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1.  Prognostic Value of the Stage 4S Metastatic Pattern and Tumor Biology in Patients With Metastatic Neuroblastoma Diagnosed Between Birth and 18 Months of Age 
Journal of Clinical Oncology  2011;29(33):4358-4364.
Purpose
Patients with neuroblastoma younger than 12 months of age with a 4S pattern of disease (metastases limited to liver, skin, bone marrow) have better outcomes than infants with stage 4 disease. The new International Neuroblastoma Risk Group (INRG) staging system extends age to 18 months for the 4S pattern. Our aim was to determine which prognostic features could be used for optimal risk classification among patients younger than 18 months with metastatic disease.
Methods
Event-free survival (EFS) and overall survival were analyzed by log-rank tests, Cox models, and survival tree regression for 656 infants with stage 4S neuroblastoma younger than 12 months of age and 1,019 patients with stage 4 disease younger than 18 months of age in the INRG database.
Results
Unfavorable biologic features were more frequent in infants with stage 4 disease than in infants with 4S tumors and higher overall in those age 12 to 18 months (although not different for stage 4 v 4S pattern). EFS was significantly better for infants younger than 12 months with 4S pattern than with stage 4 disease (P < .01) but similar for toddlers age 12 to 18 months with stage 4 versus 4S pattern. Among 717 patients with stage 4S pattern, patients age 12 to 18 months had worse EFS than those age younger than 12 months (P < .01). MYCN, 11q, mitosis-karyorrhexis index (MKI), ploidy, and lactate dehydrogenase were independently statistically significant predictors of EFS and more highly predictive than age or metastatic pattern. MYCN, 11q, MKI, histology, and 1p were combined in a survival tree for improved risk stratification.
Conclusion
Tumor biology is more critical than age or metastatic pattern for prognosis of patients age younger than 18 months with metastatic neuroblastoma and should be considered for risk stratification.
doi:10.1200/JCO.2011.35.9570
PMCID: PMC3221520  PMID: 21969516
2.  Clinical Significance of Tumor-Associated Inflammatory Cells in Metastatic Neuroblastoma 
Journal of Clinical Oncology  2012;30(28):3525-3532.
Purpose
Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.
Methods
Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.
Results
Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.
Conclusion
These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
doi:10.1200/JCO.2011.40.9169
PMCID: PMC3675667  PMID: 22927533
3.  Outcome After Surgery Alone or With Restricted Use of Chemotherapy for Patients With Low-Risk Neuroblastoma: Results of Children's Oncology Group Study P9641 
Journal of Clinical Oncology  2012;30(15):1842-1848.
Purpose
The primary objective of Children's Oncology Group study P9641 was to demonstrate that surgery alone would achieve 3-year overall survival (OS) ≥ 95% for patients with asymptomatic International Neuroblastoma Staging System stages 2a and 2b neuroblastoma (NBL). Secondary objectives focused on other low-risk patients with NBL and on those who required chemotherapy according to protocol-defined criteria.
Patients and Methods
Patients underwent maximally safe resection of tumor. Chemotherapy was reserved for patients with, or at risk for, symptomatic disease, with less than 50% tumor resection at diagnosis, or with unresectable progressive disease after surgery alone.
Results
For all 915 eligible patients, 5-year event-free survival (EFS) and OS were 89% ± 1% and 97% ± 1%, respectively. For patients with asymptomatic stage 2a or 2b disease, 5-year EFS and OS were 87% ± 2% and 96% ± 1%, respectively. Among patients with stage 2b disease, EFS and OS were significantly lower for those with unfavorable histology or diploid tumors, and OS was significantly lower for those ≥ 18 months old. For patients with stage 1 and 4s NBL, 5-year OS rates were 99% ± 1% and 91% ± 1%, respectively. Patients who required chemotherapy at diagnosis achieved 5-year OS of 98% ± 1%. Of all patients observed after surgery, 11.1% experienced recurrence or progression of disease.
