Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Jansen, Marc; Zanten, Sophie Em Veldhuijzen van; Aliaga, Esther Sánchez; Heymans, Martijn W.; Warmuth‐Metz, Monika; Hargrave, Darren; Hoeven, Erica J. van der; Gidding, Corrie; Bont, Eveline S. de; Eshghi, Omid; Reddingius, Roel E.; Peeters, Cacha M.; Meeteren, A.Y.N. Schouten-van; Gooskens, R. H. J. M.; Granzen, Bernd; Paardekooper, G.; Janssens, Geert O.; Noske, David P.; Barkhof, Frederik; Kramm, Christof M.; Vandertop, W. Peter; Kaspers, Gertjan J. L.; Vuurden, Dannis G. van

doi:10.1093/neuonc/nou104

Cited by 143 publications

(147 citation statements)

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“…In the past 40 years, the outcome of patients with DIPG has remained unchanged, with less than 10% of the patients being alive 2 years from diagnosis (1,2). Given the lack of gadolinium uptake on MRI in DIPG tumors (3,4), it is plausible that the blood-brain barrier (BBB) in DIPG often remains intact which might explain the resistance to systemic chemotherapy in these patients.…”

Section: Introductionmentioning

confidence: 99%

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

Jansen¹,

Lagerweij

Sewing³

et al. 2016

Molecular Cancer Therapeutics

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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.

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Section: Introductionmentioning

confidence: 99%

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

Jansen¹,

Lagerweij

Sewing³

et al. 2016

Molecular Cancer Therapeutics

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“…Baseline enhancement is associated with decreased survival (5,6). Recent research suggests that sites of tumor enhancement correlate with sites of reduced diffusivity, lower apparent diffusion coefficient (ADC) values, and more aggressive disease (6)(7)(8).…”

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confidence: 99%

Correlation of ¹⁸F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

et al. 2017

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See an invited perspective on this article on page 1262.The purpose of this study was to describe baseline 18 F-FDG PET voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline MRI apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS), and overall survival. Methods: Baseline brain 18 F-FDG PET and MRI scans were obtained in 33 children from Pediatric Brain Tumor Consortium clinical DIPG trials. 18 F-FDG PET images, postgadolinium MR images, and ADC MR images were registered to baseline fluid attenuation inversion recovery MR images. Three-dimensional regions of interest on fluid attenuation inversion recovery MR images and postgadolinium MR images and 18 F-FDG PET and MR ADC histograms were generated. Metrics evaluated included peak number, skewness, and kurtosis. Correlation between PET and MR ADC histogram metrics was evaluated. PET pixel values within the region of interest for each tumor were plotted against MR ADC values. The association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94%, vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET postgadolinium skewness tended toward a less favorable PFS (hazard ratio, 3.48; 95% confidence interval [CI], 0.75-16.28 [P 5 0.11]). There was a significant association between higher MR ADC postgadolinium skewness and shorter PFS (hazard ratio, 2.56; 95% CI, 1.11-5.91 [P 5 0.028]), and there was the suggestion that this also led to shorter overall survival (hazard ratio, 2.18; 95% CI, 0.95-5.04 [P 5 0.067]). Higher MR ADC postgadolinium kurtosis tended toward shorter PFS (hazard ratio, 1.30; 95% CI, 0.98-1.74 [P 5 0.073]). PET and MR ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and MR ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (hazard ratio, 0.17; 95% CI, 0.03-0.89 [P 5 0.036]), suggesting that a higher level of negative ADC-PET correlation leads to less favorable PFS. A more significant negative correlation may indicate higher-grade elements within the tumor leading to poorer outcomes. Conclusion: 18 F-FDG PET and MR ADC histogram metrics in pediatric DIPG demonstrate different characteristics with often a negative correlation between PET and MR ADC pixel values. A higher negative correlation is associated with a worse PFS, which may indicate higher-grade elements within the tumor.

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“…DIPG tumors are resistant to all kinds of systemic therapies, including targeted agents, and hardly any patient survives beyond 2 y from diagnosis (2,3). One hypothesis for therapy failure is that drugs actually do not reach the tumors, as in most DIPG tumors at diagnosis MRI shows little or no gadolinium contrast enhancement, suggesting an intact bloodbrain barrier for large molecules (4). Molecular drug imaging may help in the investigation of this hypothesis; however, despite a recent boost in molecular drug imaging in adults, no immuno-PET imaging studies have yet been performed in children (5).…”

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Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

et al. 2016

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Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89 Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging. Methods: Patients received 89 Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89 Zr-bevacizumab was quantified as SUVs. Results: Seven DIPG patients (4 boys; 6-17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89 Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0-6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter-and intratumoral heterogeneity of uptake, and 89 Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89 Zr-bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor-to-blood-pool SUV ratios increased with time after injection (P 5 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq). Conclusion: 89 Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89 Zr-bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89 Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment.

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Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Abstract: We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.

Cited by 143 publications

References 31 publications

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

Correlation of ¹⁸F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

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Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Abstract: We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.

Cited by 143 publications

References 31 publications

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

Correlation of 18F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

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Correlation of ¹⁸F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma