Abnormal development of thalamic microstructure in premature neonates with congenital heart disease.

Preterm birth is associated with alteration in corticothalamic development, which underlies poor neurodevelopmental outcomes. Our hypothesis was that preterm neonates with CHD would demonstrate abnormal thalamic microstructure when compared to critically ill neonates without CHD. A secondary aim was to identify any association between thalamic microstructural abnormalities and perioperative clinical variables. We compared thalamic DTI measurements in 21 preterm neonates with CHD to two cohorts of neonates without CHD: 28 term and 27 preterm neonates, identified from the same neonatal intensive care unit. Comparison was made with three other selected white matter regions using ROI manual-based measurements. Correlation was made with post-conceptional age and perioperative clinical variables. In preterm neonates with CHD, there were age-related differences in thalamic diffusivity (axial and radial) compared to the preterm and term non-CHD group, in contrast to no differences in anisotropy. Contrary to our hypothesis, abnormal thalamic and optic radiation microstructure was most strongly associated with an elevated first arterial blood gas pO2 and elevated preoperative arterial blood gas pH (p < 0.05). Age-related thalamic microstructural abnormalities were observed in preterm neonates with CHD. Perinatal hyperoxemia and increased perioperative serum pH were associated with abnormal thalamic microstructure in preterm neonates with CHD. This study emphasizes the vulnerability of thalamocortical development in the preterm neonate with CHD.

Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children's Oncology Group (ANBL0621).

BACKGROUND: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population. PROCEDURE: Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease. RESULTS: ABT-751 was well tolerated. The objective response rate was 7%. The median TTP was 42 days (95% CI: 36, 56) in the measureable disease stratum and 45 days (95% CI: 42, 85) in the MIBG-avid disease stratum. TTP was similar to the historical control group (n = 136, median TTP 42 days). For the combined strata (n = 91), 1-year progression free survival (PFS) was 13 ± 4% and overall survival (OS) was 48 ± 5%. CONCLUSIONS: The low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma. However, this trial demonstrates the utility of TTP as the primary endpoint in phase 2 trials in children and adolescents with neuroblastoma.

Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.

BACKGROUND: A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. PROCEDURE: 4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design. RESULTS: Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10-46 courses). 4-HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 µM. An MTD was not reached. CONCLUSIONS: 4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course.

In utero detection of retinoblastoma with fetal magnetic resonance and ultrasound: initial experience.

Purpose Our aim was to evaluate and compare the ability of prenatal ultrasound (US) and fetal magnetic resonance imaging (MRI) to detect retinoblastoma lesions in utero. Methods Fetuses at risk for having bilateral retinoblastoma were enrolled in this prospective study. High-resolution US of the fetal eye was performed at 16 to 18 weeks' gestation, every 4 weeks until 32 weeks, then every 2 weeks until delivery. Fetal MRIs were performed every 8 weeks starting at 16 to 18 weeks of gestation. An exam under anesthesia (EUA) was performed postnatally, the gold standard of this study. Lesions were classified as being elevated or minimally elevated based upon their morphology. Results Of six fetuses suspected or confirmed to be at risk for developing bilateral retinoblastoma, one had tumors on her first postnatal EUA exam. A total of two minimally elevated lesions were seen by the EUA but not detected prenatally by imaging. One elevated lesion (2 mm in height) identified by postnatal EUA was initially identified by prenatal US. Fetal MRI did not detect any lesions. Conclusion Both prenatal US and fetal MRI are limited in the detection of minimally elevated retinoblastoma lesions. Prenatal US appears to be more sensitive than fetal MRI in the detection of elevated retinoblastoma lesions.

Delayed diagnosis of injuries in pediatric trauma: the role of radiographic ordering practices.

