This paper presents a novel implementation of a three-dimensional Virtual Librarian Chatbot using IBM Watson artificial intelligence technology and virtual reality. In this method, participants interact with virtual librarian chatbots by asking specific questions about the library system. This research investigated the factors used in the Technology Acceptance Model, mainly Perceived Usefulness, Perceived Ease of Use, Perceived Enjoyment, Intention to Use, and Curiosity, to examine the effectiveness of the suggested Virtual Librarian Chatbot. These results highlight the potential for integrating Virtual Librarian Chatbots in academic libraries to enhance user experience, support remote learning and research, and streamline library services. The successful implementation of such chatbots could transform user interactions with academic libraries in the digital age, offering instant access to information and reducing the workload of human librarians.

ObjectiveThe 2-point DIXON method is widely used to assess fat fractions (FFs) in magnetic resonance images (MRIs) of the tongue, pharyngeal wall, and surrounding tissues in patients with obstructive sleep apnea (OSA). However, the method is semiquantitative and is susceptible to B-0 field inhomogeneities and R2* confounding factors. Using the method, although several studies have shown that patients with OSA have increased fat deposition around the pharyngeal cavity, conflicting findings was also reported in 1 study. This discrepancy necessitates that we examine the FF estimation method used in the earlier studies and seek a more accurate method to measure FFs.Materials and MethodsWe examined the advantages of using the GOOSE (globally optimal surface estimation) method to replace the 2-point DIXON method for quantifying fat in the tongue and surrounding tissues on MRIs. We first used phantoms with known FFs (true FFs) to validate the GOOSE method and examine the errors in the DIXON method. Then, we compared the 2 methods in the tongue, soft palate, pharyngeal wall, and parapharyngeal fat pad of 63 healthy participants to further assess the errors caused by the DIXON method. Six participants were excluded from the comparison of the tongue FFs because of technical failures. Paired Student t tests were performed on FFs to detect significant differences between the 2 methods. All measures were obtained using 3 T Siemens MRI scanners.ResultsIn the phantoms, the FFs measured by GOOSE agreed with the true FF, with only a 1.2% mean absolute error. However, the same measure by DIXON had a 10.5% mean absolute error. The FFs obtained by DIXON were significantly lower than those obtained by GOOSE (P < 0.0001) in the human participants. We found strong correlations between GOOSE and DIXON in the tongue (R-2 = 0.90), soft palate (R-2 = 0.66), and parapharyngeal fat pad (R-2 = 0.88), but the correlation was weaker in the posterior pharyngeal walls (R-2 = 0.32) in participants.ConclusionsThe widely used 2-point DIXON underestimated FFs, relative to GOOSE, in phantom measurements and tissues studied in vivo. Thus, an advanced method, such as GOOSE, that uses multiecho complex data is preferred for estimating FF.

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions ( n = 12) or hydroxyurea ( n = 32), median age 19.2 years (range 18.0–31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5–54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0–15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76–0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2–64), abnormal pediatric exam ( P = 0.00084), and elevated transcranial Doppler ultrasound velocities ( P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

Introduction: Sickle cell anemia (SCA) results in numerous adverse effects on the brain, including ischemic lesions and neurocognitive dysfunction. Hydroxyurea has been utilized extensively for management of SCA, but its effects on brain function have not been established. Methods: We examined prospectively the effects of one year of treatment with hydroxyurea on brain function in a cohort of children with SCA (HbSS/HbSβ0-thalassemia) by baseline and exit evaluations, including comprehensive neurocognitive testing, transcranial Doppler ultrasound (TCD), and brain MRI [silent cerebral infarcts (SCI), gray matter cerebral blood flow (GM-CBF), and blood oxygen level dependent (BOLD) signal from visual stimulation]. Results: Nineteen patients with SCA, mean age 12.4 years (range 7.2-17.8), were evaluated. At baseline, subjects had these mean values: full scale IQ (FSIQ) 81.9, TCD velocity 133 cm/sec, GM-CBF 64.4 ml/100g/min, BOLD signal 2.34% increase, and frequency of SCI 47%. After one year of hydroxyurea, there were significant increases in FSIQ (+2.8, p=0.036) and reading comprehension (+4.8, p=0.016), a significant decrease in TCD velocity (-11.4 cm/sec, p=0.007), and no significant changes in GM-CBF, BOLD, or SCI frequency. Furthermore, FSIQ was associated with higher hemoglobin F (HbF) and lower GM-CBF, but not with hemoglobin level. Discussion: Significant improvement of neurocognition and decreased TCD velocity following one year of treatment support the use of hydroxyurea for improving neurocognitive outcomes in SCA. Understanding the mechanisms of benefit, as indicated by relationships of neurocognitive function with HbF, hemoglobin, and CBF, requires further evaluation.

