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Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (

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Purpose:In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.Patients and Methods:We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.Results:Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS.Conclusions:This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

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Adrenal tumors other than neuroblastoma are uncommon in children. The most frequently encountered are adrenocortical carcinoma and pheochromocytoma. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary adrenal malignancy other than neuroblastoma at diagnosis and during follow-up.

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 AND PURPOSE: Atypical teratoid/rhabdoid tumors and medulloblastomas have similar imaging and histologic features but distinctly different outcomes. We hypothesized that they could be distinguished by MR imaging–based radiomic phenotypes. MATERIALS AND METHODS: We retrospectively assembled T2-weighted and gadolinium-enhanced T1-weighted images of 48 posterior fossa atypical teratoid/rhabdoid tumors and 96 match-paired medulloblastomas from 7 institutions. Using a holdout test set, we measured the performance of 6 candidate classifier models using 6 imaging features derived by sparse regression of 900 T2WI and 900 T1WI Imaging Biomarker Standardization Initiative–based radiomics features. RESULTS: From the originally extracted 1800 total Imaging Biomarker Standardization Initiative–based features, sparse regression consistently reduced the feature set to 1 from T1WI and 5 from T2WI. Among classifier models, logistic regression performed with the highest AUC of 0.86, with sensitivity, specificity, accuracy, and F1 scores of 0.80, 0.82, 0.81, and 0.85, respectively. The top 3 important Imaging Biomarker Standardization Initiative features, by decreasing order of relative contribution, included voxel intensity at the 90th percentile, inverse difference moment normalized, and kurtosis—all from T2WI. CONCLUSIONS: Six quantitative signatures of image intensity, texture, and morphology distinguish atypical teratoid/rhabdoid tumors from medulloblastomas with high prediction performance across different machine learning strategies. Use of this technique for preoperative diagnosis of atypical teratoid/rhabdoid tumors could significantly inform therapeutic strategies and patient care discussions.

Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are both malignancies originating in the lymphatic system and both affect children, but many features differ considerably, impacting workup and management. This paper provides consensus-based imaging recommendations for evaluation of patients with HL and NHL at diagnosis and response assessment for both interim and end of therapy (follow-up).

Background Crizotinib is a first-generation tyrosine kinase inhibitor used for anaplastic lymphoma kinase (ALK) positive cancers. Simple and complex renal cyst formation is a rare complication of crizotinib use that has been reported previously in the adult population. Case We report a case of a right renal mass in a 17-year-old with ALK-positive epithelioid inflammatory myofibroblastic sarcoma treated with Crizotinib. After cessation of Crizotinib and initiating Alectenib, a second generation ALK inhibitor, the mass decreased in size and the patient remained asymptomatic without evidence of recurrence at three months of follow-up.

INTRODUCTION: (131)I-metaiodobenzylguanidine ((131)I-MIBG) is effective in relapsed neuroblastoma. The Children’s Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by (131)I(-)MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma. METHODS: Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an (131)I-MIBG dose escalation (12, 15, 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of (131)I-MIBG feasibility; those who completed (131)I-MIBG therapy were evaluable for assessment of (131)I-MIBG+Bu/Mel feasibility. RESULTS: Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received (131)I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for (131)I-MIBG+Bu/Mel received this combination. Among those who received (131)I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15 and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was 1 toxic death. The (131)I-MIBG and (131)I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% [95% CI: (83.3%, 99.4%)] and 81.0% [95% CI: (60.0%, 92.3%)]. CONCLUSION: This pilot trial demonstrated feasibility and tolerability of administering (131)I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of (131)I-MIBG during induction therapy.

Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

Background Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors. Presently, MRI is the mainstay of disease diagnosis and surveillance. We identify clinically significant computational features from MRI and create a prognostic machine learning model. Methods We isolated tumor volumes of T1-post-contrast (T1) and T2-weighted (T2) MRIs from 177 treatment-naïve DIPG patients from an international cohort for model training and testing. The Quantitative Image Feature Pipeline and PyRadiomics was used for feature extraction. Ten-fold cross-validation of least absolute shrinkage and selection operator Cox regression selected optimal features to predict overall survival in the training dataset and tested in the independent testing dataset. We analyzed model performance using clinical variables (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variables. Results All selected features were intensity and texture-based on the wavelet-filtered images (3 T1 gray-level co-occurrence matrix (GLCM) texture features, T2 GLCM texture feature, and T2 first-order mean). This multivariable Cox model demonstrated a concordance of 0.68 (95% CI: 0.61–0.74) in the training dataset, significantly outperforming the clinical-only model (C = 0.57 [95% CI: 0.49–0.64]). Adding clinical features to radiomics slightly improved performance (C = 0.70 [95% CI: 0.64–0.77]). The combined radiomics and clinical model was validated in the independent testing dataset (C = 0.59 [95% CI: 0.51–0.67], Noether’s test P = .02). Conclusions In this international study, we demonstrate the use of radiomic signatures to create a machine learning model for DIPG prognostication. Standardized, quantitative approaches that objectively measure DIPG changes, including computational MRI evaluation, could offer new approaches to assessing tumor phenotype and serve a future role for optimizing clinical trial eligibility and tumor surveillance.

Background Fetal magnetic resonance imaging (MRI) and spectroscopy (MRS) provide a unique opportunity to non-invasively measure markers of neurodevelopment in survivors of twin-twin transfusion syndrome (TTTS). Objective To characterize fetal brain maturation after laser surgery for TTTS by measuring brain volumes and cerebral metabolite concentrations using fetal MRI + MRS. Study design Prospective study of dual surviving fetuses treated with laser surgery for TTTS. At 4-5 postoperative weeks, fetal MRI was used together with novel image analysis to automatically extract major brain tissue volumes. Fetal MRS was used to measure major metabolite concentrations in the fetal brain. Results Twenty-one twin pairs were studied. The average (±SD) gestational age at MRI was 25.89 (±2.37) weeks. Total brain volume (TBV) was lower in the donors, although cerebral volumes were not different between twin pairs. Recipients showed lower proportions of cortical and cerebellar volumes, normalized to TBV and cerebral volumes. MRS data showed that biochemical differences between twin brains were related to discrepancy in their brain volumes. Conclusion Although donors have a smaller TBV compared to recipients, proportionality of brain tissue volumes are preserved in donors. MRS maturational markers of fetal brain development show that recovery in donors persists 4 weeks after surgery.

Complex congenital heart disease (CHD) is associated with neurodevelopmental impairment, the mechanism of which is unknown. Cerebral cortical dysmaturation in CHD is linked to white matter abnormalities, including developmental vulnerability of the subplate, in relation to oxygen delivery and metabolism deficits. In this study, we report associations between subcortical morphology and white matter metabolism in neonates with CHD using quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS). Multi-modal brain imaging was performed in three groups of neonates close to term-equivalent age: (1) term CHD (n = 56); (2) preterm CHD (n = 37) and (3) preterm control group (n = 22). Thalamic volume and cerebellar transverse diameter were obtained in relation to cerebral metrics and white matter metabolism. Short echo single-voxel MRS of parietal and frontal white matter was used to quantitate metabolites related to brain maturation (n-acetyl aspartate [NAA], choline, myo-inositol), neurotransmitter (glutamate), and energy metabolism (glutamine, citrate, creatine and lactate). Multi-variate regression was performed to delineate associations between subcortical morphological measurements and white matter metabolism controlling for age and white matter injury. Reduced thalamic volume, most pronounced in the preterm control group, was associated with increased citrate levels in all three group in the parietal white matter. In contrast, reduced cerebellar volume, most pronounced in the preterm CHD group, was associated with reduced glutamine in parietal grey matter in both CHD groups. Single ventricle anatomy, aortic arch obstruction, and cyanotic lesion were predictive of the relationship between reduced subcortical morphometry and reduced GLX (particularly glutamine) in both CHD cohorts (frontal white matter and parietal grey matter). Subcortical morphological associations with brain metabolism were also distinct within each of the three groups, suggesting these relationships in the CHD groups were not directly related to prematurity or white matter injury alone. Taken together, these findings suggest that subplate vulnerability in CHD is likely relevant to understanding the mechanism of both cortical and subcortical dysmaturation in CHD infants. Future work is needed to link this potential pattern of encephalopathy of CHD (including the constellation of grey matter, white matter and brain metabolism deficits) to not only abnormal fetal substrate delivery and oxygen conformance, but also regional deficits in cerebral energy metabolism.

