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Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression. [ABSTRACT FROM AUTHOR]

Background: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown., Methods: Adult survivors of childhood medulloblastoma (n = 505; median [minimum-maximum] age, 29 [18-46] years) and sibling controls (n = 727; 32 [18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), standard-risk (CSI > 0 to <30 Gy + chemotherapy) and high-risk (CSI ≥ 30 Gy + chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, and marital/partner status. Multivariable models estimated the risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence., Results: Survivors in each treatment exposure group had a 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had a higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems, and seizures were associated with 33-34%, 25-26%, and 21-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with nonindependence., Conclusions: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative., (© 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.)

Since April 2024, sporadic infections with highly pathogenic avian influenza (HPAI) A(H5) viruses have been detected among dairy farm workers in the United States. To date, infections have mostly been detected through worker monitoring, and have been mild despite the possibility of more severe illness. During June-August 2024, CDC collaborated with the Michigan Department of Health and Human Services and the Colorado Department of Public Health and Environment to implement cross-sectional serologic surveys to ascertain the prevalence of recent infection with HPAI A(H5) virus among dairy workers. In both states, a convenience sample of persons who work in dairies was interviewed, and blood specimens were collected. Among 115 persons, eight (7%; 95% CI = 3.6%-13.1%) had serologic evidence of recent infection with A(H5) virus; all reported milking cows or cleaning the milking parlor. Among persons with serologic evidence of infection, four recalled being ill around the time cows were ill; symptoms began before or within a few days of A(H5) virus detections among cows. This finding supports the need to identify and implement strategies to prevent transmission among dairy cattle to reduce worker exposures and for education and outreach to dairy workers concerning prevention, symptoms, and where to seek medical care if the workers develop symptoms. Timely identification of infected herds can support rapid initiation of monitoring, testing, and treatment for human illness, including mild illness, among exposed dairy workers., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome characterized by the development of both central and peripheral nervous system tumors. Low-grade glioma (LGG) is the most prevalent central nervous system tumor occurring in children with NF1, arising most frequently within the optic pathway, followed by the brainstem. Historically, treatment of NF1-LGG has been limited to conventional cytotoxic chemotherapy and surgery. Despite treatment with chemotherapy, a subset of children with NF1-LGG fail initial therapy, have a continued decline in function, or recur. The recent development of several preclinical models has allowed for the identification of novel, molecularly targeted therapies. At present, exploration of these novel precision-based therapies is ongoing in the preclinical setting and through larger, collaborative clinical trials. Herein, we review the approach to surveillance and management of NF1-LGG in children and discuss upcoming novel therapies and treatment protocols., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

Competing Interests: This publication was supported by an institutional Clinical and Translational Science Award, National Institutes of Health/National Center for Advancing Translational Sciences (grant 1UL1TR001425) through the University of Cincinnati. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. This work was additionally supported by divisional funding from the Heart Institute, Cincinnati Children’s Hospital Medical Center. This work was completed in partial fulfillment of the Master of Science degree in Clinical and Translational Research in the Division of Epidemiology, University of Cincinnati College of Medicine. Dr Hill serves as a consultant for Ultragenyx. Dr De Blank has served as an Advisory Board member for Alexion Pharmaceuticals for selumetinib. Dr Kumar serves as a consultant for Sobi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Medulloblastoma (MB) is the most frequent malignant brain tumor in children with extensive heterogeneity that results in varied clinical outcomes. Recently, MB was categorized into four molecular subgroups, WNT, SHH, Group 3, and Group 4. While SHH and Group 4 are known for their intermediate prognosis, studies have reported wide disparities in patient outcomes within these subgroups. This study aims to create a radiomic prognostic signature, medulloblastoma radiomics risk (mRRisk), to identify the risk levels within the SHH and Group 4 subgroups, individually, for reliable risk stratification. Our hypothesis is that this signature can comprehensively capture tumor characteristics that enable the accurate identification of the risk level. In total, 70 MB studies (48 Group 4, and 22 SHH) were retrospectively curated from three institutions. For each subgroup, 232 hand-crafted features that capture the entropy, surface changes, and contour characteristics of the tumor were extracted. Features were concatenated and fed into regression models for risk stratification. Contrasted with Chang stratification that did not yield any significant differences within subgroups, significant differences were observed between two risk groups in Group 4 ( p = 0.04, Concordance Index (CI) = 0.82) on the cystic core and non-enhancing tumor, and SHH ( p = 0.03, CI = 0.74) on the enhancing tumor. Our results indicate that radiomics may serve as a prognostic tool for refining MB risk stratification, towards improved patient care.