BACKGROUND AND PURPOSE:Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation.MATERIALS AND METHODS:Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated.RESULTS:No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes.CONCLUSIONS:PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.

Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using MRI, the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether 11C-methionine PET, a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. Methods: Using 11C-methionine PET during follow-up visits, we evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities for whom tumor recurrence was of concern. We performed quantitative and qualitative assessments of both 11C-methionine PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival (OS), we plotted the time from development of the imaging changes against survival. Results: Qualitative evaluation of 11C-methionine PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for 11C-methionine PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI (P < 0.01). Quantitative MRI and 11C-methionine PET evaluation using receiver-operating characteristics demonstrated higher specificity (80%) than did qualitative evaluations (40%-60%). Postcontrast enhancement volume, metabolic tumor volume, tumor-to-brain ratio, and presence of tumor as determined by consensus MRI assessment were inversely associated with OS. Conclusion:11C-methionine PET has slightly higher sensitivity and accuracy for correctly predicting tumor recurrence, with excellent interobserver agreement, than does MRI. Quantitative 11C-methionine PET can also predict OS. These findings suggest that 11C-methionine PET can be useful for further evaluation of MRI changes during surveillance of previously treated PHGGs.

Abstract PURPOSE/OBJECTIVES Pediatric supratentorial high-grade glioma (stHGG) is a biologically heterogeneous disease defined by unique mutations, natural history and prognosis. Prior work by our group outlined a role for qualitative imaging features in aiding prognostication. We build on that work by evaluating the prognostic utility of radiomic features (RM) when paired with clinical factors. MATERIALS/ METHODS Ninety-one patients age < 21 years with stHGG treated between 1980–2007 were retrospectively reviewed. Prognostic clinical, qualitative imaging (Visually AcceSAble Rembrandt Images, VASARI), and treatment characteristics were evaluated in concert with manual and automatically segmented (DeepMedic), tumor-derived semi-quantitative radiomic features (Pyradiomics) extracted from MR images. Prognostic RM were limited to stable imaging features which were subsequently selected using bootstrapped least absolute shrinkage and selection operator (LASSO). Nonparametric descriptive statistics and prognostication model evaluation, incorporating RM and clinical variables, were developed using random forest (RF), Cox proportional hazards (CPH), and deep learning (deepsurv) algorithms and assessed for goodness of fit using (c-index). RESULTS A subset (N=80) of 386 intensity, shape, and texture derived RM were stable between pre-treatment MR. 28 RM features were independently predictive of survival when compared to models utilizing combinations of clinical, VASARI and had comparable model fit statistics. CPH, RF and deepsurv showed comparable utility in modelling RM features. Combined modelling of clinical, VASARI and RM features using CPH, RF, and deepsurv resulted in c-indices of 0.68, 0.67, 0.68, respectively. CONCLUSION RM features are stable and independently prognostic. Combined modelling of clinical, VASARI, and RM features improves prognostication in stHGG.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a devastating childhood cancer that despite being primarily diagnosed by MR imaging alone, lacks robust prognostic imaging features. This study investigated patterns and quantification of extrapontine lesion extensions as potential prognostic imaging biomarkers for survival in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: Volumetric analysis of baseline MR imaging studies was completed in 131 patients with radiographically defined typical diffuse intrinsic pontine gliomas. Extrapontine tumor extension was classified according to the direction of extension: midbrain, medulla oblongata, and right and left middle cerebellar peduncles; various extrapontine lesion extension patterns were evaluated. The Kaplan-Meier method was used to estimate survival differences; linear regression was used to evaluate clinical-radiographic variables prognostic of survival. RESULTS: At least 1 extrapontine lesion extension was observed in 125 patients (95.4%). Of the 11 different extrapontine lesion extension patterns encountered in our cohort, 2 were statistically significant predictors of survival. Any extension into the middle cerebellar peduncles was prognostic of shorter overall survival (P = .01), but extension into both the midbrain and medulla oblongata but without extension into either middle cerebellar peduncle was prognostic of longer overall survival compared with those having no extension (P = .04) or those having any other pattern of extension (P < .001). CONCLUSIONS: Within this large cohort of patients with typical diffuse intrinsic pontine gliomas, 2 specific extrapontine lesion extension patterns were associated with a significant overall survival advantage or disadvantage. Our findings may be valuable for risk stratification and radiation therapy planning in future clinical trials.