Neonates with complex congenital heart disease (CHD) demonstrate microstructural brain dysmaturation, but the relationship with structural network topology is unknown. We performed diffusion tensor imaging (DTI) in term neonates with CHD pre-operatively (N = 61) and post-operatively (N = 50) compared to healthy term controls (N = 91). We used network topology (graph) analyses incorporating different weighted and unweighted approaches and subject-specific white matter segmentation to investigate structural topology differences, as well as a voxel-based analysis (VBA) to confirm the presence of microstructural dysmaturation. We demonstrate cost-dependent network inefficiencies in neonatal CHD in the pre-operative and post-operative period compared to controls, related to microstructural differences. Controlling for cost, we show the presence of increased small-worldness (hierarchical fiber organization) in CHD infants pre-operatively, that persists in the post-operative period compared to controls, suggesting the early presence of brain reorganization. Taken together, topological microstructural dysmaturation in CHD infants is accompanied by hierarchical fiber organization during a protracted critical period of early brain development. Our methodology also provides a pipeline for quantitation of network topology changes in neonates and infants with microstructural brain dysmaturation at risk for perinatal brain injury.

We report two cases of unusual extraneural metastasis in patients with embryonal tumors without central nervous system disease progression and prolonged survival. The first patient presented at 16 years of age with atypical teratoid rhabdoid tumor of the cervical spine. The tumor was confirmed to have loss of INI1, SMARCB1 deletion of exons 1–3, and heterozygous deletion of 22q11.2. The patient received treatment initially per ACNS0333 with high dose chemotherapy and tandem autologous transplants. The patient developed a biopsy-confirmed liver metastasis six months from diagnosis and, subsequently, had disease progression including liver metastases, bony lesions, muscle involvement, and lung nodules. Two and a half years from diagnosis the patient has still not had a relapse in the CNS. The second patient presented with medulloblastoma isolated to the posterior fossa at 11 years of age and was treated on SJMB03 protocol with craniospinal irradiation and high dose chemotherapy. He had his first recurrence in the temporal lobe three years post treatment. He had multiple recurrences in the brain over the next five years treated with re-resections, adjuvant chemotherapy, and gamma knife radiotherapy. He then developed cervical lymphadenopathy, bony lesions, liver lesions, and lung nodules. Cervical lymph node biopsy confirmed medulloblastoma. Next generation sequencing from recurrent tumor showed somatic mutations in p53, KDM6A, and PPP2R1A. Fourteen years from treatment, he has now developed a temporal lobe lesion. These cases are notable for prolonged survival despite widely metastatic disease and genomics predicting poor prognosis as well as metastatic disease disproportionate to CNS disease.

Background Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan. Procedures Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m2 bolus, then 24 grams/m2/day infusion days −4 to −2), with escalating doses of intravenous melphalan (20–125 mg/m2) days −3 and −2, and autologous stem cells day 0 using 3 + 3 dose escalation. Results Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m2 melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m2 (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 μM concentration that showed neuroblastoma preclinical activity with BSO. Conclusions BSO (75 gram/m2) with melphalan (125 mg/m2) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.

After-hours radiologic interpretation by nonradiology attendings or resident radiologists introduces the risk of discrepancies. Clinical outcomes following radiologic discrepancies among pediatric emergency department (ED) patients are poorly described. In particular, children with special healthcare needs (CSHCN), have more opportunities for discrepancies and potential consequences than non- CSHCN. Our objective was to determine the rates and types of radiologic discrepancies, and to compare CSHCN to non-CSHCN.From July 2014 to February 2015, all children who underwent a diagnostic imaging study at a free-standing children's ED were included. Data collected included radiologic studies - type and location - and clinical details - chief complaint and CSHCN type. Differences between preliminary reads and final pediatric radiology attending reads were defined as discrepancies, and categorized by clinical significance. Descriptive statistics, z-tests, and chi-square were used.Over 8months, 8310 visits (7462 unique patients) had radiologic studies (2620 CSHCN, 5690 non-CSHCN). A total of 198 (2.4%) radiologic discrepancies [56 (28.3%) CSHCN, 142 (71.7%) non-CSHCN] were found. Chief complaints for CSCHN were more often within the cardiac, pulmonary and neurologic systems (p0.001 for each), whereas non-CSHCN presented with more trauma (p0.001). The rates of discrepancies (CSHCN 2.1%, non- CSHCN 2.5%, p=0.3) and severity of clinical consequences (p=0.6) were not significantly different between CSHCN and non-CSHCN.Though the frequency and type of radiologic studies performed between CSHCN and non-CSHCN were different, we found no significant difference in the rate of radiologic discrepancies or the rate of clinically significant radiologic discrepancies.

