Mn(III) porphyrin (MnP) holds the promise of addressing the emerging challenges associated with Gd-based clinical MRI contrast agents (CAs), namely, Gd-related adverse effect and decreasing sensitivity at high clinical magnetic fields. Two complementary strategies for developing new MnPs as Gd-free CAs with optimized biocompatibility were established to improve relaxivity or clearance rate. MnPs with distinct and tunable pharmacokinetic properties can consequently be constructed for different in vivo applications at clinical field of 3 T.

Background Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors’ knowledge, the long‐term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years. Methods Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome‐wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3). Results A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10‐year progression‐free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%‐53.1%). Analysis of consecutive 10‐year epochs revealed significant improvements in progression‐free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full‐scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (‐1.33 ± 0.42 points/year; P = .0042). Conclusions Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors’ knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

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BackgroundChildren with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated.MethodsWe delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively.ResultsBoth whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex.ConclusionsOur results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects.

INTRODUCTION Treatments for pediatric brain tumors (PBT) are neurotoxic and lead to long-term deficits that are driven by the perturbation of underlying white matter (WM). It is unclear if and how treatment may impair WM connectivity across the entire brain. METHODS Magnetic resonance images from 41 PBT survivors (mean age: 13.19 years, 53% M) and 41 typically developing (TD) children (mean age: 13.32 years, 51% M) were analyzed. Image reconstruction, segmentation, and node parcellation were completed in FreeSurfer. DTI maps and probabilistic streamline generation were completed in MRtrix3. Connectivity matrices were based on the number of streamlines connecting two nodes and the mean DTI (FA) index across streamlines. We used graph theoretical analyses to define structural differences between groups, and random forest (RF) analyses to identify hubs that reliably classify PBT and TD children. RESULTS For survivors treated with radiation, betweeness centrality was greater in the left insular (p < 0.000) but smaller in the right pallidum (p < 0.05). For survivors treated without radiation (surgery-only), betweeness centrality was smaller in the right interparietal sulcus (p < 0.05). RF analyses showed that differences in WM connectivity from the right pallidum to other parts of the brain reliably classified PBT survivors from TD children (classification accuracy = 77%). CONCLUSIONS The left insular, right pallidum, and right inter-parietal sulcus are structurally perturbed hubs in PBT survivors. WM connectivity from the right pallidum is vulnerable to the long-term effects of treatment for PBT.

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