OBJECTIVES: We sought to describe the use of radiographic studies in pediatric major trauma patients and determine the extent to which a selective, clinically guided use of imaging contributes to delayed diagnosis of injury (DDI). METHODS: We conducted a retrospective chart review of 324 consecutive pediatric major trauma patients at our level 1 trauma center. One radiologist reviewed all imaging. Delayed diagnosis of injury was defined as detection after more than 12 hours. Equivalency testing was performed to compare radiology use in patients with and without DDI. RESULTS: Twenty-six (8%) of 324 patients had 36 DDI; 27 (75%) of 36 were orthopedic injuries. Median time to DDI detection was 20.5 hours (interquartile range, 15-60.5). During initial evaluation, DDI patients had similar numbers of plain radiographs (3.5 vs 3, P = .54) but more computed tomographic (CT) scans (4 vs 3, P = .03) compared with patients without DDI. Sixteen percent of all patients received CT thorax; 55%, CT cervical spine; and 56%, CT abdomen. Only 1 clinically important DDI was detected solely on the basis of a later CT scan (0.3%; 95% confidence interval, 0-1.5). No cervical spine, intrathoracic, or intraabdominal DDI was attributable to failure to obtain a CT during initial evaluation. Patients with DDI had higher injury severity scores, intubation rates, and pediatric intensive care unit admission rates than those without DDI. CONCLUSIONS: Patients with DDI had similar initial plain x-ray evaluations to patients without DDI, despite DDI patients being more severely injured. Delayed diagnosis of injury was not attributable to inadequate CT use. Most DDIs were orthopedic, highlighting the importance of a tertiary survey and a low threshold for skeletal radiographs.

Hydrographic magnetic resonance imaging of the fetal eye.

Previous work has shown that fetal hydrographic magnetic resonance imaging (MRI) provided additional information complementary to T2-weighted single-shot fast spin echo (ssFSE) images. The objective of this study was to determine if hydrographic MRI provides better conspicuity of fetal eye structures compared with ssFSE MRI. ssFSE and hydrographic images were retrospectively examined in 82 consecutive fetal studies with normal central nervous system without sensitivity encoding. Relative signal intensity values on ssFSE and hydrographic MRI were obtained for vitreous and sclera. Ratios of the signal intensity of vitreous to the signal intensity of sclera were calculated to determine conspicuity. Similar measurements were obtained in a smaller separate data set (n = 41) using hydrographic imaging with sensitivity encoding techniques. The hydrographic images significantly demonstrated greater conspicuity (ratio of vitreous to sclera) than ssFSE images. This was consistent for both sensitivity encoding and no-sensitivity encoding groups. The difference in conspicuity was on average approximately two times greater in the hydrographic images compared with ssFSE images. Hydrographic MRI of the fetal eye provides on average two times greater conspicuity of fetal eye structures than ssFSE imaging. This enhancement is not affected by gestational age or the use of sensitivity encoding parallel imaging techniques.

A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study.

BACKGROUND: Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. PROCEDURE: Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m(2)/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. RESULTS: Twenty-one patients, median age 7.5 (range 0.8-25.6) years were treated with 2 mg/m(2) (n = 4), 3 mg/m(2) (n = 3), or 4 mg/m(2) (n = 14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (grade 3 hypophosphatemia) occurred at 4 mg/m(2) zoledronic acid. Other grades 3-4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 1), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. CONCLUSIONS: Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m(2) every 28 days.

Differential computed tomographic attenuation of metabolically active and inactive adipose tissues: preliminary findings.

This study investigates differences in computed tomography Hounsfield units between metabolically active (brown fat) and inactive adipose tissues (white fat) due to variations in their densities. Positron emission and computed tomographic data from 101 pediatric and adolescent patients were analyzed. Regions of metabolically active and inactive adipose tissues were identified, and standard uptake values and Hounsfield units were measured. Hounsfield units of active brown fat were more positive (P < 0.001) than inactive fat (-62.4 ± 5.3 vs -86.7 ± 7.0) and the difference was observed in both males and females.

Fatal infantile lactic acidosis and a novel homozygous mutation in the SUCLG1 gene: a mitochondrial DNA depletion disorder.

Mitochondrial DNA (mtDNA) depletion syndromes are autosomal recessive conditions in which the mtDNA copy number is greatly decreased in affected tissues. The encephalomyopathic group of these syndromes comprise mutations in SUCLA2 and SUCLG1 subunits [1]. In this report, we describe a patient with fatal infantile lactic acidosis associated with mutations in the SUCLG1 gene and mtDNA depletion. Histological and enzymatic abnormalities in skeletal muscle support the diagnosis of this recently described mitochondrial disorder. This case is unique in that prenatal imaging suggested the diagnosis and that the confirmatory molecular diagnosis was established at 2 weeks of age. We describe prenatal MRI and neonatal laboratory disturbances that can point the clinician toward consideration of this diagnosis when treating infantile lactic acidosis.

Contralateral hemimicrencephaly in neonatal hemimegalencephaly.