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, ΔCt, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between ΔCt and progression-free survival (PFS). Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their ΔCt values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow Ct was 7.9 ± 0.5 Ct stronger than blood Ct. When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood ΔCt values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood ΔCt values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055). Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374–83. ©2017 AACR.

Purpose Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m2 per day on days 1 to 7 along with irinotecan 50 mg/m2 intravenously and temozolomide 100 mg/m2 orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion Alisertib 60 mg/m2 per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.

Importance Neonatal and infant lumbar puncture is a commonly performed procedure in emergency departments, yet traumatic and unsuccessful lumbar punctures occur 30% to 50% of the time. Dehydration may be a risk factor for unsuccessful lumbar punctures, but to our knowledge, no studies have investigated the use of intravenous (IV) fluid bolus prior to lumbar puncture. Objective To investigate the association of IV fluid bolus administration with the sonographic measure of the neonatal and infant lumbar subarachnoid space. We hypothesized that IV fluids would increase subarachnoid space size. Design, Setting, and Participants Prospective observational study conducted from August 2012 to April 2015.The study took place at the emegency department of the Children’s Hospital Los Angeles, an urban pediatric emergency department with an annual census of 76 000 visits.A convenience sample of patients aged 0 to 3 months were enrolled if they had a clinical presentation consistent with pyloric stenosis. This population was used as a proxy because they are similar in age to patients undergoing lumbar puncture for evaluation of neonatal fever and are routinely given IV fluids for dehydration. Exposures Patients with a sonographic diagnosis of pyloric stenosis underwent additional ultrasonography evaluation to determine the size of the subarachnoid space before and after IV fluids. Main Outcomes and Measures Primary outcomes included the difference in the size of the subarachnoid space in millimeters squared before and 1 hour after administration of an IV fluid bolus in the emergency department. Interobserver consistency for the subarachnoid space measurement between attending radiologists was measured using intraclass correlation coefficient. The Wilcoxon signed-rank test was used to examine changes in subarachnoid space measurements (millimeters squared). Results The study sample consisted of 40 patients with a mean (SD) age of 37 (11.3) days (range, 15-71 days). The mean (SD) size of the subarachnoid space before and 1 hour after IV fluid bolus was 37.8 (11.1) mm 2 and 36.9 (11.2) mm 2 respectively ( P = .42). The intraclass correlation coefficient ranged from 0.96 to 0.99 (95% CI, 0.90-0.99). Conclusions and Relevance Intravenous fluid boluses were not associated with a significant increase in the sonographic measure of the neonatal and infant subarachnoid space.

PURPOSE: The New Approaches to Neuroblastoma Therapy Response Criteria (NANTRC) were developed to optimize response assessment in patients with recurrent/refractory neuroblastoma. Response predictors and associations of the NANTRC version 1.0 (NANTRCv1.0) and prognostic factors with outcome were analyzed. METHODS: A retrospective analysis was performed of patients with recurrent/refractory neuroblastoma enrolled from 2000 to 2009 on 13 NANT Phase 1/2 trials. NANTRC overall response integrated CT/MRI (Response Evaluation Criteria in Solid Tumors [RECIST]), metaiodobenzylguani-dine (MIBG; Curie scoring), and percent bone marrow (BM) tumor (morphology). RESULTS: Fourteen (6.9%) complete response (CR) and 14 (6.9%) partial response (PR) occurred among 203 patients evaluable for response. Five-year progression-free survival (PFS) was 16 ± 3%; overall survival (OS) was 27 ± 3%. Disease sites at enrollment included MIBG-avid lesions (100% MIBG trials; 84% non-MIBG trials), measurable CT/MRI lesions (48%), and BM (49%). By multivariable analysis, Curie score of 0 (P < 0.001), lower Curie score (P = 0.003), no measurable CT/MRI lesions (P = 0.044), and treatment on peripheral blood stem cell (PBSC) supported trials (P = 0.005) were associated with achieving CR/PR. Overall response of stable disease (SD) or better was associated with better OS (P < 0.001). In multivariable analysis, MYCN amplification (P = 0.037) was associated with worse PFS; measurable CT/MRI lesions (P = 0.041) were associated with worse OS; prior progressive disease (PD; P < 0.001/P < 0.001), Curie score > 1 (P < 0.001; P = 0.001), higher Curie score (P = 0.048/0.037), and treatment on non-PBSC trials (P = < 0.001/0.003) were associated with worse PFS and OS. CONCLUSIONS: NANTRCv1.0 response of at least SD is associated with better OS in patients with recurrent/refractory neuroblastoma. Patient and tumor characteristics may predict response and outcome. Identifying these variables can optimize Phase 1/2 trial design to select novel agents for further testing.

