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As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

Purpose:Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection.Patients and Methods:Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m2) for 7–10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts.Results:Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9–20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2–17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m2 for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22–53.4).Conclusions:Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.

Pharmacokinetic Data Analysis

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers.

Background Clinicians and machine classifiers reliably diagnose pilocytic astrocytoma (PA) on magnetic resonance imaging (MRI) but less accurately distinguish medulloblastoma (MB) from ependymoma (EP). One strategy is to first rule out the most identifiable diagnosis. Objective To hypothesize a sequential machine-learning classifier could improve diagnostic performance by mimicking a clinician's strategy of excluding PA before distinguishing MB from EP. Methods We extracted 1800 total Image Biomarker Standardization Initiative (IBSI)-based features from T2- and gadolinium-enhanced T1-weighted images in a multinational cohort of 274 MB, 156 PA, and 97 EP. We designed a 2-step sequential classifier - first ruling out PA, and next distinguishing MB from EP. For each step, we selected the best performing model from 6-candidate classifier using a reduced feature set, and measured performance on a holdout test set with the microaveraged F1 score. Results Optimal diagnostic performance was achieved using 2 decision steps, each with its own distinct imaging features and classifier method. A 3-way logistic regression classifier first distinguished PA from non-PA, with T2 uniformity and T1 contrast as the most relevant IBSI features (F1 score 0.8809). A 2-way neural net classifier next distinguished MB from EP, with T2 sphericity and T1 flatness as most relevant (F1 score 0.9189). The combined, sequential classifier was with F1 score 0.9179. Conclusion An MRI-based sequential machine-learning classifiers offer high-performance prediction of pediatric posterior fossa tumors across a large, multinational cohort. Optimization of this model with demographic, clinical, imaging, and molecular predictors could provide significant advantages for family counseling and surgical planning.

Background Longitudinal measurement of tumor burden with magnetic resonance imaging (MRI) is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors. Methods The preoperative and postoperative cohorts were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO (Response Assessment in Pediatric Neuro-Oncology) criteria (AutoRAPNO) was determined. Performance was compared to that of 2 expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared. Results A total of 794 preoperative MRIs from 794 patients and 1003 postoperative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with intraclass correlation coefficients (ICCs) of 0.912 and 0.960 for the 2 preoperative and 0.947 and 0.896 for the 2 postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC = 0.909; Rater 3 ICC = 0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions. Conclusions Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.

Purpose: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. Patients and Methods: Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m2) for 7–10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. Results: Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9–20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2–17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m2 for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22–53.4). Conclusions: Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.

BackgroundCraniopharyngiomas account for approximately 1.2–4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function.MethodsThe Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, nineteen patients (median age at enrollment, 13.1 y; range, 2–25 y) were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2).ResultsEighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 wk). Therapy was well tolerated with no grade 4 or 5 toxicities. 2 of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than 3 months. None of the 11 stratum 2 patients had an objective radiographic response, although median progression-free survival was 19.5 months.ConclusionsPegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression-free survival results are encouraging, warranting further studies.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[

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.

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging, different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [18F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [18F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine. The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible.

Brainstem necrosis is a rare, but dreaded complication of radiation therapy; however, data on the incidence of brainstem injury for tumors involving the posterior fossa in photon-treated patient cohorts are still needed.Clinical characteristics and dosimetric parameters were recorded for 107 pediatric patients who received photon radiation for posterior fossa tumors without brainstem involvement from 2000 to 2016. Patients were excluded if they received a prescription dose50.4 Gy, a brainstem maximum dose50.4 Gy, or had fewer than 2 magnetic resonance imaging scans within 18 months after radiation. Post-radiation therapy magnetic resonance imaging findings were recorded, and brainstem toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.The most common histologies were medulloblastoma (61.7%) and ependymoma (15.9%), and median age at diagnosis was 8.3 years (range, 0.8-20.7). Sixty-seven patients (62.6%) received craniospinal irradiation (median, 23.4 Gy; range, 18.0-39.6) as a component of their radiation therapy, and 39.3% and 40.2% of patients received an additional involved field or whole posterior fossa boost, respectively. Median prescribed dose was 55.8 Gy (range, 50.4-60.0). Median clinical and imaging follow-up were 4.7 years (range, 0.1-17.5) and 4.2 years (range, 0.1-17.3), respectively. No grade ≥2 toxicities were observed. The incidence of grade 1 brainstem necrosis was 1.9% (2 of 107). These patients were by definition asymptomatic and experienced resolution of imaging abnormality after 5.3 months and 2.1 years, respectively.Risk of brainstem necrosis was minimal in this multi-institutional study of pediatric patients treated with photon radiation therapy for tumors involving the posterior fossa with no cases of symptomatic brainstem injury, suggesting that brainstem injury risk is minimal in patients treated with photon therapy.

