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1.  Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: A report from the Children's Oncology Group (ANBL0621) 
Pediatric blood & cancer  2013;61(6):990-996.
ABT-751 is an orally bioavailable sulfonamide that binds the colchicine site of beta-tubulin, thus inhibiting microtubule polymerizaton. A prior phase I study established the recommended dose in children with solid tumors as 200 mg/m2 PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study in children 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.
Experimental Design
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 123I-metaiodobenzylguanine scintigraphy (MIBG, n=44). Response was evaluated using RECIST for measureable disease and the Curie scale for MIBG-avid disease.
ABT-751 was well tolerated. Two complete responses and four partial responses were achieved. 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. These values are similar to TTP in the historical control group (n=136, median TTP 42 days). One-year progression free (PFS) and overall survival (OS) for the combined strata (n=91) were 13%±4%, 48%±5%, respectively.
Although ABT-751 has many characteristics of an ideal maintenance agent for neuroblastoma, the low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma.
PMCID: PMC5127168  PMID: 24347462
neuroblastoma; time to progression; clinical trial; microtubule inhibitor; childhood cancer
2.  Phase 1 Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma 
131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase 1 study was to determine the maximum tolerated doses of vorinostat and MIBG in combination.
Experimental Design
Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily Days 1–14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on Day 3 and peripheral blood stem cells on Day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.
27 patients enrolled to 6 dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), two patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on Days 3 and 12–14.
Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase 2 trial comparing this regimen to single-agent MIBG is ongoing.
PMCID: PMC4470833  PMID: 25695691
131I-MIBG; Vorinostat; Radiation Sensitizer; Neuroblastoma; Relapse; Refractory
3.  Abnormal Development of Thalamic Microstructure in Premature Neonates with Congenital Heart Disease 
Pediatric cardiology  2015;36(5):960-969.
Background and Purpose
Preterm birth is associated with alteration in cortico-thalamic 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 peri-operative clinical variables.
Material and Methods
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 peri-operative 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 pre-operative arterial blood gas pH (p<0.05).
Age-related thalamic microstructural abnormalities were observed in preterm neonates with CHD. Perinatal hyperoxemia and increased peri-operative serum pH was associated with abnormal thalamic microstructure in preterm neonates with CHD. This study emphasizes the vulnerability of thalamo-cortical development in the preterm neonate with CHD.
PMCID: PMC4433609  PMID: 25608695
4.  Toxicity and management in CAR T-cell therapy 
T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, “on target/off tumor” recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.
PMCID: PMC5008265  PMID: 27626062
5.  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 
Pediatric blood & cancer  2013;60(11):1801-1808.
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.
4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design.
Thirty-two patients (median age = 8 years, range 3 – 27 years) enrolled with thirty evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), 125/131I-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/m2/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m2/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1700 mg/m2/day. Of twenty-nine 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 fold higher (P<0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1700 mg/m2/day was 21 μM. An MTD was not reached.
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 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.
PMCID: PMC4066886  PMID: 23813912
fenretinide; neuroblastoma; pediatric; powder; Lym-X-Sorb™
6.  Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: A report from the Children’s Oncology Group NSC #374551; IND# 40294 
To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma.
Experimental Design
Patients received 7 days of fenretinide: 2475 mg/m2/day divided TID (<18 years) or 1800 mg/m2/day divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in Stratum 1 (measurable disease on CT/MRI +/− bone marrow and/or MIBG avid sites) and Stratum 2 (bone marrow and/or MIBG avid sites only).
Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in Stratum 1 (n=38) and Stratum 2 (n=24). One partial response (PR) was seen in Stratum 2 (n=24 evaluable). No responses were seen in Stratum 1 (n=35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in Stratum 1 and 6 patients in Stratum 2 for 4–45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for Stratum 1 and 48 days (range 17–892) for Stratum 2. Mean 4-HPR steady state trough plasma concentrations were 7.25 µM (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible.
Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric Phase I studies.
PMCID: PMC3207022  PMID: 21908574
fenretinide; neuroblastoma; Phase II; ANBL0321
7.  In Utero Detection of Retinoblastoma with Fetal Magnetic Resonance and Ultrasound: Initial Experience 
AJP Reports  2012;2(1):55-62.
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.