Pediatric tumors of the central nervous system are the most common cause of cancer-related death in children. The five-year survival rate for high-grade gliomas in children is less than 20%. Due to their rarity, the diagnosis of these entities is often delayed, their treatment is mainly based on historic treatment concepts, and clinical trials require multi-institutional collaborations. The MICCAI Brain Tumor Segmentation (BraTS) Challenge is a landmark community benchmark event with a successful history of 12 years of resource creation for the segmentation and analysis of adult glioma. Here we present the CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge, which represents the first BraTS challenge focused on pediatric brain tumors with data acquired across multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. The BraTS-PEDs 2023 challenge focuses on benchmarking the development of volumentric segmentation algorithms for pediatric brain glioma through standardized quantitative performance evaluation metrics utilized across the BraTS 2023 cluster of challenges. Models gaining knowledge from the BraTS-PEDs multi-parametric structural MRI (mpMRI) training data will be evaluated on separate validation and unseen test mpMRI dataof high-grade pediatric glioma. The CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge brings together clinicians and AI/imaging scientists to lead to faster development of automated segmentation techniques that could benefit clinical trials, and ultimately the care of children with brain tumors.

Background: This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma., Methods: This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at 3 dose levels (DLs; -1, 1, and 2). The actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator., Results: Twelve patients received D1D2 ONC201 (DL1, n = 3; DL1, n = 3; DL2, n = 6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250 mg, n = 3; D1-625 mg, n = 3; D1D2-250 mg, n = 2; D1D2-625 mg, n = 2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly., Conclusions: ONC201 given D1D2 was well tolerated at all DLs and associated with greater AUC0-48., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Within the last few decades, we have witnessed tremendous advancements in the study of pediatric low-grade gliomas (pLGG), leading to a much-improved understanding of their molecular underpinnings. Consequently, we have achieved successful milestones in developing and implementing targeted therapeutic agents for treating these tumors. However, the community continues to face many unknowns when it comes to the most effective clinical implementation of these novel targeted inhibitors or combinations thereof. Questions encompassing optimal dosing strategies, treatment duration, methods for assessing clinical efficacy, and the identification of predictive biomarkers remain unresolved. Here, we offer the consensus of the international pLGG coalition (iPLGGc) clinical trial working group on these important topics and comment on clinical trial design and endpoint rationale. Throughout, we seek to standardize the global approach to early clinical trials (phase I and II) for pLGG, leading to more consistently interpretable results as well as enhancing the pace of novel therapy development and encouraging an increased focus on functional endpoints as well and quality of life for children faced with this disease., (© The Author(s) 2023. 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.)

Background: Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown., Methods: Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided., Results: Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory., Conclusion: Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Evidence for myelin regulating higher-order brain function and disease is rapidly accumulating; however, defining cellular/molecular mechanisms remains challenging partially due to the dynamic brain physiology involving deep changes during development, aging, and in response to learning and disease. Furthermore, as the etiology of most neurological conditions remains obscure, most research models focus on mimicking symptoms, which limits understanding of their molecular onset and progression. Studying diseases caused by single gene mutations represents an opportunity to understand brain dys/function, including those regulated by myelin. Here, we discuss known and potential repercussions of abnormal central myelin on the neuropathophysiology of Neurofibromatosis Type 1 (NF1). Most patients with this monogenic disease present with neurological symptoms diverse in kind, severity, and onset/decline, including learning disabilities, autism spectrum disorders, attention deficit and hyperactivity disorder, motor coordination issues, and increased risk for depression and dementia. Coincidentally, most NF1 patients show diverse white matter/myelin abnormalities. Although myelin-behavior links were proposed decades ago, no solid data can prove or refute this idea yet. A recent upsurge in myelin biology understanding and research/therapeutic tools provides opportunities to address this debate. As precision medicine moves forward, an integrative understanding of all cell types disrupted in neurological conditions becomes a priority. Hence, this review aims to serve as a bridge between fundamental cellular/molecular myelin biology and clinical research in NF1., (© 2023 Wiley Periodicals LLC.)

Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas. This article details methods used for testing in preclinical models, and outlines newer models that may identify additional, curative, strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Recent advances in artificial intelligence have greatly impacted the field of medical imaging and vastly improved the development of computational algorithms for data analysis. In the field of pediatric neuro-oncology, radiomics, the process of obtaining high-dimensional data from radiographic images, has been recently utilized in applications including survival prognostication, molecular classification, and tumor type classification. Similarly, radiogenomics, or the integration of radiomic and genomic data, has allowed for building comprehensive computational models to better understand disease etiology. While there exist excellent review articles on radiomics and radiogenomic pipelines and their applications in adult solid tumors, in this review article, we specifically review these computational approaches in the context of pediatric medulloblastoma tumors. Based on our systematic literature research via PubMed and Google Scholar, we provide a detailed summary of a total of 15 articles that have utilized radiomic and radiogenomic analysis for survival prognostication, tumor segmentation, and molecular subgroup classification in the context of pediatric medulloblastoma. Lastly, we shed light on the current challenges with the existing approaches as well as future directions and opportunities with using these computational radiomic and radiogenomic approaches for pediatric medulloblastoma tumors.

Background: Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions., Methods: Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated FASI at Cincinnati Children's Hospital Medical Center. Paired bidirectional measurements were compared over time using nonparametric tests., Results: Sixteen age-matched pairs were assessed (age range: 2.8-16.9 years, 60% male). Initial FASI burden was not different between groups (median range 138.7 cm 2 [88.4-182.0] for the treated subjects vs. 121.6 cm 2 [79.6-181.9] for the untreated subjects; p = 0.98). Over a mean follow-up of 18.9 (±5.9) months, the LGG size consistently decreased with treatment while no consistent change among the treated or untreated FASI size was seen. At the paired time points, the median treated LGG decreased significantly more than the treated FASI (-41.3% (LGG) versus -10.7% (FASI), p = 0.006). However, there was no difference in the median size change in the treated versus untreated FASI (-10.7% (treated FASI) versus -17.9% (untreated FASI), p = 0.08). Among the treated subjects, there was no correlation between the change in LGG and FASI (r = -0.04, p = 0.88)., Conclusions: Treatment with selumetinib did not affect the overall FASI size in children with NF1 treated for progressive low-grade glioma.

Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.

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.)

Medulloblastoma (MB) is the most common malignant childhood brain tumour 1,2 , yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella 3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.)

Background: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG., Methods: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression., Results: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations., Conclusions: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG., (© 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.)

Background: Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure., Methods: We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse., Results: Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment., Conclusion: Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies., (© 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.)

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG., Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed., Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression., Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m 2 and everolimus 1.5 mg/m 2 . Results will inform a molecularly guided phase II study underway to evaluate efficacy., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs., Methods: Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data., Results: Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death., Conclusions: Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Purpose: Neurofibromatosis type 1 (NF1) is associated with tumor predisposition and nonmalignant health conditions. Whether survivors of childhood cancer with NF1 are at increased risk for poor long-term health outcomes is unknown., Methods: One hundred forty-seven 5+ year survivors of childhood glioma with NF1 from the Childhood Cancer Survivor Study were compared with 2629 non-NF1 glioma survivors and 5051 siblings for late mortality, chronic health conditions, and psychosocial, neurocognitive, and socioeconomic outcomes., Results: Survivors with NF1 (age at diagnosis: 6.8 ± 4.8 years) had greater cumulative incidence of late mortality 30 years after diagnosis (46.3% [95% confidence interval: 23.9-62.2%]) compared with non-NF1 survivors (18.0% [16.1-20.0%]) and siblings (0.9% [0.6-1.2%]), largely due to subsequent neoplasms. Compared with survivors without NF1, those with NF1 had more severe/life-threatening chronic conditions at cohort entry (46.3% [38.1-54.4%] vs. 30.8% [29.1-32.6%]), but similar rates of new conditions during follow-up (rate ratio: 1.26 [0.90-1.77]). Survivors with NF1 were more likely to report psychosocial impairments, neurocognitive deficits, and socioeconomic difficulties compared with survivors without NF1., Conclusions: Late mortality among glioma survivors with NF1 is twice that of other survivors, due largely to subsequent malignancies. Screening, prevention, and early intervention for chronic health conditions and psychosocial and neurocognitive deficits may reduce long-term morbidity in this vulnerable population.

