Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood-brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. METHODS: To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53-/-). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). RESULTS: FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3-4 weeks post-RT. CONCLUSION: Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Infusion-related side-effects during convection enhanced delivery for brainstem-diffuse midline glioma/diffuse intrinsic pontine glioma.

INTRODUCTION: Side-effects during convection enhanced delivery (CED) are poorly understood. We intended to determine the frequency of side-effects during brain stem infusion and determine risk factors for side-effects persisting longer than 24 h. METHODS: Children with a radiological diagnosis of brain stem diffuse midline glioma/Diffuse Intrinsic Pontine Glioma were treated on compassionate grounds with awake infusion of carboplatin and sodium valproate into the brain stem using the 4-catheter (2 trans-cerebellar 2 trans-frontal) chronic, intermittent Renishaw Drug Delivery System. We used change in the Pontine Neurological Observation Score (PONScore), a standardised neurological assessment tool, to identify side-effects during infusion. Recovery was determined by retrospective chart review. RESULTS: 55 infusions were performed in 8 children (3-11 years). Mean PONScore increased during infusion from 3.3 to 5.7 (p-value > 0.001). One hundred and fifty-seven infusion-related side-effects were identified including headache (33/157) and limb weakness (49/157). Fifty-four side-effects persisted > 24 h. Side-effects that had occurred during a previous infusion and those that occurred during infusion via trans-cerebellar catheters were more likely to be persistent with OR 2.333 (95% CI 1.094-4.976; p-value = 0.028) and 2.155 (1.029-4.513; p-value = 0.042) respectively. If infusion was stopped or titrated at onset rather than continued, the side-effect was less likely to persist > 24 h, OR 0.473 (95% CI 0.177-0.948; p-value = 0.037). Most side-effects developed within the first three millilitre of infusion. CONCLUSIONS: Side-effects during brainstem infusion are common, can be transient or persist longer than 24 h. Neurological injury during infusion may be time dependent and accumulative rather than volume dependent.

Development of a clinical scale for assessment of patients with diffuse intrinsic pontine glioma (DIPG) receiving experimental therapy: the PONScore.

PURPOSE: Monitoring neurological side-effects in experimental therapy for diffuse intrinsic pontine glioma (DIPG) can be challenging. We aimed to develop a neurological scale that could be used by non-specialists to quantify neurological changes during experimental treatment of DIPG. METHODS: We developed the Pontine Observational Neurological Score (PONScore) to measure signs and symptoms of DIPG by adapting validated assessment scales of neurological signs and symptoms in children. We developed a prototype score, taught it to paediatric intensive care nursing staff, who used the Score to assess children receiving awake pontine infusion of chemotherapy for treatment of DIPG. We used their feedback to develop the PONScore. Points are allocated for headache, ophthalmoplegia, facial and tongue weakness, dysarthria, paraesthesia, limb weakness and dysmetria with increasing scores reflecting increasing disability. The PONScore was administered every hour during awake pontine infusion. Correlation and agreement calculations between nursing staff, as non-specialists, and a specialist rater were performed in 30 infusions in 6 children (aged 8-11). Changes in PONScore versus volume of infusion are described in a further 55 infusions in 8 children (aged 3-11). RESULTS: The PONScore demonstrated excellent intra-rater reliability with an intra-class co-efficient of 0.98 (95% CI 0.97-0.99; p-value < 0.001) between a specialist and non-specialist raters with strong correlation between scores and a Spearman correlation coefficient of 0.985 (p < 0.001). PONScores increased from 3.3 to 5.7 (p-value < 0.001) during infusion reflecting accumulation of neurological signs and symptoms during infusion. CONCLUSIONS: We describe a novel neurological scale that can be used by non-specialists to describe acute neurological changes in children receiving experimental therapy for DIPG. Prospective validation as part of a clinical trial is required.

Repeatability of derived parameters from histograms following non-Gaussian diffusion modelling of diffusion-weighted imaging in a paediatric oncological cohort.

OBJECTIVES: To examine repeatability of parameters derived from non-Gaussian diffusion models in data acquired in children with solid tumours. METHODS: Paediatric patients (<16 years, n = 17) were scanned twice, 24 h apart, using DWI (6 b-values, 0-1000 mm-2 s) at 1.5 T in a prospective study. Tumour ROIs were drawn (3 slices) and all data fitted using IVIM, stretched exponential, and kurtosis models; percentage coefficients of variation (CV) calculated for each parameter at all ROI histogram centiles, including the medians. RESULTS: The values for ADC, D, DDCα, α, and DDCK gave CV < 10 % down to the 5th centile, with sharp CV increases below 5th and above 95th centile. K, f, and D* showed increased CV (>30 %) over the histogram. ADC, D, DDCα, and DDCK were strongly correlated (ρ > 0.9), DDCα and α were not correlated (ρ = 0.083). CONCLUSION: Perfusion- and kurtosis-related parameters displayed larger, more variable CV across the histogram, indicating observed clinical changes outside of D/DDC in these models should be interpreted with caution. Centiles below 5th for all parameters show high CV and are unreliable as diffusion metrics. The stretched exponential model behaved well for both DDCα and α, making it a strong candidate for modelling multiple-b-value diffusion imaging data. KEY POINTS: • ADC has good repeatability as low 5th centile of the histogram distribution. • High CV was observed for all parameters at extremes of histogram. • Parameters from the stretched exponential model showed low coefficients of variation. • The median ADC, D, DDC α , and DDC K are highly correlated and repeatable. • Perfusion/kurtosis parameters showed high CV variations across their histogram distributions.