Primary brain tumors are the most common solid malignancy of childhood and constitute the most common cause of cancer-related death in children. It is important for the radiologist to understand the differences between pediatric and adult brain tumors. For instance, tumor type varies significantly with age; many histologic subtypes occur exclusively in childhood. An anatomic approach to pediatric brain tumors helps narrow the differential diagnosis; however, information from this approach must be considered in conjunction with recent advances in molecular subtyping of these tumors. This article emphasizes relevant clinical, molecular, and imaging features that are unique to pediatric brain tumors.

Pediatric headache is a common problem, with various underlying causes. Appropriate patient selection for neuroimaging is necessary to optimize the clinical evaluation. This review aims to provide a focused discussion of the clinical evaluation of children with headache, including published guidelines pertaining to neuroimaging, technical considerations for neuroimaging, and tailoring of examinations for specific clinical entities known to cause pediatric headache.

BACKGROUND AND PURPOSE: Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium -PBTC). MATERIALS AND METHODS: MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio). RESULTS: A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI = 0.79, 52.79, p= 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI = 0.09, 0.82, p= 0.022). There was no significant association between fDM derived metrics and overall survival. CONCLUSIONS: Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG.

BACKGROUND: A greater understanding of the Ras-MAP kinase pathway in pediatric low-grade glioma (LGG) paired with the availability of selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. METHODS: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive LGG assigned to 6 strata and treated at a dose of 25 mg/m2/dose PO BID for up to two years. Here we present stratum 5 which enrolled children without NF1, non-OPG and non-pilocytic LGG harboring either a BRAFV600E mutation or BRAF-KIAA1549 fusion. RESULTS: Twenty-four of 25 children enrolled were eligible; 23 were evaluable for the primary radiologic response endpoint. Enrollment stopped early due to slow accrual and initiation of COG ACNS1931. The most common histologies were ganglioglioma (42%) and astrocytoma NOS (33%). Thirteen tumors (54%) had BRAF-KIAA1549 fusion; 11 (46%) had the BRAFV600E mutation. Five of 23 (22%) evaluable patients achieved a centrally confirmed partial response (PR), 12 (52%) had stable disease and 6 (26%) had progression with a 2-year progression-free survival of 75 + 9%. Four of 11 (36%) patients with a BRAFV600E mutation and 1/12 (8%) with a BRAF-KIAA1549 fusion achieved a PR. The 2-year PFS did not significantly differ between tumors with BRAFV600E mutation (82 + 12%) versus BRAF-KIAA1549 fusion (68 + 13%) (n=24, p=0.548). No patient remains on therapy. The most common attributable toxicities were grade 1/2 ALT/AST elevation, dry skin and leukopenia. Rare grade 3/4 toxicities included elevated CPK, rash, paronychia, fever, weight gain and sinus tachycardia. CONCLUSIONS: Despite lower than planned accrual, selumetinib met the design threshold for success in treating children with recurrent/progressive non-pilocytic, non-OPG LGG without NF1 that harbored the common BRAF aberrations. Ongoing phase 3 prospective studies will better determine the role of this agent in this population.

INTRODUCTION: Craniopharyngioma (CP) is a histologically benign tumor of the pituitary stalk that accounts for 4% of pediatric central nervous system (CNS) tumors. Given its location, CP often causes neuro-endocrine, hypothalamic, and vision dysfunction. Standard therapy consists of maximally safe resection +/- radiation therapy (RT). Medical management, including intra-cystic therapy, may have utility in certain contexts. Survival after CP is excellent, but quality of life is often poor secondary to functional deficits from the tumor and/or treatment. Few prospective CP trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, formed of international experts in relevant subspecialties, devised consensus guidelines from published literature and/or expert opinion to assess CP response in prospective clinical trials. RESULTS: Magnetic resonance imaging (MRI) is the recommended radiological modality for baseline and follow-up CP assessment. Computed tomography can be useful for identification of calcification in the initial diagnostic work-up. The committee defined specific standard MRI-based sequences focused on comprehensive evaluation of the suprasellar space. Radiologic CP response is defined by two-dimensional measurements of both solid and cystic tumor components. Three-dimensional measurements are also encouraged in prospective trials. In certain clinical contexts, response of solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment (including transient cyst growth during or after RT). Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into CP response definitions. In most circumstances, cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSION: CP is a common pediatric CNS tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for baseline and longitudinal assessments of CP to uniformly define response in future prospective trials.