Introduction: Recently discovered molecular alterations in pediatric low-grade glioma have helped to refine the classification of these tumors and offered novel targets for therapy. Genetic aberrations may combine with histopathology to offer new insights into glioma classification, gliomagenesis and prognosis. Therapies targeting common genetic aberrations in the MAPK pathway offer a novel mechanism of tumor control that is currently under study., Methods: We have reviewed common molecular alterations found in pediatric low-grade glioma as well as recent clinical trials of MEK and BRAF inhibitors., Results: In this topic review, we examine the current understanding of molecular alterations in pediatric low-grade glioma, as well as their role in diagnosis, prognosis and therapy. We summarize current data on the efficacy of targeted therapies in pediatric low-grade gliomas, as well as the many unanswered questions that these new discoveries and therapies raise., Conclusions: The identification of driver alterations in pediatric low-grade glioma and the development of targeted therapies have opened new therapeutic avenues for patients with low-grade gliomas.

Purpose: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients., Methods: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m 2 ; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively., Results: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ ., Conclusions: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies., Trial Registration: NCT02607124.

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology 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 consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose of Review: Pediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors., Recent Findings: It is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities., Summary: Novel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.

Introduction: Fractional anisotropy (FA) of the optic radiations has been associated with vision deficit in multiple intrinsic brain pathologies including NF1 associated optic pathway glioma, but hand-drawn regions of interest used in previous tractography methods limit consistency of this potential biomarker. We created an automated method to identify white matter tracts in the optic radiations and compared this method to previously reported hand-drawn tractography., Method: Automated tractography of the optic radiation using probabilistic streamline fiber tracking between the lateral geniculate nucleus of the thalamus and the occipital cortex was compared to the hand-drawn method between regions of interest posterior to Meyer's loop and anterior to tract branching near the calcarine cortex. Reliability was assessed by two independent raters in a sample of 20 healthy child controls. Among 50 children with NF1-associated optic pathway glioma, the association of FA and visual acuity deficit was compared for both tractography methods., Results: Hand-drawn tractography methods required 2.6±0.9min/participant; automated methods were performed in <1min of operator time for all participants. Cronbach's alpha was 0.83 between two independent raters for FA in hand-drawn tractography, but repeated automated tractography resulted in identical FA values (Cronbach's alpha=1). On univariate and multivariate analyses, FA was similarly associated with visual acuity loss using both methods. Receiver operator characteristic curves of both multivariate models demonstrated that both automated and hand-drawn tractography methods were equally able to distinguish normal from abnormal visual acuity., Conclusion: Automated tractography of the optic radiations offers a fast, reliable and consistent method of tract identification that is not reliant on operator time or expertise. This method of tract identification may be useful as DTI is developed as a potential biomarker for visual acuity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Population-based data examining recent epidemiological trends in medulloblastoma, the most common pediatric brain malignancy, are limited. Therefore, we sought to examine recent population-level trends in medulloblastoma incidence and survival. Central Brain Tumor Registry of the United States (CBTRUS) data were analyzed from 2001 to 2013. Age-adjusted incidence rates (IR) and annual percent changes (APCs) with 95% confidence intervals (CI) were calculated by age, sex, and race. Relative survival rates were calculated by age, sex, and race using Surveillance, Epidemiology and End-Results (SEER) registries; subsets of CBTRUS data. Kaplan-Meier and Cox proportional hazards models were used to examine survival differences. Medulloblastoma incidence remained relatively stable from 2001 to 2013, with minor fluctuations from 2001 to 2009 (APC = 2.2, 95% CI 0.8, 3.5) and 2009-2013 (APC = -4.1, 95% CI -7.5, -0.6). Incidence was highest in patients aged 1-4 years at diagnosis, but patients aged 10-14 years showed increased incidence from 2000 to 2013 (APC = 3.2, 95% CI 0.6, 5.8). Males displayed higher IR relative to females (males: 0.16 vs. females: 0.12), except in patients <1 year-old. Compared to Whites, Blacks displayed a non-significant increase in incidence (APC = 1.7, 95% CI -0.4, 4.0) and in mortality risk (hazard ratio for survival = 0.74; p = 0.09). The current study reports no overall change in medulloblastoma incidence from 2001 to 2013. Male and female patients <1 year-old had equal medulloblastoma incidence rates and poor 5-year relative survival compared to other ages. Non-significant trends in the data suggest disparities in medulloblastoma incidence and survival by race. Thus, analysis of tumor-specific trends by demographic variables can uncover clinically informative trends in cancer burden.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1), leading to visual deficits in fewer than half of these individuals. The goal of chemotherapy is to preserve vision, but vision loss in NF1-associated OPG can be unpredictable. Determining which child would benefit from chemotherapy and, equally important, which child is better observed without treatment can be difficult. Unfortunately, despite frequent imaging and ophthalmologic evaluations, some children experience progressive vision loss before treatment. Indications for chemotherapy usually are based on a comprehensive, quantitative assessment of vision, but reliable vision evaluation can be challenging in young children with NF1-OPG. The ability to identify and predict impending vision loss could potentially improve management decisions and visual outcomes. To address this challenge, ophthalmologic, electrophysiologic, and imaging biomarkers of vision in NF1-OPG have been proposed. We review current recommendations for the surveillance of children at risk for NF1-OPG, outline guidelines for initiating therapy, and describe the utility of proposed biomarkers for vision.