Background Despite improved survival, many pediatric brain tumor survivors receiving radiation therapy (RT) experience late effects. Procedure To study calvarial lesions in this population, we retrospectively reviewed records of patients undergoing neurosurgical evaluation for calvarial bone lesions detected in posttreatment follow-up imaging at St. Jude Children's Research Hospital. Primary tumor diagnosis, treatment, imaging, surgical intervention, and histopathology from patients with radiographic evidence of lesions followed for >= 2 years post-RT were studied. Results For 17 patients with 18 index lesions, median time to lesion manifestation was 2.34 years. Medulloblastoma patients developed lesions at a shorter interval from RT than ependymoma patients (P = .05). Twelve of 14 lesions requiring surgery were benign fibro-osseous or sclerotic. Two malignant lesions distinct from the primary tumor had genetic predisposition to malignancy. Conclusion Most calvarial lesions arising post-RT are benign and fibro-osseous. Serial imaging is recommended, and high index of suspicion for malignant lesions is warranted for patients genetically predisposed to cancer.

Background: Serious morbidity in young children with sickle cell anemia (SCA, HbSS and HbSβ0thalassemia) is well-described and begins early in life with the onset of the physiologic decline of fetal hemoglobin. The BABY HUG trial showed that a fixed dose (20 mg/kg/day) of hydroxyurea initiated in infants reduces acute SCA-related complications, but participants continued to experience acute SCA-related complications and to develop end-organ damage. Aims: Evaluate if hydroxyurea escalated to maximum tolerated dose (MTD) prevents end-organ damage in young children prior to their 6th birthday, and describe the impact of known genetic modifiers disease severity on treatment outcomes. Methods: The Sickle Cell Clinical Research and Intervention Program (SCCRIP, NCT 02098863) was approved by the St. Jude Children's Research Hospital IRB, and participants provided written informed consent. SCCRIP is a multicenter, longitudinal, cohort of individuals with SCD of any genotype or treatment exposure. Children initiated hydroxyurea at a dose of 20 mg/kg per day with escalation of the dose by 5 mg/kg increments every 8–12 weeks until an MTD was identified, defined by an absolute neutrophil count (ANC) of 2,000–4,000 x106/L. The primary end-point was longitudinal development of organ damage (TCD velocity >170 cm/sec, overt stroke, abnormal MRI/MRA, or surgical splenectomy) and secondary end-points were acute SCA-related complications (pain, acute chest syndrome, splenic sequestration, or simple transfusion) in treated versus untreated infants. A generalized linear mixed model (GLMM) with quasi-poisson link function adjusted for age was performed and the slopes and standard error were estimated for each outcome. From birth, the time to first occurrence for outcomes were visualized with the use of Kaplan-Meier curves and compared with the log rank test. Univariate regression models were performed with Cox regression. All statistical tests were two-tailed and a p value of <0.05 was considered statistically significant, and analyses were performed using R software version 3.4.3. Results: None of the total 327 infants died in the first six years of life. In 142 (43.4%) infants, hydroxyurea was initiated at a mean (SD) of 2.8 (1.5) years of age and escalated to 29.1 (4.8) mg/kg. Children who received hydroxyurea had more severe disease in the first 12 months of life, with more vaso-occlusive pain (21.8 vs. 6.5 events; p = 0.006), splenic sequestration (16.9 vs. 3.2 events; p < 0.001) and transfusions (26.8 vs. 3.2 events; p < 0.001) per 100 patient-years compared to children who did not initiate hydroxyurea. As children aged, if treated with hydroxyurea at MTD they had less organ damage (HR 0.46 [95%CI:0.29–0.72]; p < 0.0001) and fewer acute SCA-related events (HR 0.41 [95%CI:0.26–0.64]; p < 0.0001) compared to untreated children. Untreated children developed end-organ damage and acute complications earlier in life and at a higher rate compared to those treated with hydroxyurea (Figure). One or two BCL11A (rs4671393) mutations reduced the incidence of any organ damage (est. −0.56; SE: 0.25, p = 0.02) and acute SCA-related complications (est. −0.43; SE: 0.14, p = 0.002), but hydroxyurea continued to be associated with less end-organ damage and acute SCA-related complications (data not shown). Toxicities were uncommon.Summary/Conclusion: In young children with SCA, hydroxyurea escalated to MTD is safe and prevents end-organ damage and reduces the frequency of acute SCA-related events. Children with BCL11A have less end-organ damage and acute complications, but continue to have therapeutic benefit from hydroxyurea therapy.