INTRODUCTION: Autophagy is a highly conserved process by which intracellular components are degraded and recycled promoting cell survival. Preclinically, autophagy has been implicated as a resistance mechanism in BRAF-mutant glioma cells treated with MAPK-pathway inhibitors. HCQ, an oral autophagy inhibitor, has been evaluated preclinically and clinically to overcome resistance. METHODS: PBTC-055 (NCT04201457) is a phase I/II trial of HCQ combined with trametinib (BRAF-fusion or NF1-associated gliomas) or trametinib and dabrafenib (BRAFV600E gliomas) in patients < 30 years with progressive glioma. Prior treatment with RAF and/or MEK inhibitor with sub-optimal response (no response or response followed by progression on therapy) was required. Here, we present phase I data combining trametinib with HCQ utilizing a rolling-6 design. HCQ was administered at escalating dose levels (8, 15, or 20 mg/kg/day divided BID) in combination with standard pediatric trametinib dosing. All patients received prior MEK inhibitor therapy; 5/18 (28%) exhibited no response and 13/18 (72%) progressed on active therapy. RESULTS: Eighteen eligible/evaluable subjects were enrolled. Median age was 9.6 years (2.5-20.4 years); 10 were male. There were 2 dose-limiting toxicities (both grade 3 rash one each at DL1 and DL3). The highest dose level of HCQ (20 mg/kg/day divided BID) was declared the RP2D. Grade 3 adverse events possibly related to therapy included skin infection, rash, cardiac ejection fraction decrease, weight loss, and anorexia. There were no grade 4 or 5 attributable toxicities. Preliminarily, combination pharmacokinetic assessment revealed similar metabolism of trametinib to that reported as a single agent; HCQ demonstrated more rapid clearance compared to adults. Pharmacodynamic assessments are ongoing. CONCLUSIONS: The combination of trametinib and HCQ is safe with a RP2D of HCQ of 20 mg/kg/day divided BID. Currently, subjects are enrolling on the phase II portion evaluating the efficacy of this novel combination.

INTRODUCTION: Ependymomas remain a major cause of cancer-related death in childhood and adolescence, with recurrence occurring in up to 50% of patients. Despite exciting molecular advances in understanding ependymoma tumorigenesis and recurrence, MRI remains the mainstay for assessing objective response to therapy and duration of disease stability. Standardized response assessment criteria for clinical trials studying pediatric intracranial ependymoma are critically needed in order to accurately compare results between studies. METHODS: To generate these standardized response criteria in pediatric intracranial ependymoma, a multidisciplinary team of pediatric neuro-oncologists, neuroradiologists, neurosurgeons, radiation oncologists, and molecular biologists formed the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. The expert members reviewed relevant published literature, assessed current clinical practices, and engaged in iterative discussions to provide consensus recommendations for objective response assessment in pediatric intracranial ependymoma for use in prospective clinical trials. RECOMMENDATIONS AND CONCLUSIONS: The primary sequences for detecting and measuring disease and assessing radiologic response to therapy should be the contrast-enhanced T1-weighted sequence or T2-weighted sequence (T2 or T2-FLAIR) depending on which sequence the tumor is best visualized. When metastatic disease is present, only the three largest lesions will be followed in addition to any residual disease at the primary tumor focus. Importantly, the RAPNO working group notes that radiologic response to therapy is of limited value in clinical trials of patients with ependymoma, since most patients enroll on clinical trials with either no evidence of disease or only minimal disease. In recurrent or progressive disease that cannot be resected, true radiologic disease response to therapy is less clinically meaningful as a study endpoint than event-free and/or overall survival (representing prolonged stable disease) but may provide a signal of efficacy worthy of future exploration in patients with complete to near complete resections.

The purpose of this study was to assess image quality and quantitative brain PET across a multicenter consortium. Methods: All academic centers and children’s hospitals in the Pediatric Brain Tumor Consortium (PBTC) scanned a phantom developed by the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network (SNMMI CTN) for the validation of brain PET studies associated with clinical trials. The phantom comprises 2 separate, fillable sections: a resolution/uniformity section and a clinical simulation section. The resolution/uniformity section is a cylinder 12.7 cm long and 20 cm in diameter; spatial resolution is evaluated subjectively with 2 sets of rods (hot and cold) of varying diameter (4.0, 5.0, 6.25, 7.81, 9.67, and 12.2 mm) and spacing (twice the rod diameter). The clinical simulation section simulates a transverse section of midbrain with ventricles and gray and white matter compartments. If properly filled, hot rods have a 4:1 target-to-background ratio, and gray–to–white matter sections have a 4:1 ratio. Uniformity and image quality were evaluated using the SUV in a small volume of interest as well as subjectively by 2 independent observers using a 4-point scale. Results: Eleven PBTC sites scanned the phantom on 13 PET scanners. The phantom’s complexity led to suboptimal filling, particularly of the hot rod section, in 5 sites. The SUV in the uniformity section was within 10% of unity on only 5 of 13 scanners, although 12 of 13 were subjectively judged to have very good to excellent uniformity. Four of 6 hot rods were discernable by all 13 scanners, whereas 3 of 6 cold rods were discernable by only 5 scanners. Four of 13 scanners had a gray–to–white matter ratio between 3.0 and 5.0 (4.0 is truth); however, 11 of 13 scanners were subjectively judged to have very good or excellent image quality. Conclusion: Eleven sites were able to image a powerful phantom developed by the SNMMI CTN that evaluated image uniformity, spatial resolution, and image quality of brain PET. There was considerable variation in PET data across the PBTC sites, possibly resulting from variations in scanning across the sites due to challenges in filling the phantom.

BackgroundDisruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein.MethodsPalbociclib was administered orally starting at 50mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities.ResultsA total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy.ConclusionsPalbociclib was safely administered to children and adolescents at a dosage of 75mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.

Background Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. Methods We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses. Results Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash. Conclusions Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.

BACKGROUND AND PURPOSE: Posterior fossa tumors are the most common pediatric brain tumors. MR imaging is key to tumor detection, diagnosis, and therapy guidance. We sought to develop an MR imaging–based deep learning model for posterior fossa tumor detection and tumor pathology classification. MATERIALS AND METHODS: The study cohort comprised 617 children (median age, 92 months; 56% males) from 5 pediatric institutions with posterior fossa tumors: diffuse midline glioma of the pons (n = 122), medulloblastoma (n = 272), pilocytic astrocytoma (n = 135), and ependymoma (n = 88). There were 199 controls. Tumor histology served as ground truth except for diffuse midline glioma of the pons, which was primarily diagnosed by MR imaging. A modified ResNeXt-50-32x4d architecture served as the backbone for a multitask classifier model, using T2-weighted MRIs as input to detect the presence of tumor and predict tumor class. Deep learning model performance was compared against that of 4 radiologists. RESULTS: Model tumor detection accuracy exceeded an AUROC of 0.99 and was similar to that of 4 radiologists. Model tumor classification accuracy was 92% with an F1 score of 0.80. The model was most accurate at predicting diffuse midline glioma of the pons, followed by pilocytic astrocytoma and medulloblastoma. Ependymoma prediction was the least accurate. Tumor type classification accuracy and F1 score were higher than those of 2 of the 4 radiologists. CONCLUSIONS: We present a multi-institutional deep learning model for pediatric posterior fossa tumor detection and classification with the potential to augment and improve the accuracy of radiologic diagnosis.

BACKGROUND AND PURPOSE: Recent advances in molecular techniques have characterized distinct subtypes of diffuse intrinsic pontine gliomas. Our aim was the identification of MR imaging correlates of these subtypes. MATERIALS AND METHODS: Initial MRIs from subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Univariate Cox proportional hazards regression was used to test the association of imaging predictors with overall and progression-free survival. Wilcoxon rank sum, Kruskal-Wallis, and Fisher exact tests were used to compare imaging measures among groups. RESULTS: Fifty patients had biopsy and MR imaging. The median age at trial registration was 6 years (range, 3.3–17.5 years); 52% were female. On the basis of immunohistochemical results, 48 patients were assigned to 1 of 4 subgroups: 28 in MGMT–/epidermal growth factor receptor (EGFR)–, 14 in MGMT–/EGFR+, 3 in MGMT+/EGFR–, and 3 in MGMT+/EGFR+. Twenty-three patients had histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HIST1H3C. Enhancing tumor volume was near-significantly different across molecular subgroups (P = .04), after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different (P ≤ .048) between patients with H3F3A and HIST1H3B/C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters are correlated with molecular subgroups and mutations in children with diffuse intrinsic pontine gliomas.

Background A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series. Methods Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity. Results Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively. Conclusion Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG. Trial Registration NCT01514201

Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. 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. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.

