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Purpose We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. Methods Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard‐dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced‐dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. Results Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). Conclusions Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.

Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Children’s National Health System (Washington, DC), or the Lucile Packard Children’s Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma.

BACKGROUND: Neurological side effects associated with childhood brain tumors and their treatments contribute to long term neurocognitive morbidity. The aims of this study were to identify the incidence of sensorineural hearing loss (SNHL) in a large sample of children treated for malignant embryonal brain tumors, and to evaluate the effect of SNHL on intellectual functioning following the completion of treatment. METHODS: We conducted a single center review of 119 prospectively followed patients treated for malignant embryonal brain tumors at the Hospital for Sick Children, between 1996–2015, to evaluate the impact of significant SNHL (Chang > 2b) on intellectual function. Hearing and intellectual function were assessed post-treatment, at comparable time points (median ages: hearing assessment 13.5y (+4.5); intellectual function 12.8y (+ 4.1)). The median interval since treatment was 5.9 y + 3.7. RESULTS: Significant SNHL was identified in half the patients (48.7%, n = 58/119), of which 53% required a hearing aid (31/58). We identified a subset of patients (n = 61) who had assessments of intellectual function. In these patients, intellectual function was significantly affected by severe SNHL, even after controlling for the effect of craniospinal radiation (severe SNHL 22.4 Gy + 13.3, no/mild hearing loss 20.4 Gy +12.8) and boost dose. Severe hearing loss resulted in lower overall IQ (severe SNHL: 72.4 + 16.6; no/mild hearing loss: 92.0 + 20.5) p

Facial emotion recognition (FER) deficits are evident and pervasive across neurodevelopmental, psychiatric, and acquired brain disorders in children, including children treated for brain tumours. Such deficits are thought to perpetuate challenges with social relationships and decrease quality of life. The present study combined eye-tracking, neuroimaging and cognitive assessments to evaluate if visual attention, brain structure, and general cognitive function contribute to FER in children treated for posterior fossa (PF) tumours (patients: n = 36) and typically developing children (controls: n = 18). To assess FER, all participants completed the Diagnostic Analysis of Nonverbal Accuracy (DANVA2), a computerized task that measures FER using photographs, while their eye-movements were recorded. Patients made more FER errors than controls (p

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

SC1 is a member of the SPARC family of glycoproteins that regulate cell-matrix interactions in the developing brain. SC1 is expressed in astrocytes, but nothing is known about the expression in the aged or after stroke. We found that after focal striatal ischemic infarction in adult rats, SC1 increased in astrocytes surrounding the infarct and in the glial scar, but in aged rats, SC1 was lower at the lesion edge. Glial fibrillary acidic protein (GFAP) also increased, but it was less prominent in reactive astrocytes further from the lesion in the aged rats. On the basis of their differential expression of several molecules, 2 types of reactive astrocytes with differing spatiotemporal distributions were identified. On Days 3 and 7, SC1 was prevalent in cells expressing markers of classic reactive astrocytes (GFAP, vimentin, nestin, S100A), as well as apoliprotein E (ApoE), interleukin 1A, aggrecanase 1 (ADAMTS4), and heat shock protein 25 (Hsp25). Adjacent to the lesion on Days 1 and 3, astrocytes with low GFAP levels and a ‘‘starburst’’ SC1 pattern expressed S100A, ApoE, and Hsp32 but not vimentin, nestin, interleukin 1A, ADAMTS4, or Hsp25. Neither cell type was immunoreactive for NG2, CC-1, CD11b, or ionized calcium-binding adapter-1. Their differing expression of inflammation-related and putatively protective molecules suggests different roles for starburst and classic reactive astrocytes in the early glial responses to ischemia.

Neutrophils are thought to contribute to damage after intracerebral hemorrhage (ICH), but there is little direct evidence for this. We depleted circulating blood neutrophils with an anti-polymorphonuclear leukocyte antibody (anti-PMN) before inducing ICH in the rat striatum. Neutrophil infiltration, which was mainly at the edge of the hematoma, was decreased by more than 60% by anti-PMN mediated depletion. We then analyzed neutrophil contributions to BBB breakdown, white matter damage (axons and myelin), and glial and inflammatory responses, both spatially and temporally. Neutrophil depletion reduced BBB leakiness in the peri-hematoma region. Matrix metalloprotease 9, which is thought to contribute to BBB breakdown, was restricted to neutrophils after ICH and was thus reduced by neutrophil depletion. Early perihematomal axonal injury seen at 1 and 3 days after ICH was decreased by depleting neutrophils, and at later times (7 and 14 days), the astrocytic and microglia/macrophage responses were reduced in the perihematoma region and the surrounding striatum. Detailed spatial analysis showed that neutrophil depletion reduced infiltration of activated microglia/macrophages in the peri-hematoma white matter tracts and decreased myelin fragmentation and axon damage. These results show that, in experimental ICH, neutrophils produce matrix metalloprotease9and contribute to blood vessel disruption, BBB breakdown, axon damage, and astrocytic and microglial/macrophage responses that evolve after ICH.