Background:Oxygenated sickle hemoglobin (HbS) does not polymerize; therefore, increasing oxygen affinity to HbS is a therapeutic strategy for sickle cell anemia (SCA; HbSS and HbSβ0thalassemia), and voxelotor (GBT440) is a first‐in‐class, small molecule that increases the affinity of hemoglobin for oxygen. It has been postulated that increasing hemoglobin‐oxygen affinity could limit oxygen offloading from hemoglobin, thus impairing tissue oxygenation which could lead to an increase in cerebral blood flow and potential risk of stroke. This study used MRI techniques to evaluate cerebrovascular hemodynamics to inform on cerebral oxygenation with voxelotor therapy.Aims:To assess effects of voxelotor on grey matter cerebral blood flow (CBF) in children with SCA.Methods:This was a St. Jude Children's Research Hospital (St. Jude) investigator‐initiated, ancillary study of children enrolled in the HOPE‐KIDS1 (NCT02850406) trial. Study activities were approved by the St. Jude IRB and all participants provided documentation of informed consent. Participants underwent two non‐sedated functional magnetic resonance imaging with angiography (MRI/MRA) evaluations, once prior to receiving voxelotor and again following multiple doses (Table). Time resolved phase‐contrast (PC) MR imaging was used to measure CBF during multiple phases of the cardiac cycle at several anatomic locations, including the internal carotid arteries and anterior, middle and posterior cerebral arteries, and arterial spin labeling (ASL) sequences utilizing a multi‐channel head coil in a 3T scanner were performed.Results:Preliminary data on three patients are available. All three participants (Table) were being treated with a stable dose of hydroxyurea and had normal transcranial doppler velocities upon study entry. As per the HOPE‐KIDS1 study design, two received voxelotor at 900 mg per day and one received 1500 mg per day. Baseline MRI/MRA exams were normal in two participants and one had silent cerebral infarcts without vasculopathy. Generally, participants had higher hemoglobin levels and decreased hemolysis while receiving voxelotor. Two patients had lower global CBF while receiving voxelotor and the third showed essentially no change in CBF. Repeat MRI/MRAs showed no new or evolving areas of ischemia and EPO levels did not increase over time.Summary/Conclusion:Vasodilatory autoregulation of the cerebral vasculature enables a rapid and effective mechanism to titrate blood flow based on metabolic demand; increasing cerebral blood flow to offset impaired tissue oxygenation (Guilliams, K. Stroke 2019). In our small cohort of adolescents with SCA, the lack of increase in CBF after treatment with voxelotor suggests that there is no impairment in oxygen unloading to brain tissue. In fact, these preliminary findings of decreasing CBF with rising hemoglobin levels in two patients suggest improved oxygen delivery to the brain. Further study on the effects of voxelotor on cerebral hemodynamics and oxygen delivery is warranted.image