Purpose Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. Methods and Materials Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. Results The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. Conclusions Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

BACKGROUND AND PURPOSE: Accurate tumor grading is essential for treatment planning of pediatric brain tumors. We hypothesized that multiparametric analyses of a combination of permeability metrics and ADC histogram metrics would differentiate high- and low-grade tumors with high accuracy. MATERIALS AND METHODS: DTI and dynamic contrast-enhanced MR imaging using T1-mapping with flip angles of 2°, 5°, 10°, and 15°, followed by a 0.1-mmol/kg body weight gadolinium-based bolus was performed on all patients in addition to standard MR imaging. Permeability data were processed and transfer constant from the blood plasma into the extracellular extravascular space, rate constant from the extracellular extravascular space back into blood plasma, extravascular extracellular volume fraction, and fractional blood plasma volume were calculated from 3D tumor volumes. Apparent diffusion coefficient histogram metrics were calculated for 3 separate tumor volumes derived from T2-FLAIR sequences, T1 contrast-enhanced sequences, and permeability maps, respectively. RESULTS: Results from 41 patients (0.3–16.76 years of age; mean, 6.22 years) with newly diagnosed contrast-enhancing brain tumors (16 low-grade; 25 high-grade) were included in the institutional review board–approved retrospective analysis. Wilcoxon tests showed a higher transfer constant from blood plasma into extracellular extravascular space and rate constant from extracellular extravascular space back into blood plasma, and lower extracellular extravascular volume fraction (P < .001) in high-grade tumors. The mean ADCs of FLAIR and enhancing tumor volumes were significantly lower in high-grade tumors (P < .001). ROC analysis showed that a combination of extravascular volume fraction and mean ADC of FLAIR volume differentiated high- and low-grade tumors with high accuracy (area under receiver operating characteristic curve = 0.918). CONCLUSIONS: ADC histogram metrics combined with permeability metrics differentiate low- and high-grade pediatric brain tumors with high accuracy.

Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.

The purpose of this study was to describe baseline 18F-FDG PET voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline MRI apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS), and overall survival. Methods: Baseline brain 18F-FDG PET and MRI scans were obtained in 33 children from Pediatric Brain Tumor Consortium clinical DIPG trials. 18F-FDG PET images, postgadolinium MR images, and ADC MR images were registered to baseline fluid attenuation inversion recovery MR images. Three-dimensional regions of interest on fluid attenuation inversion recovery MR images and postgadolinium MR images and 18F-FDG PET and MR ADC histograms were generated. Metrics evaluated included peak number, skewness, and kurtosis. Correlation between PET and MR ADC histogram metrics was evaluated. PET pixel values within the region of interest for each tumor were plotted against MR ADC values. The association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94%, vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET postgadolinium skewness tended toward a less favorable PFS (hazard ratio, 3.48; 95% confidence interval [CI], 0.75-16.28 [P = 0.11]). There was a significant association between higher MR ADC postgadolinium skewness and shorter PFS (hazard ratio, 2.56; 95% CI, 1.11-5.91 [P = 0.028]), and there was the suggestion that this also led to shorter overall survival (hazard ratio, 2.18; 95% CI, 0.95-5.04 [P = 0.067]). Higher MR ADC postgadolinium kurtosis tended toward shorter PFS (hazard ratio, 1.30; 95% CI, 0.98-1.74 [P = 0.073]). PET and MR ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and MR ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (hazard ratio, 0.17; 95% CI, 0.03-0.89 [P = 0.036]), suggesting that a higher level of negative ADC-PET correlation leads to less favorable PFS. A more significant negative correlation may indicate higher-grade elements within the tumor leading to poorer outcomes. Conclusion:18F-FDG PET and MR ADC histogram metrics in pediatric DIPG demonstrate different characteristics with often a negative correlation between PET and MR ADC pixel values. A higher negative correlation is associated with a worse PFS, which may indicate higher-grade elements within the tumor.

Pediatric brain tumors are the leading cause of death from solid tumors in childhood. The most common posterior fossa tumors in children are medulloblastoma, atypical teratoid/rhabdoid tumor, cerebellar pilocytic astrocytoma, ependymoma, and brainstem glioma. Location, and imaging findings on computed tomography (CT) and conventional MR (cMR) imaging may provide important clues to the most likely diagnosis. Moreover, information obtained from advanced MR imaging techniques increase diagnostic confidence and help distinguish between different histologic tumor types. Here we discuss the most common posterior fossa tumors in children, including typical imaging findings on CT, cMR imaging, and advanced MR imaging studies.

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.

BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common CNS tumor of childhood. Progression-free survival (PFS) is much lower than overall survival emphasizing the need for alternative treatments. In addition, many children suffer functional morbidities such as visual and motor disturbances. Recently, there has been an appropriate prioritization of functional outcomes in children with pLGG. METHODS: We present the results of a PBTC phase II trial evaluating selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor, in children with recurrent/progressive pLGG on 2 strata, including visual outcomes. RESULTS: Stratum 3 enrolled Neurofibromatosis type 1 (NF1)-associated pLGG. Ten of 25 (40%) eligible patients had partial response (PR), 14/25 (56%) had stable disease (SD) and 1/25 (4%) had progressive disease (PD); 2-year PFS was 96+4%. Ten patients with optic pathway glioma (OPG) were evaluable for visual acuity (VA) at baseline and 1 year. VA improved in 2/10 patients (20%) and was stable in 8/10 (80%). One patient (10%) had improvement in visual fields (VF) and 9 patients (90%) had stable VF. Stratum 4 included patients with non-NF1-associated recurrent/progressive hypothalamic and OPG. Five of 25 (20%) eligible patients had PR, 16/25 (64%) had SD and 4 (16%) had PD; 2-year PFS was 78+8.5%. Nineteen of 25 patients were evaluable for VA. VA improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five patients (26%) had improved VF and 14 (74%) had stable VF. The most common toxicities included grade 1/2 CPK elevation, diarrhea, hypoalbuminemia and rash. Rare grade 3 toxicities included elevated CPK, rash and paronychia. CONCLUSIONS: Selumetinib was tolerable and effective in treating children with NF1-associated and sporadic recurrent/progressive hypothalamic and OPG based upon radiographic response and PFS. Twenty-seven of 29 (93%) evaluable patients had stable or improved vision based on VA and VF testing.

PURPOSE: To correlate MR imaging findings with molecular analyses in DIPG. METHODS: Baseline MR imaging studies, including standard pre- and post-contrast MR sequences, were reviewed from patients included in our multi-institutional, IRB-approved DIPG trial NCT01182350. Prospectively acquired imaging data were analyzed after study closure, including FLAIR/T2 tumor volume; tumor volume enhancement and cyst/necrosis; median, mean, mode, skewness, and kurtosis of apparent diffusion coefficient (ADC) tumor volume based on both FLAIR and enhancement at baseline. Whole-genome and RNA-sequencing identified histone mutations. We applied univariate Cox proportional-hazards regression modeling to test the association of imaging predictors with overall (OS) and progression-free survival (PFS). Wilcoxon rank-sum, Kruskal-Wallis, and Fisher’s exact tests compared imaging measures between groups. RESULTS: Fifty patients underwent biopsy and MRI. Median age at trial registration was 6 years (range,3.3–17.5 years); 52% of patients were female. Molecular subgroup study assignments for 48 patients’ tumors were as follows: 28 in MGMT-/EGFR-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Further genetic testing identified mutations in histones, PDGFRA, ACVR1, TP53, EGFR, PPM1D, FGFR, and/or PI3K. Twenty-three tumors possessed histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HISTH3C. Median follow-up time was 11 months (range,0.4–33 months). Poorer OS (p=0.01) and PFS (p=0.001) were significantly associated with increased enhancing tumor volume. Enhancing tumor volume also differed significantly across molecular subgroups (p=0.047). Tumor enhancement, mode, skewness, and kurtosis ADC-FLAIR differed significantly (p≤0.048) between patients with H3F3A and HIST1H3B mutations. Tumor enhancement, median, mode, skewness, and kurtosis ADC-FLAIR also differed significantly (p≤0.048) between patients with H3F3A and HIST1H3B or HISTH3C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters correlate to molecular subgroups in DIPG. Further studies are required to verify and refine these findings in a larger cohort.

BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor of childhood. Although overall survival is very good, many children suffer from multiple progressions and functional morbidities. There is no one universally accepted therapy for children with recurrent disease, however, standard cytotoxic chemotherapies are often utilized by most practitioners. The Pediatric Brain Tumor Consortium conducted a multi-institutional phase II study evaluating selumetinib (AZD6244, ARRY-142886), a MAP/ERK Kinase I/II inhibitor, in patients with recurrent, refractory or progressive pLGG assigned to numerous strata. The aim of the study was to evaluate the efficacy of selumetinib in these patients. METHODS: Eligibility required age 3–21 y/o, a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory or progressive pLGG after at least one standard therapy. Stratum 1 included children with World Health Organization (WHO) grade I pilocytic astrocytoma (PA) harboring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAF(V600E) mutation). Stratum 3 included children with any neurofibromatosis type 1 (NF1)-associated pLGG (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase II dose of 25 mg/m(2) twice daily. The primary endpoint was stratum-specific objective response rate assessd by the local site and sustained for at least 8 weeks. All responses were reviewed centrally and statistical analyses were done as per protocol. Although the trial (NCT01089101) is still ongoing in other strata, enrollment and planned follow-up is compete on both strata 1 and 3. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable children were accrued to stratum 1, and between August 28, 2013, and June 25, 2015, 25 eligible and evaluable children were accrued to stratum 3. On stratum 1, 9/25 (36%) patients achieved a partial response (PR). The median follow-up for the 11 patients who have not yet experienced an event is 36.4 months (4.4–50.5; IQR=23.9). On stratum 3, 10/25 (40%) patients achieved a PR with a median follow-up of 48.6 months (8.6–59.1; IQR=12.2) for the 17 subjects without progressions. All patients evaluable for visual acuity had improved or stable vision. The most common attributable toxicities on both strata were grade 1 and 2 CPK elevation, hypoalbuminemia, dyspnea, rash, duodenal ulcer, anemia, dry skin, fatigue and diarrhea. Rare grade 3 toxicities included elevated CPK (n=5), maculopapular rash (n=5), neutropenia (n=3), nausea (n=3), paronychia (n=3), acneiform rash (n=2), diarrhea (n=2), elevated ALT (n=1), decreased ejection fraction (n=1), gastric hemorrhage (n=1), headache (n=1), skin infection (n=1), tooth infection (n=1) and weight gain (n=1). There was only one grade 4 toxicity, lymphopenia. There were no treatment-realted deaths. Patient reported outcomes and quality of life assessments were not part of the current study. INTERPRETATION: Selumetinib is active against recurrent, refractory or progressive PA harboring common BRAF aberrations and NF1-associated pLGG. To our knowledge, this is one of the first prospectively tested and successful molecularly-targeted agents in pLGG. These data not only provide an alternative to standard chemotherapy for these subgroups of patients, but this success has led to an interest in exploring efficacy in patients as a first-line therapy. In fact, these data have directly led to the development of two Children’s Oncology Group phase III studies in newly diagnosed pLGG patients both with and without NF1 comparing standard chemotherapy to selumetinib. The current trial was funded by a National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) PBTC U01 Grant: 2UM1CA081457 (UM1) and by the American Lebanese Syrian Associated Charities.