Conclusion
Excellent survival rates can be achieved in asymptomatic low-risk patients with stages 2a and 2b NBL after surgery alone. Immediate use of chemotherapy may be restricted to a minority of patients with low-risk NBL. Patients with stage 2b disease who are older or have diploid or unfavorable histology tumors fare less well. Future studies will seek to refine risk classification.
doi:10.1200/JCO.2011.37.9990
PMCID: PMC3383182  PMID: 22529259
4.  Promising therapeutic targets in neuroblastoma 
Clinical Cancer Research  2012;18(10):2740-2753.
Neuroblastoma, the most common extra- cranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease, and have 5-year EFS of less than 50%. New approaches with targeted therapy may improve efficacy without increased toxicity. The current review will evaluate three promising targeted therapies, including 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical taken up by the human norepinephrine transporter expressed in 90% of neuroblastomas, immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, expressed on 98% of neuroblastoma cells, and inhibitors of ALK, a tyrosine kinase which is mutated or amplified in approximately 10% of neuroblastoma and expressed on the surface of most neuroblastoma cells. Early phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of about 30%, but the technical aspects of administration of large amounts of radioactivity in young children and the limited access have hindered incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also demonstrated activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small molecule inhibitor of ALK has promising pre-clinical activity for neuroblastoma, and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma.
doi:10.1158/1078-0432.CCR-11-1939
PMCID: PMC3382042  PMID: 22589483
5.  Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study 
Cancer chemotherapy and pharmacology  2011;68(4):1057-1065.
Purpose
TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma.
Methods
Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle.
Results
Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M2/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3–4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M2 with uniform inhibition at 120 mg/M2. There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M2/dose BID was established.
Conclusions
Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.
doi:10.1007/s00280-011-1581-4
PMCID: PMC4238911  PMID: 21340605
Neuroblastoma; Receptor tyrosine kinase; Targeted therapy; Lestaurtinib; Signal transduction
6.  Evaluation of plasma annexin V levels in children and young adults with solid tumors 
Background
Annexin V staining has become a standard approach for identifying cells undergoing apoptosis in vitro and can be detected in plasma. We hypothesized that plasma annexin V levels might serve as a clinical marker of tumor burden and cell turnover in children and young adults with solid tumors.
Methods
Nine patients aged 4–22 with newly diagnosed solid tumors were enrolled. Plasma samples were obtained prior to and, in a subset of patients, after initiation of chemotherapy from which annexin V levels were determined by enzyme-linked immunosorbent assay (ELISA).
Results
Three of nine patients had elevated plasma annexin V levels (> 10 ng/mL) at diagnosis and there was poor correlation to LDH levels, a commonly used marker of cell turnover (r = 0.66). Of the five patients with annexin V levels obtained after starting chemotherapy, only one showed an increase over the time period assessed.
Conclusions
Plasma annexin V does not appear to be a useful marker of tumor burden or early response to chemotherapy in children with solid tumors.
doi:10.5301/JBM.2012.9288
PMCID: PMC4222526  PMID: 22610756
annexin V; apoptosis; laboratory correlates; pediatric cancers; Sarcoma/soft tissue malignancies
7.  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.
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 - 2210 mg/m2/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 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.
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 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.
doi:10.1002/pbc.24643
PMCID: PMC4066886  PMID: 23813912
fenretinide; neuroblastoma; pediatric; powder; Lym-X-Sorb™
8.  Pilot Induction Regimen Incorporating Pharmacokinetically Guided Topotecan for Treatment of Newly Diagnosed High-Risk Neuroblastoma: A Children's Oncology Group Study 
Journal of Clinical Oncology  2011;29(33):4351-4357.
Purpose
To assess the feasibility of adding dose-intensive topotecan and cyclophosphamide to induction therapy for newly diagnosed high-risk neuroblastoma (HRNB).
Patients and Methods
Enrolled patients received two cycles of topotecan (approximately 1.2 mg/m2/d) and cyclophosphamide (400 mg/m2/d) for 5 days followed by four cycles of multiagent chemotherapy (Memorial Sloan-Kettering Cancer Center [MSKCC] regimen). Pharmacokinetically guided topotecan dosing (target systemic exposure with area under the curve of 50 to 70 ng/mL/hr) was performed. Peripheral-blood stem cell (PBSC) harvest and surgical resection of residual primary tumor occurred after cycles 2 and 5, respectively. Patients achieving at least a partial response received myeloablative chemotherapy with PBSC rescue and radiation to the presurgical primary tumor volume. Oral 13-cis-retinoic acid maintenance therapy was administered twice daily for 14 days in six 28-day cycles.