Introduction Silent cerebral infarcts (SCI) and cerebral vessel stenosis are common and progressive in sickle cell anemia (SCA). Most data regarding brain lesions in SCA are cross-sectional or derive from pediatric cohorts with short follow-up not spanning the transition into adulthood. While hydroxyurea and transfusions may reduce the incidence of SCI and abnormal transcranial Doppler (TCD) in children with SCA, data on the effectiveness of these therapies in young adults are lacking. We tested the hypothesis that SCI and cerebral vessel stenosis progressed in young adults with SCA, relative to their childhood years. In addition, we explored the relationship between progression of brain vasculopathy and exposure to disease-modifying therapy. Methods We obtained brain magnetic resonance imaging (MRI) and MR angiography (MRA) in adults with SCA (HbSS or HbSβ0-thalassemia) on chronic transfusions or hydroxyurea. Participants were recruited from the IRB-approved longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program (Hankins et al., PBC 2018). Participants were ages 18.0 to 32.0 at adult imaging and had at least one prior MRI/MRA between 0 and 17.9 years. Pediatric MRI/MRAs were performed for clinical indications (e.g., neurologic concern). All pediatric and adult MRI/MRAs had similar imaging protocols and were centrally reviewed by a neuroradiologist. SCIs were defined as focal T2-weighted or FLAIR hyperintensity. MRIs were considered abnormal if SCI or overt strokes were present. MRI progression was defined as new SCI or new overt strokes. Vessel stenoses were graded using a validated vasculopathy scale from 0 to 6 (Helton et al., Blood 2014). Abnormal MRA was defined as a score ≥1 and progression as any increase in the vasculopathy grading. We retrospectively ascertained childhood TCDs, treatments, overt strokes, and transient ischemic attacks (TIA, <24 hours neurologic symptoms with no imaging change). The proportion of abnormal brain MRI/MRA was calculated for the participants' pediatric (0-11.9), adolescent (12.0-17.9), and young adult (18.0-32.0) years and compared using multivariate generalized linear mixed model. Multivariate logistic regression investigated the association of exposure to hydroxyurea or chronic transfusion with MRI/MRA progression from child to adulthood. Results Forty-one young adults with SCA, all African American, median age 19.0 years, (range 18.0-31.5) were included (Table 1). All received disease-modifying therapy prior to adult MRI/MRA; median duration of hydroxyurea was 10.4 years (range, 0.3 to 20.35) and chronic transfusion was 9.2 years (range, 2.5 to 14.6). Indications for chronic transfusion were: abnormal TCD (N=6), overt stroke (N=4), recurrent vaso-occlusive events (VOE) (N=1), and chronic kidney disease (N=1). Indications for hydroxyurea were: VOE (N=27), overt stroke (N=1), and abnormal TCD (N=1). The total follow-up time from pediatric to adult brain MRI/MRA was 804 person-years, during which 2 patients had new strokes and 5 had TIAs. Progression of MRI and MRA occurred in 12 (29%) and 8 (20%) young adults, respectively, in relation to their pediatric exams (p=0.04 and p=0.01), both among hydroxyurea (Figure 1a) and transfusion (Figure 1b) groups. Both MRI and MRA progression occurred more frequently among those with prior stroke or conditional or abnormal TCD velocities, p=0.015. Controlling for age at adult imaging, exposure to hydroxyurea was associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.01~0.52, p=0.01), but not MRA (OR=0.22, 95%CI: 0.02~2.34, p=0.2). When further adjusting for transfusions, exposure to hydroxyurea was still associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.4~0.64, p=0.021) but not transfusions (OR 0.94, 95%CI: 0.16~5.39, p=0.95). Conclusion Close to a quarter of young adults with SCA treated with disease-modifying therapies for approximately a decade, experienced progression of brain lesions despite treatment with disease-modifying therapies. Among patients exposed to hydroxyurea, less progression of SCIs occurred. Overt stroke or TCD elevation in childhood increased the risk of brain lesion progression. In children with SCA, the presence of SCI and vessel stenosis in childhood should prompt consideration of alternative treatments given the evidence that brain lesions progress as they emerge into adulthood. Disclosures Kang: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Estepp:Forma Therapeutics: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Eli Lilly and Co: Research Funding; Pfizer: Research Funding; Esperion: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. King:Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; Cell Works: Consultancy; Bioline: Consultancy; Celgene: Consultancy; Amphivena Therapeutics: Research Funding; Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; RiverVest: Consultancy; WUGEN: Equity Ownership. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy. Hankins:NHLBI: Honoraria; ASPHO: Honoraria; Novartis: Research Funding; LYNKS Foundation: Research Funding; Bluebird Bio: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Research Funding; National Committee for Quality Assurance: Consultancy.