Feasibility and applicability of diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging in routine assessments of children with high-grade gliomas.

Diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) have been used as imaging biomarkers in adults with high-grade gliomas (HGGs). We incorporated free-breathing DW-MRI and DCE-MRI, at a single time point, in the routine follow-up of five children (median age 9 years, range 8-15) with histologically confirmed HGG within a prospective imaging study. It was feasible to incorporate DW-MRI and DCE-MRI in routine assessments of children with HGG. DW and DCE parameters were repeatable in paediatric HGG. Higher median ADC100-1000 significantly correlated with longer survival in our sample.

Craniospinal irradiation with concomitant and adjuvant temozolomide--a feasibility assessment of toxicity in patients with glioblastoma with a PNET component.

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35-40 Gy in 20-24 daily fractions with a focal boost to the tumour of 14-23.4 Gy in 8-13 daily fractions. Concurrent TMZ was administered at 75 mg/m(2) for seven of the cohort, with the other patient receiving 50 mg/m(2). The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.

Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study.

Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m(2) daily or etoposide 50 mg/m(2)/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9-24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk-benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients.

Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma.

Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.

Central Versus Extraventricular Neurocytoma in Children: A Clinicopathologic Comparison and Review of the Literature.

BACKGROUND: Central neurocytomas (CN) are rare pediatric CNS tumors most often with a benign clinical course. Occasionally, these tumors occur outside the ventricles and are called extraventricular neurocytomas (EVN). We present a retrospective institutional analysis of children with neurocytoma with prolonged follow-up. PROCEDURE: Twelve patients were diagnosed with neurocytoma at our institution between 1993 and 2004. RESULTS: Six patients were male and the median age at diagnosis was 12 years (1.5 to 16 y). Seven patients had CN and 5 had EVN. Presenting symptoms included headaches (67%), vomiting (50%), nausea (33%), seizures (33%), and mental status changes (25%). Obstructive hydrocephalus was present at diagnosis in 42% of the cases. Younger age and seizures were more common in patients with EVN. Gross total resection (GTR) was achieved in 42% (5/12) of the patients. Patients with GTR received no adjuvant therapy upfront; 1 patient subsequently had recurrence with leptomeningeal disease. Patients with subtotal resection received additional treatment: 1 underwent reoperation (GTR), 2 patients received focal radiation, 2 patients received adjuvant chemotherapy, and 2 patients received craniospinal irradiation followed by chemotherapy. The 20-year overall survival for this cohort was 83% with event free survival of 56%. Overall survival for CNs was 100%, versus 40% for EVN. Event free survival for CNs was 57% and 53% for the EVNs. An MIB-1 fraction >2% was associated with worse prognosis. CONCLUSIONS: Neurocytomas are rare brain tumors in children usually cured with GTR. Adjuvant focal radiation therapy and/or chemotherapy may improve disease control in cases with subtotal resection, but case-by-case analysis should be done. EVNs might be associated with worse outcome due to a higher proliferative index.

Demonstration of the reproducibility of free-breathing diffusion-weighted MRI and dynamic contrast enhanced MRI in children with solid tumours: a pilot study.

OBJECTIVES: The objectives are to examine the reproducibility of functional MR imaging in children with solid tumours using quantitative parameters derived from diffusion-weighted (DW-) and dynamic contrast enhanced (DCE-) MRI. METHODS: Patients under 16-years-of age with confirmed diagnosis of solid tumours (n = 17) underwent free-breathing DW-MRI and DCE-MRI on a 1.5 T system, repeated 24 hours later. DW-MRI (6 b-values, 0-1000 sec/mm(2)) enabled monoexponential apparent diffusion coefficient estimation using all (ADC0-1000) and only ≥100 sec/mm(2) (ADC100-1000) b-values. DCE-MRI was used to derive the transfer constant (K(trans)), the efflux constant (kep), the extracellular extravascular volume (ve), and the plasma fraction (vp), using a study cohort arterial input function (AIF) and the extended Tofts model. Initial area under the gadolinium enhancement curve and pre-contrast T1 were also calculated. Percentage coefficients of variation (CV) of all parameters were calculated. RESULTS: The most reproducible cohort parameters were ADC100-1000 (CV = 3.26%), pre-contrast T1 (CV = 6.21%), and K(trans) (CV = 15.23%). The ADC100-1000 was more reproducible than ADC0-1000, especially extracranially (CV = 2.40% vs. 2.78%). The AIF (n = 9) derived from this paediatric population exhibited sharper and earlier first-pass and recirculation peaks compared with the literature's adult population average. CONCLUSIONS: Free-breathing functional imaging protocols including DW-MRI and DCE-MRI are well-tolerated in children aged 6 - 15 with good to moderate measurement reproducibility. KEY POINTS: • Diffusion MRI protocol is feasible and well-tolerated in a paediatric oncology population. • DCE-MRI for pharmacokinetic evaluation is feasible and well tolerated in a paediatric oncology population. • Paediatric arterial input function (AIF) shows systematic differences from the adult population-average AIF. • Variation of quantitative parameters from paired functional MRI measurements were within 20%.

