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Background and purposeSelumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib.Materials and methodsChildren with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment.ResultsEach stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG.ConclusionsADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

Purpose To evaluate nnU-Net-based segmentation models for automated delineation of medulloblastoma tumors on multi-institutional MRI scans. Materials and Methods This retrospective study included 78 pediatric patients (52 male, 26 female), with ages ranging from 2 to 18 years, with medulloblastomas, from three different sites (28 from hospital A, 18 from hospital B, and 32 from hospital C), who had data available from three clinical MRI protocols (gadolinium-enhanced T1-weighted, T2-weighted, and fluid-attenuated inversion recovery). The scans were retrospectively collected from the year 2000 until May 2019. Reference standard annotations of the tumor habitat, including enhancing tumor, edema, and cystic core plus nonenhancing tumor subcompartments, were performed by two experienced neuroradiologists. Preprocessing included registration to age-appropriate atlases, skull stripping, bias correction, and intensity matching. The two models were trained as follows: (a) the transfer learning nnU-Net model was pretrained on an adult glioma cohort ( n = 484) and fine-tuned on medulloblastoma studies using Models Genesis and (b) the direct deep learning nnU-Net model was trained directly on the medulloblastoma datasets, across fivefold cross-validation. Model robustness was evaluated on the three datasets when using different combinations of training and test sets, with data from two sites at a time used for training and data from the third site used for testing. Results Analysis on the three test sites yielded Dice scores of 0.81, 0.86, and 0.86 and 0.80, 0.86, and 0.85 for tumor habitat; 0.68, 0.84, and 0.77 and 0.67, 0.83, and 0.76 for enhancing tumor; 0.56, 0.71, and 0.69 and 0.56, 0.71, and 0.70 for edema; and 0.32, 0.48, and 0.43 and 0.29, 0.44, and 0.41 for cystic core plus nonenhancing tumor for the transfer learning and direct nnU-Net models, respectively. The models were largely robust to site-specific variations. Conclusion nnU-Net segmentation models hold promise for accurate, robust automated delineation of medulloblastoma tumor subcompartments, potentially leading to more effective radiation therapy planning in pediatric medulloblastoma. Keywords: Pediatrics, MR Imaging, Segmentation, Transfer Learning, Medulloblastoma, nnU-Net, MRI Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Rudie and Correia de Verdier in this issue.

Background: Children with neuromuscular early onset scoliosis (EOS) receive numerous radiographic studies both from orthopaedic and other specialties. Ionizing radiation doses delivered by computed tomography (CT) are reportedly 100 times higher than conventional radiography. The purpose of this study was to evaluate the number of radiographic studies ordered for neuromuscular EOS patients during their care., Methods: Retrospective review at a tertiary children's hospital from January 2010 to June 2021 included all patients with neuromuscular EOS followed by an orthopaedic specialist for a minimum of 3 years. Patients were excluded if the majority of their nonorthopaedic care was provided by outside institutions., Results: Eighteen patients met inclusion criteria with mean follow up of 6.4±2.3 years. A total of 1312 plain radiographs and 35 CT scans were performed. Of the plain radiographs, 34.7% were ordered by orthopaedic providers and 65.3% (857/1312) were ordered by other providers. Of the CT scans, 4 were ordered by orthopaedic providers, while 88.5% (21/35) were ordered by other providers. An average of 74.7 (range: 29 to 124) radiographs and 1.9 (range: 0 to 9) CT scans ordered over the course of each patient's treatment for an average of 13.0±6.0 radiographs and 0.3 CT scans per year., Conclusions: With an average of 75 radiographs and 1.9 CT scans performed per patient, consideration for steps to limit exposure to ionizing radiation should be made a particularly high priority in this unique subset of patients. This requires interdisciplinary coordination as 65% of the radiographs and over 80% of the CT scans were ordered by nonorthopaedic providers., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Pineal parenchymal tumors are rare neoplasms for which evidence-based treatment recommendations are lacking. These tumors vary in biology, clinical characteristics, and prognosis, requiring treatment that ranges from surgical resection alone to intensive multimodal antineoplastic therapy. Recently, international collaborative studies have shed light on the genomic landscape of these tumors, leading to refinement in molecular-based disease classification in the 5th edition of the World Health Organization (WHO) classification of tumors of the central nervous system. In this review, we summarize the literature on diagnostic and therapeutic approaches, and suggest pragmatic recommendations for the clinical management of patients presenting with intrinsic pineal region masses including parenchymal tumors (pineocytoma, pineal parenchymal tumor of intermediate differentiation, and pineoblastoma), pineal cyst, and papillary tumors of the pineal region., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation., Methods and Materials: A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose., Results: The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya, or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%)., Conclusions: Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we introduce a regimen that is well-tolerated and effective at inducing remission., Methods: The primary objectives of this study were to assess tolerability of the regimen and overall response rate (ORR). A retrospective chart review of patients with recurrent medulloblastoma, treated at two institutions with a re-induction regimen of intravenous irinotecan and cyclophosphamide with oral temozolomide and etoposide, was performed. Demographic, clinicopathologic, toxicity, and response data were collected and analyzed., Results: Nine patients were identified. Median age was 5.75 years. Therapy was well-tolerated with no therapy-limiting toxicities and no toxic deaths. Successful stem cell collection was achieved in all 5 patients in whom it was attempted. ORR after 2 cycles was 78%. Three patients had a complete response, 4 patients had a partial response, 1 patient had stable disease, and 1 patient had progressive disease. Four patients are alive with no evidence of disease (NED), 2 patients are alive with disease, 2 patients have died of disease, and 1 patient died of toxicity related to additional therapy (NED at time of death)., Conclusions: This regimen is well-tolerated and effective. Tumor response was noted in the majority of cases, allowing patients to proceed to additional treatment with no or minimal disease. Further study of this regimen in a clinical trial setting is an important next step., Competing Interests: There are no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Medulloblastoma is the most common malignant brain tumor in childhood. Initial treatment generally includes surgery, irradiation, and chemotherapy. Approximately 20-30% of patients will experience a recurrence, which portends a very poor prognosis. The current standard of care for evaluation for relapse includes radiographic surveillance with magnetic resonance imaging at regular intervals. The presence of circulating tumor DNA in the cerebrospinal fluid has been demonstrated to be a predictor of a higher risk of progression in a research setting for patients with medulloblastoma treated on a prospective single institution clinical trial. We have previously published and clinically validated a liquid-biopsy-based genetic assay utilizing low-pass whole genome sequencing to detect copy number alterations in circulating tumor DNA. Here, we present two teenage patients with posterior fossa medulloblastoma with recurrent disease who have been monitored with serial liquid biopsies showing tumor evolution over time, demonstrating the clinical utility of these approaches.