Uncertainty in defining radiographic treatment failure in pediatric high-grade glioma (pHGG) remains a significant barrier to demonstrating efficacy of novel therapeutics. We employed a large-scale discovery approach in a cohort of pHGG patients to identify quantitative imaging features, which impacted the hazard for death in order to refine radiographic treatment failure criteria. Magnetic Resonance (MR) imaging studies from 108 consecutively treated patients with supratentorial pHGG were evaluated at all serial imaging timepoints (N=1190). The cohort was split into two subsets for discovery (N=56) and validation (N=52). Contrast enhancing tumor and tumoral edema from each time point was segmented using a tumor classifier trained for pHGG. Quantitative radiomic features and their relative and absolute difference between timepoints were calculated from T1, T1+Gd, T2, and FLAIR sequences and were evaluated as time-dependent covariates into a univariate cox proportional hazards model for selection of imaging features which impacted the hazard for death after false discovery rate (FDR) adjustment. Patient (age, KPS), tumor (location, extent of resection), time-point specific as well as relative and absolute change in imaging covariates were evaluated for their relative impact on the hazard for death. All analyses were completed in either SAS v9.3 or R 3.3.3. Quantitative imaging features were noted to have a significant impact on the hazard for death before, and after FDR adjustment in 13% (N=185) and 3.6% (N=52) of 1422 total radiomic features. Edema extracted radiomic features differentially impacted the hazard for death when their absolute and relative difference relative to the prior imaging study was accounted for. Imaging features from individual time-points were more frequently prognostic when derived from tumor (80%) than edema (20%) suggesting a differential impact of T1+Gd enhancing volume on the hazard for death. Validation of the prognostic impact of imaging features from the training dataset in the remaining 52 patients is ongoing. Changes in quantitative imaging measurements from longitudinal MR scans impact the hazard for death and may improve the radiographic definition for treatment failure.

To evaluate the potential of quantitative (radiomic) and qualitative (Visually Accessible Rembrandt Imaging, VASARI) imaging features to distinguish between molecularly defined subgroups in supratentorial pediatric high grade glioma (pHGG) and improve prognostication. METHOD AND Eighty-eight consecutive cases of newly diagnosed supratentorial pHGG with complete pre-operative imaging were systematically reviewed and scored for VASARI and radiomic features. Agreement between two expert reviewers was scored for VASARI features. Calculated radiomic features describing intensity, shape, and texture were extracted from T1, T1+Gd, T2, and FLAIR MRI sequences. Hierarchical clustering is used with the distance based on Spearman correlation and complete-linkage. Bootstrapped patient clusters were verified by reviewing the consensus matrix from bootstrapped samples. Subgroup specific survival was related to pHGG defining mutations, fusions, and amplifications. All analyses were completed in either SAS v9.3 or R 3.3.3. VASARI features were variably concordant across reviewers (median 60% (range, 29-79%)). Univariate cox proportional hazards analysis of VASARI features identified deep white matter invasion (HR 4.1 95% CI 1.9-8.9, p<0.001), multi-centric disease (HR 2.5 95% CI 1.2-5.3, p=0.02), lack of calvarial remodelling (HR 4.5 95% CI 1.6-12.5, p=0.004), and cerebellar invasion (HR 4.5 95% CI 1.7-12.1, p=0.003) as features which increased the hazard for death. Hierarchical clustering of radiomic features identified 2 dominant and 1 lesser patient subgroup with distinctive imaging features, histologic identity and differential survival. Evaluation of the relationship between imaging defined patient subgroups and molecular features is ongoing. Quantitative and qualitative imaging features refine patient subgrouping and improve prognostication.

BACKGROUND AND PURPOSE: Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol. MATERIALS AND METHODS: One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up. RESULTS: Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum (P = .04), corona radiata (P = .02), and superior fronto-occipital fasciculi (P = .02). CONCLUSIONS: Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

Background and Purpose Lower grade gliomas (LGGs), lesions of WHO grades II and III, comprise 10-15% of primary brain tumors. In this first-of-a-kind study, we aim to carry out a radioproteomic characterization of LGGs using proteomics data from the TCGA and imaging data from the TCIA cohorts, to obtain an association between tumor MRI characteristics and protein measurements. The availability of linked imaging and molecular data permits the assessment of relationships between tumor genomic/proteomic measurements with phenotypic features. Materials and Methods Multiple-response regression of the image-derived, radiologist scored features with reverse-phase protein array (RPPA) expression levels generated correlation coefficients for each combination of image-feature and protein or phospho-protein in the RPPA dataset. Significantly-associated proteins for VASARI features were analyzed with Ingenuity Pathway Analysis software. Hierarchical clustering of the results of the pathway analysis was used to determine which feature groups were most strongly correlated with pathway activity and cellular functions. Results The multiple-response regression approach identified multiple proteins associated with each VASARI imaging feature. VASARI features were found to be correlated with expression of IL8, PTEN, PI3K/Akt, Neuregulin, ERK/MAPK, p70S6K and EGF signaling pathways. Conclusion Radioproteomics analysis might enable an insight into the phenotypic consequences of molecular aberrations in LGGs.