IMPORTANCE: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. OBJECTIVE: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. SETTING, DESIGN, AND PARTICIPANTS: Case series of patients (age

PBTC-042 was a phase I trial of palbociclib to determine the maximum tolerated dose (MTD) and describe toxicities in children. Palbociclib is an oral, selective cyclin dependent kinase 4/6 inhibitor. METHODS: A rolling-6 design was utilized. Eligible patients were children ≥4 and ≤21 years-old with a progressive/refractory CNS tumor with intact retinoblastoma protein, measurable disease, and ability to swallow capsules. Pharmacokinetic studies were performed during the first course. Here, we report on the heavily pretreated stratum, which included patients who received >4 prior treatment regimens (either chemotherapy or biologic agent), and/or craniospinal irradiation, and/or myeloablative chemotherapy plus stem cell rescue. Palbociclib was initiated at 50 mg/m2/day for 21 consecutive days of a 28-day course. This was one dosage level below the MTD for the less heavily pretreated stratum (75 mg/m2). RESULTS: Fourteen eligible patients were enrolled (median age 12.8 years; male 79%). Eleven patients (79%) had either ependymoma or medulloblastoma. Four eligible and evaluable patients were enrolled at 50 mg/m2 with no DLTs. This prompted a dosage increase to 75 mg/m2. Ten eligible subjects were enrolled and 7 were evaluable for DLT assessment. One of 7 evaluable patients experienced a DLT (grade 3 thrombocytopenia). This established 75 mg/m2 as the MTD for more heavily pretreated patients. Mean ± SD palbociclib apparent oral clearance was 34.6 ± 18.4 L/h/m2. CONCLUSION: The MTD for palbociclib on a 3 week on/1 week off schedule in children with brain tumors is 75 mg/m2 and does not appear to be influenced by the degree of prior therapy.

The PBTC conducted a re-treatment study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive pLGG. Eligible patients must have previously enrolled on PBTC-029 or PBTC-029B and progressed after coming off treatment with selumetinib. Patients must have maintained stable disease (SD) for ≥12 courses or had a sustained radiographic response (partial or complete) during their first exposure to selumetinib. Thirty-five eligible patients (median age: 13.11 years [range 7.96–25.33]) were enrolled, 57% of whom had optic pathway or hypothalamic target lesions. At the time of submission, median duration of treatment was 18 courses (range 2–48) and 21 subjects remained on therapy. Best responses reported to date are 6/35 (17%) partial response, 22/35 (63%) SD and 7/35 (20%) progressive disease with a 2-year progression-free survival of 75.7 + 8.3%, which met the design parameters for success. The most common attributable toxicities were grade 1 diarrhea, elevated AST, hypoalbuminemia, elevated CPK, maculo-papular rash, fatigue, paronychia, ALT elevation, acneiform rash and grade 2 CPK elevation. Rare grade 3 toxicities included CPK elevation (3), lymphopenia (2), paronychia (2) and ALT elevation (2). There was only one grade 4 CPK elevation. Five patients (14%) required dose reductions due to toxicity. There does not appear to be a notable difference in toxicities observed during initial selumetinib therapy versus re-treatment. In pLGG that has recurred/progressed following treatment with selumetinib, re-treatment with selumetinib appears to be effective with 80% of patients again achieving response or prolonged stable disease. Long-term follow-up is ongoing.