PMCID: PMC3653521  PMID: 23946908
retinoblastoma; prenatal ultrasound; fetal MRI; extraocular abnormalities
8.  A Phase I Study of Zoledronic Acid and Low Dose Cyclophosphamide in Recurrent/Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) Study 
Pediatric blood & cancer  2010;57(2):275-282.
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.
Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m2/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated.
Twenty-one patients, median age 7.5 (range 0.8 - 25.6) years were treated with 2 mg/m2 (n=4), 3 mg/m2 (n=3), or 4 mg/m2 (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/m2 zoledronic acid. Other Grade 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.
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/m2 every 28 days.
PMCID: PMC3117015  PMID: 21671363
Phase I; neuroblastoma; bisphosphonate
9.  Functional Brown Adipose Tissue is Related to Muscle Volume in Children and Adolescents 
The Journal of Pediatrics  2010;158(5):722-726.
We examined whether the depiction of brown adipose tissue (BAT) with positron emission tomography/computed tomography (PET/CT) in pediatric patients is associated with anthropometric meaures.
Study design
We determined measures of body mass, adiposity, and musculature in 71 children and adolescents who underwent PET/CT examinations and compared patients with and without BAT. We used regression analyses to assess the relation between BAT and anthropometric measures.
A total of 30 patients (42%) had BAT depicted on PET/CT, 10 of 26 girls (38%) and 20 of 45 boys (44%). Compared with patients without functional BAT, patients with BAT had significantly greater neck musculature (1880 ± 908 cm3 versus 1299 ± 806 cm3; P = .028 for boys and 1295 ± 586 cm3 versus 854 ± 392 cm3; P = .030 for girls) and gluteus musculature (1359 ± 373 cm3 versus 1061 ± 500 cm3; P = .032 for boys and 1138 ± 425 cm3 versus 827 ± 297 cm3; P = .038 for girls), but no differences in age, body mass index, or measures of subcutaneous fat. With logistic regression analyses, neck and pelvic musculature predicted the presence of BAT independently of age, sex, body size, and season of scan (P = .018 and .009, respectively).
Pediatric patients with visualized BAT on PET/CT examinations had significantly greater muscle volume than patients with no visualized BAT.
PMCID: PMC3319332  PMID: 21168855
10.  Differential CT Attenuation of Metabolically Active and Inactive Adipose Tissues — Preliminary Findings 
This study investigates differences in CT Hounsfield units (HUs) between metabolically active (brown fat) and inactive adipose tissues (white fat) due to variations in their densities. PET/CT data from 101 pediatric and adolescent patients were analyzed. Regions of metabolically active and inactive adipose tissues were identified and standard uptake values (SUVs) and HUs were measured. HUs of active brown fat were more positive (p<0.001) than inactive fat (−62.4±5.3 versus −86.7±7.0) and the difference was observed in both males and females.
PMCID: PMC3074500  PMID: 21245691
Brown adipose tissue; White adipose tissue; PET/CT; Tissue attenuation; Hounsfield units
11.  Comparison of Iodine-123 Metaiodobenzylguanidine (MIBG) Scan and [18F]Fluorodeoxyglucose Positron Emission Tomography to Evaluate Response After Iodine-131 MIBG Therapy for Relapsed Neuroblastoma 
Journal of Clinical Oncology  2009;27(32):5343-5349.
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 [18F]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 (131I) MIBG (NANT-2000-01) were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. 131I-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.
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.
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.
PMCID: PMC2773221  PMID: 19805691
12.  Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study 
Journal of Clinical Oncology  2009;27(8):1290-1296.
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.
Fourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m2/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.
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.
PMCID: PMC2667827  PMID: 19171709
13.  Iodine-131—Metaiodobenzylguanidine Double Infusion With Autologous Stem-Cell Rescue for Neuroblastoma: A New Approaches to Neuroblastoma Therapy Phase I Study 
Journal of Clinical Oncology  2009;27(7):1020-1025.
Iodine-131—metaiodobenzylguanidine (131I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of 131I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose.
Patients and Methods
The 131I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg.
Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative 131I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/μL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients.
The lack of toxicity with this approach allowed dramatic dose intensification of 131I-MIBG, with minimal toxicity and promising activity.
PMCID: PMC2738616  PMID: 19171714

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