults and account for only 1%-2% of intracranial gliomas. They represent a heterogeneous group of tumors that differ from those found in their pediatric counterparts. In adults, a low-grade phenotype predominates, which is a feature that likely explains their better prognosis compared to that in children. Because biopsies are rarely performed, classifications based on the radiological aspect of magnetic resonance imaging results have been proposed to establish treatment strategies and to determine outcomes: (a) diffuse intrinsic low-grade, (b) enhancing malignant glioma, (c) focal tectal gliomas, and (d) exophytic gliomas. Despite significant advances in neuroradiology techniques, a purely radiological classification remains imperfect in the absence of a histological diagnosis. Whereas a biopsy may often be reasonably avoided in the diffuse nonenhancing forms, obtaining histological proof seems necessary in many contrast-enhanced brainstem lesions because of the wide variety of differential diagnoses in adults. Conventional radiotherapy is the standard treatment for diffuse intrinsic low-grade brainstem gliomas in adults (the median survival is 5 years). In malignant brainstem gliomas, radiotherapy is the standard treatment. However, the possible benefit of combined radiotherapy and chemotherapy (temozolomide or other agents) has not been thoroughly evaluated in adults. The role of anti-angiogenic therapies in brainstem gliomas remains to be defined. A better understanding of the biology of these tumors is of primary importance for identifying homogeneous subgroups and for improving therapy options and outcomes.

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.

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.

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.

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.

Evaluation of 18F-FDG PET and MRI Associations in Pediatric Diffuse Intrinsic Brain Stem Glioma: A Report from the Pediatric Brain Tumor Consortium

The purpose of this study was to assess (18)F-FDG uptake in children with a newly diagnosed diffuse intrinsic brain stem glioma (BSG) and to investigate associations with progression-free survival (PFS), overall survival (OS), and MRI indices. Two Pediatric Brain Tumor Consortium (PBTC) therapeutic trials in children with newly diagnosed BSG were designed to test radiation therapy combined with molecularly targeted agents (PBTC-007: phase I/II study of gefitinib; PBTC-014: phase I/II study of tipifarnib). Baseline brain (18)F-FDG PET scans were obtained in 40 children in these trials. Images were evaluated by consensus between 2 PET experts for intensity and uniformity of tracer uptake. Associations of (18)F-FDG uptake intensity and uniformity with both PFS and OS, as well as associations with tumor MRI indices at baseline (tumor volume on fluid-attenuated inversion recovery, baseline intratumoral enhancement, diffusion and perfusion values), were evaluated. In most of the children, BSG (18)F-FDG uptake was less than gray-matter uptake. Survival was poor, irrespective of intensity of (18)F-FDG uptake, with no association between intensity of (18)F-FDG uptake and PFS or OS. However, hyperintense (18)F-FDG uptake in the tumor, compared with gray matter, suggested poorer survival rates. Patients with (18)F-FDG uptake in 50% or more of the tumor had shorter PFS and OS than did patients with (18)F-FDG uptake in less than 50% of the tumor. There was some evidence that tumors with higher (18)F-FDG uptake were more likely to show enhancement, and when the diffusion ratio was lower, the uniformity of (18)F-FDG uptake appeared higher. Children with BSG for which (18)F-FDG uptake involves at least half the tumor appear to have poorer survival than children with uptake in less than 50% of the tumor. A larger independent study is needed to verify this hypothesis. Intense tracer uptake in the tumors, compared with gray matter, suggests decreased survival. Higher (18)F-FDG uptake within the tumor was associated with enhancement on MR images. Increased tumor cellularity as reflected by restricted MRI diffusion may be associated with increased (18)F-FDG uniformity throughout the tumor.

A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma

Purpose Survival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients. Methods Children aged 18 years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85 mg/m 2/day for 6 weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers. Results Fifteen eligible patients were enrolled, with a median age of 6.4 years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13 months (95% CI = 6.4, 10.8) and median overall survival (OS) was 9.8 months (95% CI = 6.4, 10.8). Six-months OS was 80% ± 10.3%, with a 1-year OS of 20% ± 10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy. Conclusion Chemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.

Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies

Diffuse intrinsic pontine gliomas constitute ~ 60-75% of tumors found within the pediatric brainstem. These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions. Magnetic resonance imaging is usually sufficient to establish the diagnosis and obviates the need for surgical biopsy in most cases. The prognosis of the disease is dismal, and the median survival is < 12 months. Resection is not a viable option. Standard therapy involves radiotherapy, which produces transient neurological improvement with a progression-free survival benefit, but provides no improvement in overall survival. Clinical trials have been conducted to assess the efficacy of chemotherapeutic and biological agents in the treatment of diffuse pontine gliomas. In this review, the authors discuss recent studies in which systemic therapy was administered prior to, concomitantly with, or after radiotherapy. For future perspective, the discussion includes a rationale for stereotactic biopsies as well as possible therapeutic options of local chemotherapy in these lesions.