Objective: To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses., Methods: A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities., Results: In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities., Interpretation: This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Study Design: Retrospective review., Objective: Our goal was to investigate the incidence of cervical degenerative disk disease (DDD) in patients with adolescent idiopathic scoliosis (AIS), before surgical intervention., Summary of Background Data: AIS is often associated with thoracic hypokyphosis and compensatory cervical kyphosis. In adults, cervical kyphosis is associated with DDD. Although cervical kyphosis has been reported in up to 60% AIS patients, the association with cervical DDD has not been reported., Materials and Methods: A retrospective review was conducted from January 2014 to December 2019 of all consecutive AIS patients. Inclusion criteria were AIS patients over 10 years of age with cervical magnetic resonance imaging and anterior-posterior and lateral spine radiographs within 1 year of each other. Magnetic resonance imaging were reviewed for evidence of cervical DDD. Severity of cervical changes were graded using the Pfirrmann classification and by a quantitative measure of disk degeneration, the magnetic resonance signal intensity ratio., Results: Eighty consecutive patients were included (mean age: 14.1 years, SD=2.5 years). Increasing cervical kyphosis was significantly correlated to decreasing thoracic kyphosis ( r =0.49, P <0.01) and increasing major curve magnitude ( r =0.22, P =0.04). Forty-five patients (56%) had the presence of DDD (grades 2-4) with a mean cervical kyphosis of 11.1° (SD=9.5°, P <0.01). More cervical kyphosis was associated with more severe cervical DDD as graded by Pfirrmann classification level ( P <0.01). Increasing cervical kyphosis was also positively associated with increasing magnetic resonance signal intensity ratio ( P <0.01). Nine patients had ventral cord effacement secondary to DDD with a mean cervical kyphosis of 22.8° (SD=8.6°) compared with 2.6° (SD=11.2°) in those who did not ( P <0.01)., Conclusions: Cervical kyphosis was significantly associated with increasing severity of cervical DDD in patients with AIS. Patients with evidence of ventral cord effacement had the largest degree of cervical kyphosis with a mean of 22.8±8.6°. This is the first study to evaluate the association between cervical kyphosis in AIS with cervical DDD., Competing Interests: D.L.S. has received royalties from Wolters Kluwer Health, Zimmer Biomet, Globus Medical, and Medtronic; consulting fees from Zimmer Biomet, Globus Medical, Top Doctors, and Orthobullets; research funding from NuVasive; has ownership interest in Zipline Medical Inc., Green Sun Medical, and Orthobullets; and has held leadership or advisory positions in the Pediatric Spine Foundation and CHLA Foundation. V.T. holds a leadership or advisory position for the Journal of Bone and Joint Surgery . K.D.I. has received consulting fees from Orthopediatrics and has served on a safety or advisory board with Medtronic. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Standard MRI protocols lack a quantitative sequence that can be used to evaluate shunt-treated patients with a history of hydrocephalus. The objective of this study was to investigate the use of phase-contrast MRI (PC-MRI), a quantitative MR sequence, to measure CSF flow through the shunt and demonstrate PC-MRI as a useful adjunct in the clinical monitoring of shunt-treated patients., Methods: The rapid (96 seconds) PC-MRI sequence was calibrated using a flow phantom with known flow rates ranging from 0 to 24 mL/hr. Following phantom calibration, 21 patients were scanned with the PC-MRI sequence. Multiple, successive proximal and distal measurements were gathered in 5 patients to test for measurement error in different portions of the shunt system and to determine intrapatient CSF flow variability. The study also includes the first in vivo validations of PC-MRI for CSF shunt flow by comparing phase-contrast-measured flow rate with CSF accumulation in a collection burette obtained in patients with externalized distal shunts., Results: The PC-MRI sequence successfully measured CSF flow rates ranging from 6 to 54 mL/hr in 21 consecutive pediatric patients. Comparison of PC-MRI flow measurement and CSF volume collected in a bedside burette showed good agreement in a patient with an externalized distal shunt. Notably, the distal portion of the shunt demonstrated lower measurement error when compared with PC-MRI measurements acquired in the proximal catheter., Conclusions: The PC-MRI sequence provided accurate and reliable clinical measurements of CSF flow in shunt-treated patients. This work provides the necessary framework to include PC-MRI as an immediate addition to the clinical setting in the noninvasive evaluation of shunt function and in future clinical investigations of CSF physiology.