Choroid plexus tumors (CPT) are rare neoplasms accounting for 1-4% of all pediatric brain tumors. They are divided into choroid plexus papilloma (CPP), atypical choroid plexus papilloma (APP) and choroid plexus carcinoma (CPC). CPTs are known to primarily affect children less than 2 years of age. Gross total resection is the most important predictor of survival especially in CPC. Although small case series have been published, limited clinical data are available to describe treatment and outcome of CPTs. More clinical data would be necessary to complete the picture, particularly in populations that are not age limited. Here we share data from the two major hospitals in Cleveland to describe treatment and outcome of adult and pediatric patients. We performed a retrospective analysis of patients with CPT seen in Cleveland Clinic from 1990 to 2015 and at University Hospitals from 1994 to 2015. Results were compared to previously published historical controls. We identified 30 cases with CPT, including 22 pediatric and eight adult cases; 11 females and 19 males. The mean age at presentation was 12.4 years with a median age of 4.5 years (range 2 months-51 years). Gross total surgical resection was achieved in 22, subtotal resection in four, partial resection in two and unknown in two. The histology was CPP in 23 patients, two of whom developed recurrence requiring repeat resection and adjuvant therapy. Median event free survival (EFS) for CPP patients was 7.6 years. The histology was CPC in seven patients. All CPC patients were treated with adjuvant therapy. Median EFS of CPC patients was 4.4 years. Overall survival of all CPT patients was 100% with a median follow up of 7 years. A systematic literature review identified 1012 CPT patients treated from 1989 to 2013. The mean and median age of CPT patients was 13 and 3 years respectively. The median survival of 541 CPP patients was undefined vs. 2.7 years for the 452 CPC patients. The difference between the two populations was highly significant (p < 0.001). Kaplan-Meier survival curves comparing CPTs at Cleveland Clinic and University Hospitals versus a systematic literature review showed a statistically significant advancement in overall survival among the patients treated at Cleveland Clinic and University Hospitals. Our data are consistent with the literature review regarding epidemiology, clinical presentation, and treatment modalities but differed in regards to survival. Differences in survival may be related to different methods of data collection or details in patient care.

Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials., (© 2016 American Academy of Neurology.)

The correct treatment of diabetes is vital to a patient's health: Staying within defined blood glucose levels prevents dangerous short- and long-term effects on the body. Mobile devices informing patients about their future blood glucose levels could enable them to take counter-measures to prevent hypo or hyper periods. Previous work addressed this challenge by predicting the blood glucose levels using regression models. However, these approaches required a physiological model, representing the human body's response to insulin and glucose intake, or are not directly applicable to mobile platforms (smart phones, tablets). In this paper, we propose an algorithm for mobile platforms to predict blood glucose levels without the need for a physiological model. Using an online software simulator program, we trained a Support Vector Regression (SVR) model and exported the parameter settings to our mobile platform. The prediction accuracy of our mobile platform was evaluated with pre-recorded data of a type 1 diabetes patient. The blood glucose level was predicted with an error of 19 % compared to the true value. Considering the permitted error of commercially used devices of 15 %, our algorithm is the basis for further development of mobile prediction algorithms.

Background: Children with neurofibromatosis type 1 (NF1) are predisposed to both brain tumors and cognitive deficits. While changes in white matter integrity after multimodal therapy are associated with cognitive dysfunction, the effect of isolated chemotherapy in NF1 is unknown. To determine whether chemotherapy is associated with white matter microstructural changes, we examined diffusion tensor imaging (DTI) in NF1 subjects., Procedure: We reviewed DTI measures in tracts associated with cognition but free from tumor in 24 children with NF1-associated optic pathway gliomas unexposed to surgery or radiation. Twelve age-matched pairs were identified based on exposure to chemotherapy. A paired t-test was used to compare fractional anisotropy (FA) in tracts of interest between subjects with and without chemotherapy exposure., Results: On paired t-test, FA was significantly lower in the corpus callosum (P = 0.015) and cerebellothalamic (P = 0.038) tracts of subjects exposed to chemotherapy. There was no effect of age or time from chemotherapy on the difference between groups. In multivariable analysis, FA of these tracts was associated with chemotherapy exposure after adjusting for age, tumor location, and DTI acquisition. In longitudinal measures, FA decreased after chemotherapy exposure while FA increased with age in unexposed subjects., Conclusions: Exposure to low-intensity chemotherapy in NF1 is associated with changes in white matter microstructure in tracts associated with cognition. Future studies should determine whether these changes are associated with cognitive decline. While chemotherapy may spare cognition relative to radiation and surgery, children with NF1 exposed to chemotherapy may benefit from early cognitive testing to allow for earlier intervention., (© 2016 Wiley Periodicals, Inc.)