Identification of abnormalities in the contralateral hemisphere in patients with hemimegalencephaly is critical in their management. In this report, we present a 5-day-old neonate with hemimegalencephaly who demonstrated an enlarged ipsilateral cerebral hemisphere and diffuse volume loss in the contralateral hemisphere on conventional MR imaging sequences. The ipsilateral frontal white matter demonstrated relatively increased NAA, fractional anistropy, and cerebral blood volume values compared to published normative data. In addition, the white matter of the contralateral hemisphere demonstrated elevated lactate and increased mean diffusivity compared to published normative data, supporting the abnormal conventional MR findings. Advanced MR neuroimaging techniques may help further confirm and characterize abnormalities in the smaller contralateral hemisphere in neonatal hemimegalencephaly.

PET imaging in pediatric neuroradiology: current and future applications.

Molecular imaging with positron emitting tomography (PET) is widely accepted as an essential part of the diagnosis and evaluation of neoplastic and non-neoplastic disease processes. PET has expanded its role from the research domain into clinical application for oncology, cardiology and neuropsychiatry. More recently, PET is being used as a clinical molecular imaging tool in pediatric neuroimaging. PET is considered an accurate and noninvasive method to study brain activity and to understand pediatric neurological disease processes. In this review, specific examples of the clinical use of PET are given with respect to pediatric neuroimaging. The current use of co-registration of PET with MR imaging is exemplified in regard to pediatric epilepsy. The current use of PET/CT in the evaluation of head and neck lymphoma and pediatric brain tumors is also reviewed. Emerging technologies including PET/MRI and neuroreceptor imaging are discussed.

Comparison of iodine-123 metaiodobenzylguanidine (MIBG) scan and [18F]fluorodeoxyglucose positron emission tomography to evaluate response after iodine-131 MIBG therapy for relapsed neuroblastoma.

PURPOSE: Children with relapsed neuroblastoma have poor survival. It is crucial to have a reliable method for evaluating functional response to new therapies. In this study, we compared two functional imaging modalities for neuroblastoma: metaiodobenzylguanidine (MIBG) scan for uptake by the norepinephrine transporter and [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) uptake for glucose metabolic activity. PATIENTS AND METHODS: Patients enrolled onto a phase I study of sequential infusion of iodine-131 ((131)I) MIBG (NANT-2000-01) were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. (131)I-MIBG therapy was administered on days 0 and 14. For each patient, we compared all lesions identified on concomitant FDG-PET and MIBG scans and gave scans a semiquantitative score. RESULTS: The overall concordance of positive lesions on concomitant MIBG and FDG-PET scans was 39.6% when examining the 139 unique anatomic lesions. MIBG imaging was significantly more sensitive than FDG-PET overall and for the detection of bone lesions (P < .001). There was a trend for increased sensitivity of FDG-PET for detection of soft tissue lesions. Both modalities showed similar improvement in number of lesions identified from day 0 to day 56 scan and in semiquantitative scores that correlated with overall response. FDG-PET scans became completely negative more often than MIBG scans after treatment. CONCLUSION: MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET can sometimes play a complementary role, particularly in soft tissue lesions. Complete response by FDG-PET metabolic evaluation did not always correlate with complete response by MIBG uptake.

Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study.

PURPOSE: Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma. PATIENTS AND METHODS: Patients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea. RESULTS: Fourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m(2)/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng . hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression. CONCLUSION: This all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.

Complementary roles of sonography and magnetic resonance imaging in the assessment of fetal urinary tract anomalies.

OBJECTIVE: The purpose of our study was to determine whether fetal magnetic resonance imaging (MRI) provides additional information that might affect the obstetric management of pregnancies complicated by sonographically diagnosed fetal urinary tract anomalies. METHODS: Fetal MRI and sonography were used to study 39 women with suspected fetal urinary tract anomalies in the second and third trimesters of pregnancy. RESULTS: In 24 of 39 cases (61%), fetal MRI confirmed the sonographic diagnosis. In 14 cases (36%), fetal MRI modified the initial sonographic diagnosis and counseling but did not change obstetric management. In 1 case (3%), the addition of fetal MRI resulted in a substantial change in the management of the pregnancy. CONCLUSIONS: During the second and third trimesters of pregnancy, fetal MRI showed fetal urinary tract anomalies in excellent anatomic detail. Fetal MRI is a useful complementary tool in the assessment of sonographically diagnosed fetal urinary tract anomalies. In a small percentage of cases, it can have a substantial impact on obstetric management.