Mobilisation of haematopoietic stem cells in paediatric patients, prior to autologous transplantation following administration of plerixafor and G-CSF.

Previous chemotherapy and radiation exposure can make adequate stem cell mobilisation prior to autologous transplant extremely difficult in paediatrics. Plerixafor, a selective reversible CXCR4 antagonist interferes with CXCR4 interaction with Stromal cell-derived factor 1 alpha (SDF-1). Combination with granulocyte-colony stimulating factor (G-CSF) amplifies G-CSF affects in mobilising haematopoietic stem cells. Whilst licensed for use with G-CSF for enhancement of mobilisation of haematopoietic stem cells in adults, paediatric data for use of plerixafor remain limited. We present a retrospective review of outcomes seen with plerixafor and G-CSF to mobilise stem cells heavily pre-treated paediatric patients with cancer.

Patient-derived xenografts for individualized care in advanced sarcoma.

BACKGROUND: Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-of-care therapeutics available is small. The rarity of this tumor, combined with the wide range of subtypes, leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with a variety of common solid tumors who received treatment with drug regimens that were first tested in patient-derived xenografts using a proprietary method ("TumorGrafts"). METHODS: Tumors resected from 29 patients with sarcoma were implanted into immunodeficient mice to identify drug targets and drugs for clinical use. The results of drug sensitivity testing in the TumorGrafts were used to personalize cancer treatment. RESULTS: Of 29 implanted tumors, 22 (76%) successfully engrafted, permitting the identification of treatment regimens for these patients. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 13 of 16 (81%) of the remaining individuals. No patients progressed during the TumorGraft-predicted therapy. CONCLUSIONS: The current data support the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors such as sarcomas. A randomized phase 3 trial versus physician's choice is warranted.

Toxicity and outcome of children and adolescents participating in phase I/II trials of novel anticancer drugs: the Royal Marsden experience.

Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.

Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations.

Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis-whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-up in vivo validation. While individual drugs predicted to target individual subpopulations-including avapritinib, larotrectinib, and ruxolitinib-produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG. METHODS: In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy. RESULTS: Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT. CONCLUSIONS: As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.

Role of platelet derived growth factor receptor (PDGFR) over-expression and angiogenesis in ependymoma.

New molecularly targeted therapies are needed for childhood ependymoma. Angiogenesis and the PDGFR pathway could be potential therapeutic targets. This study aimed to screen ependymomas for the expression and clinicopathological correlates of angiogenic factors and potential therapeutic targets including VEGFR, endoglin (CD105), CD34, CD31, c-Kit, PDGFR-α and PDGFR-ß. Immunohistochemistry for angiogenesis factors and PDGFR-α and ß was performed in 24 archival tumor samples from children and adults treated for ependymoma at our institution. CD31 density, CD105 density and pericyte coverage index (PCI) were calculated. These findings were correlated with clinical outcome. VEGFR2 was overexpressed in tumor cells in only one out of 24 cases, but was found overexpressed in the vessels in 6 cases. PDGFR-α and ß were found to be over-expressed in the ependymoma tumor cells in seven out of 24 cases (29.2 %). CD31 density, CD105 density and PCI did not correlate with expression of PDGFRs. Overexpression of PDGFR-α and ß in tumor cells and overexpression of PDGFR-α in tumor endothelium had prognostic significance and this was maintained in multivariate analysis for overexpression of PDGFR-α in tumor cells (2 year progression free survival was 16.7 ± 15.2 for cases with overexpression of PDGFR-α in the tumor vs. 74.5 ± 15.2 for those with low/no expression, hazard ratio = 5.78, p = 0.04). A number of angiogenic factors are expressed in ependymoma tumor cells and tumor endothelium. Preliminary evidence suggests that the expression of PDGFRs could have a prognostic significance in ependymoma. This data suggests that PDGFRs should be further evaluated as targets using novel PDGFR inhibitors.