BACKGROUND: Medulloblastoma subgroups have distinct demographic, genetic and clinical features, yet their respective intellectual outcomes are unknown. With the advent of subgroup-specific therapy de-escalation strategies, it is critical to characterize intellectual functioning in each subgroup according to treatment intensity. METHODS: One hundred and twenty one patients with medulloblastoma (51 Group 4; 25 Group 3; 28 SHH; 17 WNT), treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Canada), Children's National Medical Center (Washington, DC) or the Lucile Packard Children's Hospital (Palo Alto, CA), had longitudinal intellectual functioning evaluations. First, we compared IQ measures between subgroups, controlling for relevant clinical and demographic variables. Next, we evaluated the effect of: a) radiation intensity (i.e. reduced-dose radiation with a focal tumor bed boost vs. treatments with higher radiation doses and/or larger boost volumes), and b) mutism, on full scale IQ (FSIQ) in each subgroup. Growth curve analysis was used to determine stability or change in IQ scores over time. RESULTS: Subgroups declined comparably in all IQ measures except processing speed (PS). SHH had lower baseline PS, and declined less, than Groups 3 and 4 (all P 0.05). Although FSIQ decline did not differ according to mutism status for any subgroup (all P > 0.05), Group 3 patients with mutism had lower baseline FSIQ (P = 0.014). CONCLUSION: Therapy de-escalation appears to be a suitable way to achieve optimal intellectual functioning in patients with WNT and Group 4 medulloblastoma.

2029 Background: Neurological side effects associated with childhood brain tumors and their treatments contribute to long term neurocognitive morbidity. The aims of this study were to identify the incidence of sensorineural hearing loss (SNHL) in a large sample of children treated for malignant brain tumors, and to evaluate the potential relationship between SNHL and intellectual functioning following the completion of treatment. Methods: We conducted a prospective follow-up study at a single center with review of 119 patients treated for embryonal brain tumors at the Hospital for Sick Children, between 1996-2015, to analyze the impact of significant SNHL (Chang > 2b) on intellectual function. Hearing was assessed post-treatment (median age: 13.5y (+4.5)) and the median age for neurocognitive testing was 12.8y (+ 4.1). The median interval from time of diagnosis was 5.8y (+ 3.7). Results: Severe SNHL was identified in half the patients (50.4%, n = 60/119). We identified a subset of patients (n = 61) who had assessments of intellectual function. In this cohort, intellectual function was significantly poorer in the group with severe SNHL, even after controlling for the effect of craniospinal radiation (severe SNHL 22.4 Gy + 13.3, no or mild hearing loss 20.4 Gy +12.8) and boost dose and volume. Children experiencing severe SNHL had lower overall IQ (severe SNHL 72.4 + 16.6; no/mild hearing loss 92.0 + 20.5) p < 0.001 and in significantly lower verbal comprehension (severe SNHL 78.7 + 15.9; no/mild hearing loss 94.7 + 13.8) p < 0.001, and working memory (severe SNHL 78.2+ 17.6; no/mild hearing loss 94.8 + 16.4) p < 0.001, scores. Conclusions: Hearing loss is a much more significant complication in children with embryonal brain tumors than previously estimated. We show the profound impact of hearing loss on intellectual deficit in children. Namely, patients with severe SNHL have difficulty using and understanding verbal language, and they have a reduced ability to concentrate and manipulate information in short-term memory. Our results have implications on future trial designs and follow-up of children treated for embryonal brain tumors.

After an ischemic stroke, there is a prolonged inflammatory response and secondary phase of injury that is more amenable to treatment than acute neurotoxicity. Surprisingly, little is known about temporal and spatial relationships between inflammation and white matter injury. Here, we quantified development of white matter damage, inflammation, and a glial limitans at 1, 3, and 7 days after transient ischemia in the rat striatum using immunohistochemistry. Quantitative analysis showed that decreased staining for myelin basic protein and increased staining for damaged myelin basic protein began in the core, coincided with neutrophil infiltration, and progressed outward over time. Axon damage (i.e. accumulation of amyloid precursor protein) began at the edge of the lesion, coinciding with substantial microglia/macrophage activation, and progressed into the core. During the 7 days, activated microglia/macrophages dramatically increased only in the core and edge of the lesion. Detailed spatial analyses revealed that activated microglia/macrophages that surrounded undamaged axon bundles did not express ED1, a marker of phagocytic cells, whereas those inside damaged bundles expressed ED1. These results imply different contributions of neutrophils and microglia/macrophages to white matter injury after ischemic stroke. The distinct localizations of activated microglia/macrophages imply complex signals that regulate their migration toward and infiltration of damaged white matter.