INTRODUCTION Pediatric low-grade gliomas (pLGG) show clinical and biological features that are distinct from their adult counterparts. Consequently, additional considerations are needed for response assessment in children compared to the established adult Response Assessment in Neuro-Oncology (RANO) criteria. Standardized response criteria in pediatric clinical trials are lacking, complicating comparisons of responses across studies. We therefore established an international committee of the Radiologic Assessment in Pediatric Neuro-Oncology (RAPNO) working group to develop consensus recommendations for response assessment in pLGG. METHODS The committee consisted of 25 international experts in the areas of Pediatric Neuro-Oncology, Neuroradiology and Neurosurgery. The committee first developed a set of agreed upon topics they deemed necessary to understand the controversies of imaging utilization and assessment in pLGG. These topics were divided up among the committee members who presented all available literature to the entire RAPNO committee via web teleconference. Once presented, the group discussed these data and developed consensus statements and recommendations based on available literature, committee expertise and clinical experience. Each topic was discussed until a consensus was reached. RESULTS Final consensus included recommendations about the following topics: specific imaging sequences, advanced imaging techniques, NF1-associated pLGG, molecular and histologic classification, assessment of cysts, vision and other functional outcomes as well as overall radiologic response assessment. CONCLUSIONS The RAPNO pLGG consensus establishes systemic recommendations that represent an initial effort to uniformly collect and assess response in pLGG. These recommendations should now be evaluated internationally and prospectively in an effort to assess clinical utility, validate and modify as appropriate.

BACKGROUND CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors. RESULTS Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled. CONCLUSION The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

INTRODUCTION Response criteria for pediatric high-grade gliomas (pHGG) have varied historically and across clinical trials. Compared to adult HGG, pHGG response assessment has unique challenges. An international Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was established to develop pHGG response assessment criteria. METHODS Pediatric and adult neuro-oncologists, neuro-radiologists and experts in imaging informatics developed a consensus statement and established a unified response assessment for biopsy-proven pHGG, excluding DIPG. This was achieved by identifying major challenges, reviewing existing literature and current practices, and finally developing recommendations through an iterative process. RESULTS Categories for response assessment include complete response, partial response, minor response, stable disease and progressive disease. Refractory disease is excluded. Criteria used to determine response assessment include quantitative evaluation of measurable disease, qualitative assessment of diffusion imaging, presence or absence of new lesions, clinical status using performance score, and vascular endothelial growth factor inhibitor and/or corticosteroid use. Response is determined over 2-time points ≥ 8 weeks apart, and when progressive disease is unclear, guidance for repeat MRI imaging and/or utility of repeat biopsy is described. A number of recommendations are also given to standardize response assessment across clinical trials including MRI protocol sequence recommendations for brain and spine, definitions for measurable and non-measurable disease, and imaging time points with post-operative considerations. In addition, guidance is given for differentiating vasogenic edema versus tumor invasion in non-enhancing disease. CONCLUSION Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.

BACKGROUND Brain tumors are the most common solid malignancies in childhood, many of which develop in the posterior fossa (PF). Manual tumor measurements are frequently required to optimize registration into surgical navigation systems or for surveillance of nonresectable tumors after therapy. With recent advances in artificial intelligence (AI), automated MRI-based tumor segmentation is now feasible without requiring manual measurements. Our goal was to create a deep learning model for automated PF tumor segmentation that can register into navigation systems and provide volume output. METHODS 720 pre-surgical MRI scans from five pediatric centers were divided into training, validation, and testing datasets. The study cohort comprised of four PF tumor types: medulloblastoma, diffuse midline glioma, ependymoma, and brainstem or cerebellar pilocytic astrocytoma. Manual segmentation of the tumors by an attending neuroradiologist served as “ground truth” labels for model training and evaluation. We used 2D Unet, an encoder-decoder convolutional neural network architecture, with a pre-trained ResNet50 encoder. We assessed ventricle segmentation accuracy on a held-out test set using Dice similarity coefficient (0–1) and compared ventricular volume calculation between manual and model-derived segmentations using linear regression. RESULTS Compared to the ground truth expert human segmentation, overall Dice score for model performance accuracy was 0.83 for automatic delineation of the 4 tumor types. CONCLUSIONS In this multi-institutional study, we present a deep learning algorithm that automatically delineates PF tumors and outputs volumetric information. Our results demonstrate applied AI that is clinically applicable, potentially augmenting radiologists, neuro-oncologists, and neurosurgeons for tumor evaluation, surveillance, and surgical planning.

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.