Objective: To determine cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during therapeutic hypothermia (TH)., Methods: This was an observational study in which cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan. Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected. The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist. Student t test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were performed., Results: Three-hundred-sixty blood glucose values and 402 MR spectra from 54 infants (30 female infants; mean gestational age 38.6 ± 1.9 weeks) were analyzed. In total, 41 infants had normal-mild and 13 had moderate-severe injury. Median GIR and blood glucose during TH were 6.0 mg/kg/min (IQR 5-7) and 90 mg/dL (IQR 80-102), respectively. GIR did not correlate with blood or cerebral glucose. Cerebral glucose was significantly greater during than after TH (65.9 ± 22.9 vs 60.0 ± 25.2 mg/dL, P < .01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r = 0.42, thalamus: r = 0.42, cortical gray matter: r = 0.39, white matter: r = 0.39, all P < .01). There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern., Conclusions: During TH, cerebral glucose concentration is partly dependent on blood glucose concentration. Further studies to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection are needed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B-cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood-brain barrier and cause an immune effector cell-associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood-brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T-cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T-cell therapy using illustrative cases from two tertiary care institutions., (© 2023 American Society of Neuroimaging.)

Background: Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized., Methods: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively., Results: Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment., Conclusions: Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To develop an MR multitasking-based dynamic imaging for cerebrovascular evaluation (MT-DICE) technique for simultaneous quantification of permeability and leakage-insensitive perfusion with a single-dose contrast injection., Methods: MT-DICE builds on a saturation-recovery prepared multi-echo fast low-angle shot sequence. The k-space is randomly sampled for 7.6 min, with single-dose contrast agent injected 1.5 min into the scan. MR multitasking is used to model the data into six dimensions, including three spatial dimensions for whole-brain coverage, a saturation-recovery time dimension, and a TE dimension for dynamic INLINEMATH measurements in eight healthy subjects and, in three of them, inter-session repeatability of permeability and leakage-insensitive perfusion parameters. Its feasibility was also demonstrated in four patients with brain tumors., Results: MT-DICE INLINEMATH values of normal gray matter and white matter were in excellent agreement with reference values (intraclass correlation coefficients = 0.860/0.962 for gray matter and 0.925/0.975 for white matter ). Both permeability and perfusion parameters demonstrated good to excellent intersession agreement with the lowest intraclass correlation coefficients at 0.694. Contrast kinetic parameters in all healthy subjects and patients were within the literature range., Conclusion: Based on dynamic INLINEMATH mapping, MT-DICE allows for simultaneous quantification of permeability and leakage-insensitive perfusion metrics with a single-dose contrast injection., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: Medulloblastoma (MB) is a malignant, heterogenous brain tumor. Advances in molecular profiling have led to identifying four molecular subgroups of MB (WNT, SHH, Group 3, Group 4), each with distinct clinical behaviors. We hypothesize that (1) aggressive MB tumors, growing heterogeneously, induce pronounced local structural deformations in the surrounding parenchyma, and (b) these local deformations as captured on Gadolinium (Gd)-enhanced-T1w MRI are independently associated with molecular subgroups, as well as overall survival in MB patients., Methods: In this work, a total of 88 MB studies from 2 institutions were analyzed. Following tumor delineation, Gd-T 1w scan for every patient was registered to a normal age-specific T 1w -MRI template via deformable registration. Following patient-atlas registration, local structural deformations in the brain parenchyma were obtained for every patient by computing statistics from deformation magnitudes obtained from every 5mm annular region, 0 < d < 60 mm, where d is the distance from the tumor infiltrating edge., Results: Multi-class comparison via ANOVA yielded significant differences between deformation magnitudes obtained for Group 3, Group 4, and SHH molecular subgroups, observed up to 60-mm outside the tumor edge. Additionally, Kaplan-Meier survival analysis showed that the local deformation statistics, combined with the current clinical risk-stratification approaches (molecular subgroup information and Chang's classification), could identify significant differences between high-risk and low-risk survival groups, achieving better performance results than using any of these approaches individually., Discussion: These preliminary findings suggest there exists significant association of our tumor-induced deformation descriptor with overall survival in MB, and that there could be an added value in using the proposed radiomic descriptor along with the current risk classification approaches, towards more reliable risk assessment in pediatric MB., Competing Interests: Dr. AM is an equity holder in Picture Health, Elucid Bioimaging, and Inspirata Inc. Currently he serves on the advisory board of Picture Health, Aiforia Inc, and SimBioSys. He also currently consults for Biohme, SimBioSys and Castle Biosciences. He also has sponsored research agreements with AstraZeneca, Boehringer-Ingelheim, Eli-Lilly and Bristol Myers-Squibb. His technology has been licensed to Picture Health and Elucid Bioimaging. He is also involved in 3 different R01 grants with Inspirata Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Iyer, Ismail, Tamrazi, Salloum, de Blank, Margol, Correa, Chen, Bera, Statsevych, Ho, Vaidya, Verma, Hawes, Judkins, Fu, Madabhushi and Tiwari.)