To determine associations between patient and clinical factors with postnatal brain metabolism in term neonates with congenital heart disease (CHD) via the use of quantitative magnetic resonance spectroscopy.Neonates with CHD were enrolled prospectively to undergo pre- and postoperative 3T brain magnetic resonance imaging. Short-echo single-voxel magnetic resonance spectroscopy of parietal white matter was used to quantify metabolites related to brain maturation (n-acetyl aspartate, choline, myo- inositol), neurotransmitters (glutamate and gamma-aminobutyric acid), energy metabolism (glutamine, citrate, glucose, and phosphocreatine), and injury/apoptosis (lactate and lipids). Multivariable regression was performed to search for associations between (1) patient-specific/prenatal/preoperative factors with concurrent brain metabolism and (2) intraoperative and postoperative factors with postoperative brain metabolism.A total of 83 magnetic resonance images were obtained on 55 subjects. No patient-specific, prenatal, or preoperative factors associated with concurrent metabolic brain dysmaturation or elevated lactate could be identified. Chromosome 22q11 microdeletion and age at surgery were predictive of altered concurrent white matter phosphocreatine (P .0055). The only significant intraoperative association found was increased deep hypothermic circulatory arrest time with reduced postoperative white matter glutamate and gamma-aminobutyric acid (P .0072). Multiple postoperative factors, including increased number of extracorporeal membrane oxygenation days (P .0067), intensive care unit, length of stay (P .0047), seizures in the intensive care unit (P .0009), and home antiepileptic use (P .0002), were associated with reduced postoperative white matter n-acetyl aspartate.Multiple postoperative factors were found to be associated with altered brain metabolism in term infants with CHD, but not patient-specific, preoperative, or intraoperative factors.

10556Background: In phase I testing in 22 patients with neuroblastoma, the maximum tolerated dose of alisertib tablets with irinotecan/temozolomide was 60 mg/m2/dose. This combination showed signif...

Background Radiolabeled metaiodobenzylguanidine (MIBG) is sensitive and specific for detecting neuroblastoma. The extent of MIBG-avid disease is assessed using Curie scores. Although Curie scoring is prognostic in patients with high-risk neuroblastoma, there is no standardized method to assess the response of specific sites of disease over time. The goal of this study was to develop approaches for Curie scoring to facilitate the calculation of scores and comparison of specific sites on serial scans. Procedure We designed three semiautomated methods for determining Curie scores, each with increasing degrees of computer assistance. Method A was based on visual assessment and tallying of MIBG-avid lesions. For method B, scores were tabulated from a schematic that associated anatomic regions to MIBG-positive lesions. For method C, an anatomic mesh was used to mark MIBG-positive lesions with automatic assignment and tallying of scores. Five imaging physicians experienced in MIBG interpretation scored 38 scans using each method, and the feasibility and utility of the methods were assessed using surveys. Results There was good reliability between methods and observers. The user-interface methods required 57 to 110 seconds longer than the visual method. Imaging physicians indicated that it was useful that methods B and C enabled tracking of lesions. Imaging physicians preferred method B to method C because of its efficiency. Conclusions We demonstrate the feasibility of semiautomated approaches for Curie score calculation. Although more time was needed for strategies B and C, the ability to track and document individual MIBG-positive lesions over time is a strength of these methods.