Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

Both diastolic and systolic blood pressure are significantly increased in survivors of childhood ALL. Female survivors treated with cranial radiation therapy have the highest prevalence and greatest risk of overweight/obesity. Therefore, survivors of childhood ALL are likely to be at an increased risk of cardiovascular disease later in life, which stresses the need for follow-up and adequate medical and/or life style interventions.

The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ( 89 Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after 89 Zrbevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo.

OBJECTIVEPediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models.METHODSThe sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model.RESULTSBoth pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors.CONCLUSIONSLocal delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.

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To assess the efficacy of temozolomide in children and adolescents with newly diagnosed and progressive DIPG. 1 Temozolomide for children and adolescents with diffuse intrinsic pontine glioma (Protocol)

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INTRODUCTION: High grade gliomas (HGG) represent approximately 10% of all pediatric central nervous system (CNS) tumors. Despite a variety of therapies, outcomes remain dismal. In contrast to adults with HGG, there is no apparent standard of care (SOC) for the treatment of children with HGG after surgery. We undertook an internet-based survey to better understand what the perceived SOC is for children. 3 years with newly diagnosed HGG. METHODS: An 8 question internet-based survey was e-mailed to 120 physicians who treat children with CNS tumors. Demographic data, including medical specialty, experience and institutional affiliations were collected. Respondents were asked what they consider as SOC for children with newly diagnosed HGG after a maximal surgical resection. RESULTS: The entire survey was completed by 62.5% (75/120) of respondents. 83% (62/75) identified themselves as pediatric oncologists/neuro-oncologists. The remaining were pediatric neurosurgeons, radiation oncologists and neurologists. 65% had .10 years' experience and approximately 84% worked in a large academic or cancer center. More than 70% answered that their affiliated institution sees more than 5 pediatric HGG patients each year. The most commonly answered SOC was to treat patients on any available Phase I or II clinical trial (26.7%). In the absence of a clinical trial, physicians most commonly answered that they personally would treat a newly diagnosed patient with focal radiation plus temozolomide followed by maintenance temozolomide (30.7%).