Quantitative susceptibility mapping (QSM) is an MRI-based technique for iron quantification of targeted tissue. QSM provides information relevant to clinicians in a broad range of diagnostic contexts, including sickle cell disease, inflammatory/demyelinating processes, and neoplasms. However, major MRI vendors do not offer QSM post-processing in a form ready for general use. This work describes a vendor-agnostic approach for scaling QSM analysis from a research technique to a routine diagnostic test. We provide the details needed to seamlessly integrate hardware, software, and clinical systems to provide QSM processing for a busy clinical radiology workflow. This approach can be generalized to other advanced MRI acquisitions and analyses with proven diagnostic utility, yet without crucial MR vendor support.

In vivo MR spectroscopy is a non -invasive methodology that provides information about the biochemistry of tissues. It is available as a "push-button" application on state-of-the-art clinical MR scanners. MR spectroscopy has been used to study various brain diseases including tumors, stroke, trauma, degenerative disorders, epilepsy/seizures, inborn errors, neuropsychiatric disorders, and others. The purpose of this review is to provide an overview of MR spectroscopy findings in the pediatric population and its clinical use.

Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a 4-yr-old female who initially presented with generalized tonic-clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T 2 -weighted magnetic resonance imaging (MRI) revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T > C ( MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T > C variant occurred de novo. The m.3685T > C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T > C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information., (© 2022 Jean et al.; Published by Cold Spring Harbor Laboratory Press.)

Background and Purpose: Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib., Materials and Methods: Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment., Results: Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC&#95;total as well as a larger decrease with time on treatment in ADC&#95;total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC&#95;total. In stratum 4, higher baseline ADC&#95;total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC&#95;total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC&#95;total mean, mode, and median as well as ADC&#95;enhancement mean and median and higher values of ADC&#95;total skewness and kurtosis at baseline. The longitudinal decrease in ADC&#95;total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG., Conclusions: ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas., (© 2022 by American Journal of Neuroradiology.)

Background and Purpose: ADC changes are useful in detecting ischemic brain injury, but mechanisms other than tissue pathology may affect the kinetic movement and diffusion of water molecules. We aimed to determine the effects of brain temperature on the corresponding ADC in infants undergoing therapeutic hypothermia., Materials and Methods: Brain temperature and ADC values in the basal ganglia, thalamus, cortical GM, and WM were analyzed during and after therapeutic hypothermia. The study cohort was categorized as having no-injury or injury. Among infants without injury, the correlation between ADC values and temperature was analyzed using the Pearson correlation. Intrasubject comparison of ADC changes during and after therapeutic hypothermia were analyzed, excluding patients who had an MR image interval of >5 days to minimize the effects of injury evolution., Results: Thirty-nine infants with hypoxic-ischemic encephalopathy were enrolled (23 no-injury; 16 injury). The median ADC was significantly lower during therapeutic hypothermia (837; interquartile range, 771-928, versus 906; interquartile range, 844-1032 ×10 -6 mm 2 /s; P < .001). There was no difference in the ADC between the no-injury and injury groups during therapeutic hypothermia (823; interquartile range, 782-868, versus 842; interquartile range, 770-1008 ×10 -6 mm 2 /s; P   = .4). In the no-injury group, in which ADC is presumed least affected by the evolution of injury, the median ADC was significantly lower during therapeutic hypothermia (826; interquartile range, 771-866, versus 897; interquartile range, 846-936 ×10 -6 mm 2 /s; P   < .001). There was a moderate correlation between temperature and ADC in the no-injury group (during therapeutic hypothermia: Spearman ρ, 0.48; P   < .001; after therapeutic hypothermia: ρ, 0.4; P   < .001)., Conclusions: Aside from brain injury, reduced tissue temperature may also contribute to diffusion restriction on MR imaging in infants undergoing therapeutic hypothermia., (© 2022 by American Journal of Neuroradiology.)