Results
Thirty-one patients were enrolled onto the study. No deaths related to toxicity or dose-limiting toxicities occurred during induction. Mucositis rarely occurred after topotecan cycles (9.7%) in contrast to 30% after MSKCC cycles. Thirty patients underwent PBSC collection with median 31.1 × 106 CD34+ cells/kg (range, 1.8 to 541.8 × 106 CD34+ cells/kg), all negative for tumor contamination by immunocytochemical analysis. Targeted topotecan systemic exposure was achieved in 26 (84%) of 31 patients. At the end of induction, 26 patients (84%) had tumor response and one patient had progressive disease. In the overall cohort, 3-year event-free and overall survival were 37.8% ± 9.4% and 57.1% ± 9.4%, respectively.
Conclusion
This pilot induction regimen was well tolerated with expected and reversible toxicities. These data support investigation of efficacy in a phase III clinical trial for newly diagnosed HRNB.
doi:10.1200/JCO.2010.34.3293
PMCID: PMC3221519  PMID: 22010014
9.  Response, Survival and Toxicity after 131I-MIBG Therapy for Neuroblastoma in Pre-Adolescents, Adolescents and Adults 
Cancer  2011;117(18):4286-4293.
BACKGROUND
Adolescent and adult patients with neuroblastoma appear to have a more indolent disease course but a lower survival than their younger counterparts. The majority of neuroblastoma tumors specifically accumulate the radiolabeled norepinephrine analogue 131I-metaiodobenzylguanidine (MIBG). 131I-MIBG has therefore become increasingly used as targeted radiotherapy for relapsed or refractory neuroblastoma. The aim of this study was to characterize the toxicity and activity of this therapy in older patients.
METHODS
We performed a retrospective analysis of 39 consecutive patients ages 10 years and older with relapsed or refractory neuroblastoma who were treated with 131I-MIBG monotherapy at UCSF under Phase I, Phase II, and compassionate access protocols.
RESULTS
Sixteen patients were ≥18 years old at MIBG treatment initiation, whereas twenty-three were 10–17 years old. The median cumulative administered dose of 131I-MIBG was 17.8 mCi/kg. The majority of treatments led to grade 3 or 4 hematologic toxicities which were similar in frequency among age strata. Three patients subsequently developed hematologic malignancy or myelodysplasia. The overall rate of complete plus partial response was 46%. Patients ≥18 years old at time of first MIBG treatment had a significantly higher response rate compared to patients 10–17 years old (56% vs 39%, p=0.023). Median overall survival was 23 months with a trend toward longer overall survival for the ≥18 year old subgroup (p = 0.12).
CONCLUSIONS
Our findings suggest that 131I-MIBG is a highly effective salvage agent for adolescents and adults with neuroblastoma.
doi:10.1002/cncr.25987
PMCID: PMC3125487  PMID: 21387264
neuroblastoma; adult; adolescent; MIBG; radiopharmaceutical
10.  Clinical and Biologic Features Predictive of Survival After Relapse of Neuroblastoma: A Report From the International Neuroblastoma Risk Group Project 
Journal of Clinical Oncology  2011;29(24):3286-3292.
Purpose
Survival after neuroblastoma relapse is poor. Understanding the relationship between clinical and biologic features and outcome after relapse may help in selection of optimal therapy. Our aim was to determine which factors were significantly predictive of postrelapse overall survival (OS) in patients with recurrent neuroblastoma—particularly whether time from diagnosis to first relapse (TTFR) was a significant predictor of OS.
Patients and Methods
Patients with first relapse/progression were identified in the International Neuroblastoma Risk Group (INRG) database. Time from study enrollment until first event and OS time starting from first event were calculated. Cox regression models were used to calculate the hazard ratio of increased death risk and perform survival tree regression. TTFR was tested in a multivariable Cox model with other factors.