The role of perfusion imaging in the management of pediatric high grade glioma is unclear. We evaluated the ability of dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) to determine grade, evaluate post-treatment response and predict treatment failure.

PURPOSE:We sought to investigate the pattern of treatment failure with respect to anatomic extent, radiation dose, and criteria for failure according to the Response Assessment in Neuro-Oncology (RANO). We evaluated the corresponding prognostic significance of these factors in patients with pediatric high-grade glioma (pHGG). METHODS AND MATERIALS:Fifty-six patients with pHGG were enrolled in an institutional phase 1 to 2 prospective trial that included maximal safe resection and radiation therapy with concurrent and adjuvant erlotinib. The radiation therapy dose administered was 54 to 59.4 Gy at 1.8 Gy/d. Tumor progression was defined according to clinical symptoms and imaging features and was classified in relation to the original extent of the tumor, radiation prescription target volume coverage, and RANO criteria (RANOc). RESULTS:With a median follow-up period of 90 months (range, 70-124 months), progression occurred in 48 patients (85.7%) while 8 (14.3%) were without progression. Central failure represented 42.6% of the total cohort, while in-field, marginal, and distant failures occurred in 7.4%, 9.3%, and 22.2%, respectively. Patients with biopsy or subtotal resection had increased rates of central failure and represented 14.81% and 16.67% of the total cohort, respectively. Tumor progression was classified as local, local plus distant, or distant. Among patients with local failure as a component of failure, 5 were considered to have marginal failure. Patients with frontal, temporal, and parietal disease had the highest rates of multifocal failure. A comparison between responses defined by RANOc demonstrated varied time to death (TTD) from progression. CONCLUSIONS:Pediatric high-grade glioma was shown to have high rates of central failure, particularly in cases with limited resection. Patients with central failure had a trend toward more prolonged TTD from failure relative to other failure patterns. The low marginal failure rates seen in this group suggest that less conservative radiation target margins may be possible. TTD from failure varied according to RANO type, suggesting that adult RANOc require modification before being applied to pHGG.

Bithalamic gliomas are rare cancers diagnosed based on poorly defined radiologic criteria. Infiltrative astrocytomas account for most cases. While some previous studies reported dismal outcomes for patients with bithalamic gliomas irrespective of therapy and histologic grade, others described better prognoses even without anticancer therapy. Little is known about their molecular characteristics. We reviewed clinical, radiologic, and histologic features of patients with bithalamic gliomas treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, HIST1H3B, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Eleven patients with bithalamic gliomas were identified. Their median age at diagnosis was 4.8 years (range: 1-15.7). Additional involvement of the brainstem, basal ganglia, and cerebral lobes occurred in 11, 9, and 3 cases, respectively. All patients presented with hydrocephalus. Two-thirds of the patients had a histologic diagnosis of anaplastic astrocytoma. Despite aggressive therapy, our youngest patient, the only one diagnosed before 1 year of age, is the sole long-term survivor. DNA methylation could be performed in seven tumors, all of which clustered with the RTK I 'PDGFRA' subgroup by unsupervised hierarchical analysis of methylation array against a previously published cohort of 59 pediatric high-grade gliomas. Sequencing of hotspots mutations could be done in 10 tumors, none of which harbored H3F3A p.K27 and/or the respective DNA methylation signature, and any other hotspot mutations. Amplification of MDM4 (n = 2), PDGFRA (n = 2), and ID2 combined with MYCN (n = 1) were observed in 7 tumors available for analysis. In comparison with the previously published experience with unilateral high-grade thalamic astrocytomas where H3F3A p.K27 was present in two-thirds of cases, the absence of this molecular subgroup in bithalamic gliomas was striking. This finding suggests that unilateral and bithalamic high-grade gliomas may represent two distinct molecular entities.