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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 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.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

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.

Simple Summary: Medulloblastoma (MB) is the most common malignant brain tumor in children and has a dismal prognosis. A challenge with MB is identifying patients who could be candidates for reduced doses of radiation therapy, but are still treated effectively, as well as those that need intensified doses. Recently, MB was classified into four molecular subgroups with distinct clinical outcomes (WNT, SHH, Group 3, and Group 4). Though two of these subgroups (SHH and Group 4) are known for their intermediate prognosis, wide disparities of outcomes have been reported within each of these subgroups. This work aims to develop a prognostic signature using radiomics (computationally derived tumor measurements), acquired on MRI scans, to risk-stratify patients within the SHH and Group 4 subgroups. Our signature includes two key attributes that capture aspects of the disease microenvironment. We believe that our signature will provide a better understanding of the disease's heterogeneity and, hence, develop better personalized treatment plans. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]