Hollie Lai

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

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/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) 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/m(2), 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/m(2) 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.

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High‐Risk Neuroblastoma

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.

Intravenous Fluid Bolus Prior to Neonatal and Infant Lumbar Puncture: A Sonographic Assessment of the Subarachnoid Space After Intravenous Fluid Administration

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 emergency department of the Childrens 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.

Clinical Factors Associated with Cerebral Metabolism in Term Neonates with Congenital Heart Disease

Objective 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. Study design 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. Results 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. Conclusion 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.

Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease

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.

Predictors of response, progression-free survival, and overall survival using NANT Response Criteria (v1.0) in relapsed and refractory high-risk neuroblastoma

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.

Structural network topology correlates of microstructural brain dysmaturation in term infants with congenital heart disease

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 preoperatively (N = 61) and postoperatively (N = 50) compared with 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‐ and postoperative period compared with controls, related to microstructural differences. Controlling for cost, we show the presence of increased small‐worldness (hierarchical fiber organization) in CHD infants preoperatively, that persists in the postoperative period compared with 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.

Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis

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.

Radiologic discrepancies in children with special healthcare needs in a pediatric emergency department

Background: 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. Methods: From July 2014 to February 2015, all children who underwent a diagnostic imaging study at a free‐standing childrens 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. Results: Over 8 months, 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 (p < 0.001 for each), whereas non‐CSHCN presented with more trauma (p < 0.001). 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. Conclusion: 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.