Background: The impact of impaired vision on cognitive and psychosocial outcomes among long-term survivors of childhood low-grade gliomas has not been investigated previously but could inform therapeutic decision making., Methods: Data from the Childhood Cancer Survivor Study were used to investigate psychological outcomes (measures of cognitive/emotional function) and socioeconomic outcomes (education, income, employment, marital status, and independent living) among astroglial tumor survivors grouped by 1) vision without impairment, 2) vision with impairment (including unilateral blindness, visual field deficits, and amblyopia), or 3) bilateral blindness. The effect of vision status on outcomes was examined with multivariate logistic regression with adjustments for age, sex, cranial radiation therapy, and medical comorbidities., Results: Among 1233 survivors of childhood astroglial tumors 5 or more years after their diagnosis, 277 (22.5%) had visual impairment. In a multivariate analysis, survivors with bilateral blindness were more likely to be unmarried (adjusted odds ratio (OR), 4.7; 95% confidence interval [CI], 1.5-15.0), live with a caregiver (adjusted OR, 3.1; 95% CI, 1.3-7.5), and be unemployed (adjusted OR, 2.2; 95% CI, 1.1-4.5) in comparison with those without visual impairment. Bilateral blindness had no measurable effect on cognitive or emotional outcomes, and vision with impairment was not significantly associated with any psychological or socioeconomic outcomes., Conclusions: Adult survivors of childhood astroglial tumors with bilateral blindness were more likely to live unmarried and dependently and to be unemployed. Survivors with visual impairment but some remaining vision did not differ significantly with respect to psychological function and socioeconomic status from those without visual impairment. Cancer 2016;122:730-739. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Increased demand and government mandates for bioenergy crops in the United States could require a large allocation of agricultural land to bioenergy feedstock production and substantially alter current landscape patterns. Incorporating bioenergy landscape design into land-use decision making could help maximize benefits and minimize trade-offs among alternative land uses. We developed spatially explicit landscape scenarios of increased bioenergy crop production in an 80-km radius agricultural landscape centered on a potential biomass-processing energy facility and evaluated the consequences of each scenario for bird communities. Our scenarios included conversion of existing annual row crops to perennial bioenergy grasslands and conversion of existing grasslands to annual bioenergy row crops. The scenarios explored combinations of four biomass crop types (three potential grassland crops along a gradient of plant diversity and one annual row crop [corn]), three land conversion percentages to bioenergy crops (10%, 20%, or 30% of row crops or grasslands), and three spatial configurations of biomass crop fields (random, clustered near similar field types, or centered on the processing plant), yielding 36 scenarios. For each scenario, we predicted the impact on four bird community metrics: species richness, total bird density, species of greatest conservation need (SGCN) density, and SGCN hotspots (SGCN birds/ha ≥ 2). Bird community metrics consistently increased with conversion of row crops to bioenergy grasslands and consistently decreased with conversion of grasslands to bioenergy row crops. Spatial arrangement of bioenergy fields had strong effects on the bird community and in some cases was more influential than the amount converted to bioenergy crops. Clustering grasslands had a stronger positive influence on the bird community than locating grasslands near the central plant or at random. Expansion of bioenergy grasslands onto marginal agricultural lands will likely benefit grassland bird populations, and bioenergy landscapes could be designed to maximize biodiversity benefits while meeting targets for biomass production.