Molecular subtypes of medulloblastoma [Sonic Hedgehog (SHH), Wingless/INT (WNT), Group 3, and Group 4] are defined by common patterns of gene expression. These differential gene expression patterns appear to result in different histomorphology and prognosis. Quantitative histomorphometry is a well-known method of computer-aided pathology image analysis. The hypotheses we sought to examine in this preliminary proof of concept study were whether computer extracted nuclear morphological features of medulloblastomas from digitized tissue slide images could independently: (1) distinguish between molecularly determined subgroups and (2) identify patterns within these subgroups that correspond with clinical outcome. Our dataset was composed of 46 medulloblastoma patients: 16 SHH (5 dead, 11 survived), 3 WNT (0 dead, 3 survived), 12 Group 3 (4 dead, 8 survived), and 15 were Group 4 (5 dead, 10 survived). A watershed-based thresholding scheme was used to automatically identify individual nuclei within digitized whole slide hematoxylin and eosin tissue images. Quantitative histomorphometric features corresponding to the texture (variation in pixel intensity), shape (variations in size, roundness), and architectural rearrangement (distances between, and number of connected neighbors) of nuclei were subsequently extracted. These features were ranked using feature selection schemes and these top-ranked features were then used to train machine-learning classifiers via threefold cross-validation to separate patients based on: (1) molecular subtype and (2) disease-specific outcomes within the individual molecular subtype groups. SHH and WNT tumors were separated from Groups 3 and 4 tumors with a maximum area under the receiver operating characteristic curve (AUC) of 0.7, survival within Group 3 tumors was predicted with an AUC of 0.92, and Group 3 and 4 patients were separated into high- and low-risk groups with p = 0.002. Model prediction was quantitatively compared with age, stage, and histological subtype using univariate and multivariate Cox hazard ratio models. Age was the most statistically significant variable for predicting survival in Group 3 and 4 tumors, but model predictions had the highest hazard ratio value. Quantitative nuclear histomorphometry can be used to study medulloblastoma genetic expression phenotypes as it may distinguish meaningful features of disease pathology., (© 2022 The Authors.)

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase . Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase , accompanied by enhanced glycolysis and TCA cycle metabolism. AMPK α -2 , a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Introduction: Sickle cell disease (SCD) is a hereditary blood disorder in which the oxygen-carrying hemoglobin molecule in red blood cells is abnormal. SCD patients are at increased risks for strokes and neurocognitive deficit, even though neurovascular screening and treatments have lowered the rate of overt strokes. Tract-specific analysis (TSA) is a statistical method to evaluate microstructural WM damage in neurodegenerative disorders, using diffusion tensor imaging (DTI)., Methods: We utilized TSA and compared 11 major brain WM tracts between SCD patients with no history of overt stroke, anemic controls, and healthy controls. We additionally examined the relationship between the most commonly used DTI metric of WM tracts and neurocognitive performance in the SCD patients and healthy controls., Results: Disruption of WM microstructure orientation-dependent metrics for the SCD patients was found in the genu of the corpus callosum (CC), cortico-spinal tract, inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculus, and left uncinate fasciculus. Neurocognitive performance indicated slower processing speed and lower response inhibition skills in SCD patients compared to controls. TSA abnormalities in the CC were significantly associated with measures of processing speed, working memory, and executive functions., Conclusion: Decreased DTI-derived metrics were observed on six tracts in chronically anemic patients, regardless of anemia subtype, while two tracks with decreased measures were unique to SCD patients. Patients with WMHs had more significant FA abnormalities. Decreased FA values in the CC significantly correlated with all nine neurocognitive tests, suggesting a critical importance for CC in core neurocognitive processes., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT)., Methods: Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social-emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined., Results: The z-score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = -0.82 to -0.91) and higher FA in the thalamus (R = 0.73-0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82)., Conclusions: Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores., (© 2020 Wiley Periodicals LLC.)

Background: Obstructive sleep apnea and nocturnal oxygen desaturations, which are prevalent in sickle cell disease (SCD) and chronic anemia disorders, have been linked to risks of stroke and silent cerebral infarcts (SCI). Cerebrovascular response to intermittent desaturations has not been well studied and may identify patients at greatest risk., Purpose: To investigate the cerebral dynamic response to induced desaturation in SCD patients with and without SCI, chronic anemia, and healthy subjects., Study Type: Prospective., Subjects: Twenty-six SCD patients (age = 21 ± 8.2, female 46.2%), including 15 subjects without SCI and nine subjects with SCI, 15 nonsickle anemic patients (age = 22 ± 5.8, female 66.7%), and 31 controls (age = 28 ± 12.3, female 77.4%)., Field Strength/sequence: 3T, gradient-echo echo-planar imaging., Assessment: A transient hypoxia challenge of five breaths of 100% nitrogen gas was performed with blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS) acquisitions. Hypoxia responses were characterized by desaturation depth, time-to-peak, return-to-baseline half-life, and posthypoxia recovery in the BOLD and NIRS time courses. SCI were documented by T 2 fluid-attenuation inversion recovery (FLAIR)., Statistical Tests: Univariate and multivariate regressions were performed between hypoxic parameters and anemia predictors. Voxelwise two-sample t-statistic maps were used to assess the regional difference in hypoxic responses between anemic and control groups., Results: Compared to controls, SCD and chronically anemic patients demonstrated significantly higher desaturation depth (P < 0.01) and shorter return-to-baseline timing response (P < 0.01). Patients having SCI had shorter time-to-peak (P < 0.01), return-to-baseline (P < 0.01), and larger desaturation depth (P < 0.01) in both white matter regions at risk and normal-appearing white matter than patients without infarcts. On multivariate analysis, desaturation depth and timing varied with age, sex, blood flow, white blood cells, and cell-free hemoglobin (r 2 = 0.25 for desaturation depth; r 2 = 0.18 for time-to-peak; r 2 = 0.37 for return-to-baseline)., Data Conclusion: Transient hypoxia revealed global and regional response differences between anemic and healthy subjects. SCI was associated with extensive heterogeneity of desaturation dynamics, consistent with extensive underlying microvascular remodeling., (© 2020 International Society for Magnetic Resonance in Medicine.)

The neurocranium changes rapidly in early childhood to accommodate the growing brain. Developmental disorders and environmental factors such as sleep position may lead to abnormal neurocranial maturation. Therefore, it is important to understand how this structure develops, in order to provide a baseline for early detection of anomalies. However, its anatomy has not yet been well studied in early childhood due to the lack of available imaging databases. In hospitals, CT is typically used to image the neurocranium when a pathology is suspected, but the presence of ionizing radiation makes it harder to construct databases of healthy subjects. In this study, instead, we use a dataset of MRI data from healthy normal children in the age range of 6 months to 36 months to study the development of the neurocranium. After extracting its outline from the MRI data, we used a conformal geometry-based analysis pipeline to detect local thickness growth throughout this age span. These changes will help us understand cranial bone development with respect to the brain, as well as detect abnormal variations, which will in turn inform better treatment strategies for implicated disorders.

H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments., Competing Interests: Declaration of Interests J.B.S. and Z.B. declare the following competing financial interest(s): both are current employees of AbbVie. The small-molecule WT-IDH1 inhibitors were provided by AbbVie after a material transfer agreement. AbbVie participated in the interpretation of inhibitor data, review, and approval of the publication. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To assess differences in regional brain temperatures during whole-body hypothermia and test the hypothesis that brain temperature profile is nonhomogenous in infants with hypoxic-ischemic encephalopathy., Study Design: Infants with hypoxic-ischemic encephalopathy were enrolled prospectively in this observational study. Magnetic resonance (MR) spectra of basal ganglia, thalamus, cortical gray matter, and white matter (WM) were acquired during therapeutic hypothermia. Regional brain tissue temperatures were calculated from the chemical shift difference between water signal and metabolites in the MR spectra after performing calibration measurements. Overall difference in regional temperature was analyzed by mixed-effects model; temperature among different patterns and severity of injury on MR imaging also was analyzed. Correlation between temperature and depth of brain structure was analyzed using repeated-measures correlation., Results: In total, 53 infants were enrolled (31 girls, mean gestational age: 38.6 ± 2 weeks; mean birth weight: 3243 ± 613 g). MR spectroscopy was acquired at mean age of 2.2 ± 0.6 days. A total of 201 MR spectra were included in the analysis. The thalamus, the deepest structure (36.4 ± 2.3 mm from skull surface), was lowest in temperature (33.2 ± 0.8°C, compared with basal ganglia: 33.5 ± 0.9°C; gray matter: 33.6 ± 0.7°C; WM: 33.8 ± 0.9°C, all P < .001). Temperatures in more superficial gray matter and WM regions (depth: 21.9 ± 2.4 and 21.5 ± 2.2 mm) were greater than the rectal temperatures (33.4 ± 0.4°C, P < .03). There was a negative correlation between temperature and depth of brain structure (r rm  = -0.36, P < .001)., Conclusions: Whole-body hypothermia was effective in cooling deep brain structures, whereas superficial structures were warmer, with temperatures significantly greater than rectal temperatures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Primary diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare tumors, recently recognized as a unique entity based on their unique pathologic and clinical characteristics. We report three cases of DLGNT and compare their clinical characteristics and presentation with other reported cases, and with primary leptomeningeal gliomatosis. Because their prognosis is better than that of diffuse leptomeningeal gliomatosis, and pathologic diagnosis may be difficult, clinicians should consider this diagnosis in patients who present with new neurological symptoms, hydrocephalus and diffuse leptomeningeal enhancement on MRI. Further studies are required to better understand the unique biological characteristics of these tumors and to improve therapy.