Incidence and survival rates are commonly reported statistics, but these may fail to capture the full impact of childhood cancers. We describe the years of potential life lost (YPLL) and years of life lived with disease (YLLD) in children and adolescents who died of cancer in the United States to estimate the impact of childhood cancer in the United States in 2009. We examined mortality data in 2009 among children and adolescents <20 years old in both the National Vital Statistics System (NVSS) and the Surveillance, Epidemiology, and End Results (SEER) datasets. YPLL and YLLD were calculated for all deaths due to cancer. Histology-specific YPLL and YLLD of central nervous system (CNS) tumors, leukemia, and lymphoma were estimated using SEER. There were 2233 deaths and 153,390.4 YPLL due to neoplasm in 2009. CNS tumors were the largest cause of YPLL (31%) among deaths due to cancer and were the cause of 1.4% of YPLL due to all causes. For specific histologies, the greatest mean YPLL per death was due to atypical teratoid/rhabdoid tumor (78.0 years lost). The histology with the highest mean YLLD per death in children and adolescents who died of cancer was primitive neuroectodermal tumor (4.6 years lived). CNS tumors are the most common solid malignancy in individuals <20 years old and have the highest YPLL cost of all cancers. This offers the first histology-specific description of YPLL in children and adolescents and proposes a new measure of cancer impact, YLLD, in individuals who die of their disease. YPLL and YLLD complement traditional indicators of mortality and help place CNS tumors in the context of other childhood malignancies., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Antibiotic exposure is common among children with leukemia. However, limited data exist regarding the risk of Clostridium difficile infection (CDI) across anti-pseudomonal β-lactam antibiotics commonly used for fever and neutropenia., Methods: A multicenter cohort of children with newly diagnosed acute lymphoblastic leukemia (ALL) was established from 43 freestanding children's hospitals from 1999 to 2009. Patients were followed until their index CDI event, defined by the CDI ICD-9 code plus a C difficile test charge, or until 180 days from ALL diagnosis. Cox proportional hazards models were performed to identify the hazards of CDI after exposure to anti-pseudomonal β-lactams, adjusting for demographics, other antibiotic exposures, severity of illness, antacids, gastrointestinal manipulation, and confounding by hospital., Results: A cohort of 8268 ALL patients was assembled; median age was 5.5 years (interquartile range, 3.26-10.58). Two-hundred sixty-eight (3.2%) patients developed CDI within 180 days of ALL diagnosis. Each 1-day increase in exposure to an anti-pseudomonal β-lactam within the prior 30 days was associated with a significantly increased risk for CDI (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.01, 1.09). Ceftazidime (HR, 1.05; 95% CI, 1.02, 1.08) and cefepime (HR, 1.07; 95% CI, 1.02, 1.12) were each independently associated with CDI., Conclusions: Efforts to reduce total exposure to anti-pseudomonal β-lactam agents may help to reduce the risk of CDI in children with newly diagnosed ALL. Cefepime and ceftazidime were independently associated with CDI, whereas anti-pseudomonal penicillins and carbapenems were not. These findings, if confirmed, have potential implications for antibiotic choice during periods of fever and neutropenia., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To study the trend of Clostridium difficile infection (CDI) and risk factors for hospital acquired CDI (HA-CDI) among children with cancer., Study Design: We analyzed 33 095 first pediatric hospitalizations for malignancy among 43 pediatric hospitals between 1999 and 2011. The effect of demographics, disease characteristics, and weekly drug exposure (antibiotics, antacids, and chemotherapy) on HA-CDI was assessed with multivariate Cox regression. CDI was defined by the combination of International Classification of Diseases, 9th edition-Clinical Modification (ICD-9CM), CDI diagnostic assay billing code, and concurrent administration of a CDI-active antibiotic. HA-CDI was defined as CDI with assay occurring after the sixth hospital day., Results: A total of 1736 admissions with CDI were identified, of which 380 were HA-CDI. CDI incidence increased from 1999-2006 (P = .01); however, CDI testing frequency and disease decreased from 2006-2010 (P < .05). Admissions with HA-CDI had longer lengths of stay compared with those without HA-CDI (35 days vs 12 days, P < .01) and greater risk of inpatient mortality (relative risk 2.3, P < .01). Increased risk of HA-CDI (hazard ratio [95% CI]) was seen after exposure to the following drugs: aminoglycoside (1.357 [1.053-1.749]), third generation cephalosporin (1.518 [1.177-1.959]), cefepime (2.383 [1.839-3.089]), and proton pump inhibiting agent (1.398 [1.096-1.784]) in the prior week, and chemotherapy (1.942 [1.491-2.529]) in the 8-14 days prior to HA-CDI onset. Histamine-2 receptor antagonist exposure in the prior week was associated with decreased risk of HA-CDI (0.730 [0.584-0.912])., Conclusions: Despite an apparent decrease in CDI incidence from 2006-2010, HA-CDI remains prevalent and morbid among children with cancer. Recent exposure to chemotherapy, proton pump inhibitor, and certain antibiotics were independent risk factors for HA-CDI., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Maryland's Green Infrastructure (GI) is a network of large, intact natural areas (hubs), interconnected by linear swaths of riparian or upland vegetation (corridors). The GI serves significant ecological functions and provides the bulk of the state's natural support system. This study examined whether the GI as mapped does, in fact, identify Maryland's most ecologically valuable forested lands, using forest interior dwelling birds (hereafter called "forest birds") as bio-indicators. We conducted bird point counts within forest both inside and outside of hubs on Maryland's Eastern Shore. We also collected a wide variety of habitat data. We found that both the condition of a forest and its surrounding landscape influenced the bird communities. On average, forest bird richness was significantly higher within hubs; furthermore, almost all sites with at least five forest bird species present were in hubs. Forest bird richness and abundance were highest in undisturbed, mature broadleaf forest with wetlands and streams nearby. We detected a significant relationship between forest bird richness and the ecological score of a finer-scale landscape assessment, focused on "cells" of about 0.1 ha in size. This field study also validated the Rapid Field Assessment (RFA) protocol developed in 2001 to assess, on the ground, the relative condition of individual sites or properties within the GI. Forest bird richness and abundance were positively correlated with the RFA community scores. Our results underscore the importance of maintaining regional biological diversity by retaining large blocks of forest, especially mature forest containing streams and wetlands.