Purpose: To determine the significance of large tumour size as a criteria for classifying advanced intraocular retinoblastoma, analysing rates of globe survival and high-risk (HE) histopathologic features., Methods: Retrospective chart review of 212 eyes diagnosed with Group D (111 eyes) or Group E (101 eyes) retinoblastoma in at least one eye from January 1, 2006 to December 31, 2016 using the Los Angeles (LA) Classification System (no tumour size criteria for Group E). The 111 Group D tumours were then reclassified to Group E using 10, 12, 14, 16, 18 mm tumour size criteria, as determined by ultrasound or magnetic resonance imaging dimensions., Results: For eyes in the original LA classification, 66.7% of Group D and 10.5% of Group E eyes undergoing globe preservation therapy avoided enucleation or radiotherapy (p < 0.0001; median follow-up of 33.0 months). In the LA classification, 8.5% of Group D and 26.3% of Group E enucleated globes had HE histopathologic features (p = 0.0065). When Group D eyes with tumours meeting the size criteria were reclassified to Group E, 65.7-74.4% of Group D and 16.1-36.7% of Group E eyes avoided enucleation or radiotherapy. Applying the tumour size criteria, 0-10.9% of Group D and 20.7-23.8% of Group E eyes had HE histopathologic features., Conclusion: Our retrospective analysis suggests that a large tumour size criteria for Group E retinoblastoma have no clinical basis, given that the LA classification system provided the greatest separation in globe salvage rates between Group D and E eyes. The LA classification system was also able to show a statistically significant difference in the rates of HE histopathologic features between Group D and E eyes. To avoid discrepancies in the literature, we recommend that centres use one uniform system for classifying advanced intraocular retinoblastoma., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background and Purpose: Diffuse midline gliomas with histone H3 K27M mutation are biologically aggressive tumors with poor prognosis defined as a new diagnostic entity in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. There are no qualitative imaging differences (enhancement, border, or central necrosis) between histone H3 wildtype and H3 K27M-mutant diffuse midline gliomas. Herein, we evaluated the utility of diffusion-weighted imaging to distinguish H3 K27M-mutant from histone H3 wildtype diffuse midline gliomas., Materials and Methods: We identified 31 pediatric patients (younger than 21 years of age) with diffuse gliomas centered in midline structures that had undergone assessment for histone H3 K27M mutation. We measured ADC within these tumors using a voxel-based 3D whole-tumor measurement method., Results: Our cohort included 18 infratentorial and 13 supratentorial diffuse gliomas centered in midline structures. Twenty-three (74%) tumors carried H3-K27M mutations. There was no difference in ADC histogram parameters (mean, median, minimum, maximum, percentiles) between mutant and wild-type tumors. Subgroup analysis based on tumor location also did not identify a difference in histogram descriptive statistics. Patients who survived <1 year after diagnosis had lower median ADC (1.10 × 10 -3 mm 2 /s; 95% CI, 0.90-1.30) compared with patients who survived >1 year (1.46 × 10 -3 mm 2 /s; 95% CI, 1.19-1.67; P < .06). Average ADC values for diffuse midline gliomas were 1.28 × 10 -3 mm 2 /s (95% CI, 1.21-1.34) and 0.86 × 10 -3 mm 2 /s (95% CI, 0.69-1.01) for hemispheric glioblastomas with P < .05., Conclusions: Although no statistically significant difference in diffusion characteristics was found between H3-K27M mutant and H3 wildtype diffuse midline gliomas, lower diffusivity corresponds to a lower survival rate at 1 year after diagnosis. These findings can have an impact on the anticipated clinical course for this patient population and offer providers and families guidance on clinical outcomes., (© 2019 by American Journal of Neuroradiology.)

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are newly recognized as an entity in the 2016 revision of the WHO Classification of tumors of the central nervous system. They typically present as diffuse leptomeningeal infiltrates along the neuraxis with focal and superficial involvement of the parenchyma. Here, we report a DLGNT with unusual radiological and histological features. A 13-year-old girl presented with scoliosis and back pain. Magnetic resonance imaging demonstrated a syrinx from C2 to T11 and an intramedullary mass from T6 to T9-10. No leptomeningeal involvement was recognized. Histological examination of the gross total resection specimen revealed a low-grade neuroepithelial neoplasm predominantly infiltrating the spinal cord and only focally involving the leptomeninges. Chromosome microarray identified co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19 as well as fusion of the KIAA1549 and BRAF genes. Next-generation sequencing demonstrated wild-type alleles at the mutational hotspots of IDH1 (R132) and IDH2 (R140 and R172). In contrast to most reported DLGNTs, the tumor described in this manuscript was characterized by a predominant parenchymal component and only minor leptomeningeal involvement both radiographically and histologically. Our case, therefore, expands the spectrum of radiological and histopathological features of this new entity. It also highlights the critical role of molecular genetic testing in establishing the diagnosis of DLGNT in unusual cases.

Background: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients., Methods: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAF V600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m 2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101., Findings: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported., Interpretation: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1., Funding: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Study Design: Diagnostic accuracy., Objective: The purpose of this study was to determine if neural axis abnormalities in early onset scoliosis (EOS) patients can be reliably detected with limited magnetic resonance imaging (MRI) sequences (sagittal T1, sagittal T2)., Summary of Background Data: MRIs are often performed in EOS patients as studies have shown there are neural axis abnormalities in up to 40% of this population. MRIs are expensive, lengthy, and often require general anesthesia. In young children prolonged or repeated exposure to general anesthesia may be associated with neurocognitive damage., Methods: A retrospective review of consecutive EOS patients from February to December 2017 who received an MRI of the cervical, thoracic, and lumbar spine was conducted. MRI images were reviewed for neural axis abnormalities. Two sequences (sagittal T1, sagittal T2) of these previously reviewed MRIs were read at a separate time by an attending pediatric neuroradiologist. The imaging findings from these two select sequences were then compared with the prior radiology report based on all of the standard MRI sequences., Results: Fifty patients met criteria. Ten patients (20%) had neural axis abnormalities detected by the full MRI. All of these neural axis abnormalities were detected on the combination of sagittal T1 + sagittal T2 images. Standard MRIs lasted 66 ± 20 minutes and patients required 90 ± 22 minutes of anesthesia. Sagittal T1 + sagittal T2 sequences lasted 21 ± 7 minutes (P < 0.0001)., Conclusion: Limited sequence MRIs with sagittal T1 and T2 sequences for EOS patients had 100% sensitivity for the detection of neural axis abnormalities and would allow for a 68% reduction in the length of MRI and significant reduction in anesthesia time., Level of Evidence: 3.

Background and Purpose: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors., Materials and Methods: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples., Results: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression ( P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine ( P < .05) and myo-inositol ( P < .05) concentrations., Conclusions: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies., (© 2019 by American Journal of Neuroradiology.)

Although modern medical management has lowered overt stroke occurrence in patients with sickle cell disease (SCD), progressive white matter (WM) damage remains common. It is known that cerebral blood flow (CBF) increases to compensate for anemia, but sufficiency of cerebral oxygen delivery, especially in the WM, has not been systematically investigated. Cerebral perfusion was measured by arterial spin labeling in 32 SCD patients (age range: 10-42 years old, 14 males, 7 with HbSC, 25 HbSS) and 25 age and race-matched healthy controls (age range: 15-45 years old, 10 males, 12 with HbAS, 13 HbAA); 8/24 SCD patients were receiving regular blood transfusions and 14/24 non-transfused SCD patients were taking hydroxyurea. Imaging data from control subjects were used to calculate maps for CBF and oxygen delivery in SCD patients and their T-score maps. Whole brain CBF was increased in SCD patients with a mean T-score of 0.5 and correlated with lactate dehydrogenase (r 2  = 0.58, P < 0.0001). When corrected for oxygen content and arterial saturation, whole brain and gray matter (GM) oxygen delivery were normal in SCD, but WM oxygen delivery was 35% lower than in controls. Age and hematocrit were the strongest predictors for WM CBF and oxygen delivery in patients with SCD. There was spatial co-localization between regions of low oxygen delivery and WM hyperintensities on T2 FLAIR imaging. To conclude, oxygen delivery is preserved in the GM of SCD patients, but is decreased throughout the WM, particularly in areas prone to WM silent strokes., (© 2019 Wiley Periodicals, Inc.)