Results
In the INRG database (N = 8,800), 2,266 patients experienced first progression/relapse. Median time to relapse was 13.2 months (range, 1 day to 11.4 years). Five-year OS from time of first event was 20% (SE, ± 1%). TTFR was statistically significantly associated with OS time in a nonlinear relationship; patients with TTFR of 36 months or longer had the lowest risk of death, followed by patients who relapsed in the period of 0 to less than 6 months or 18 to 36 months. Patients who relapsed between 6 and 18 months after diagnosis had the highest risk of death. TTFR, age, International Neuroblastoma Staging System stage, and MYCN copy number status were independently predictive of postrelapse OS in multivariable analysis.
Conclusion
Age, stage, MYCN status, and TTFR are significant prognostic factors for postrelapse survival and may help in the design of clinical trials evaluating novel agents.
doi:10.1200/JCO.2010.34.3392
PMCID: PMC3158599  PMID: 21768459
11.  Clinical Features and Outcomes Differ between Skeletal and Extraskeletal Osteosarcoma 
Sarcoma  2014;2014:902620.
Background. Extraskeletal osteosarcoma (ESOS) is a rare subtype of osteosarcoma. We investigated patient characteristics, overall survival, and prognostic factors in ESOS. Methods. We identified cases of high-grade osteosarcoma with known tissue of origin in the Surveillance, Epidemiology, and End Results database from 1973 to 2009. Demographics were compared using univariate tests. Overall survival was compared with log-rank tests and multivariate analysis using Cox proportional hazards methods. Results. 256/4,173 (6%) patients with high-grade osteosarcoma had ESOS. Patients with ESOS were older, were more likely to have an axial tumor and regional lymph node involvement, and were female. Multivariate analysis showed ESOS to be favorable after controlling for stage, age, tumor site, gender, and year of diagnosis [hazard ratio 0.75 (95% CI 0.62 to 0.90); p = 0.002]. There was an interaction between age and tissue of origin such that older patients with ESOS had superior outcomes compared to older patients with skeletal osteosarcoma. Adverse prognostic factors in ESOS included metastatic disease, larger tumor size, older age, and axial tumor site. Conclusion. Patients with ESOS have distinct clinical features but similar prognostic factors compared to skeletal osteosarcoma. Older patients with ESOS have superior outcomes compared to older patients with skeletal osteosarcoma.
doi:10.1155/2014/902620
PMCID: PMC4175789  PMID: 25294959
12.  Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial 
The lancet oncology  2013;14(10):999-1008.
Summary
Background
Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma.
Methods
Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either nonpurged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus metaiodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188.
Findings
495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33–46) in the purged group versus 36% (30–42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43–56) in the purged group compared with 51% (44–57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group).
Interpretation
Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma.
Funding
National Cancer Institute and Alex’s Lemonade Stand Foundation.
doi:10.1016/S1470-2045(13)70309-7
PMCID: PMC3963485  PMID: 23890779
13.  Thyroid and Hepatic Function After High Dose 131I-Metaiodobenzylguanidine (131I-MIBG) Therapy for Neuroblastoma 
Pediatric blood & cancer  2010;56(2):191-201.
Background
131I-Metaiodobenzylguanidine (131I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and MIBG is concentrated in the liver after MIBG therapy. The aim of our study was to analyze the effects of 131I-MIBG therapy on thyroid and liver function.
Procedure
Pre and post therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with 131I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.
Results
In patients who presented with Grade 0 or Grade 1 thyroid toxicity at baseline, 12±4% experienced onset or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by two years after 131I-MIBG therapy. At two years post 131I-MIBG therapy, 76±4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23±5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity usually was transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.
Conclusion
The prophylactic regimen of potassium iodide and potassium perchlorate with 131I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following 131I-MIBG therapy were primarily reversible and did not result in late toxicity. 131I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.
doi:10.1002/pbc.22767
PMCID: PMC3006009  PMID: 20830775
Neuroblastoma; 131I-MIBG; Hypothyroidism
14.  Relevance of Historical Therapeutic Approaches to the Contemporary Treatment of Pediatric Solid Tumors 
Pediatric blood & cancer  2013;60(7):10.1002/pbc.24487.
Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects.
doi:10.1002/pbc.24487
PMCID: PMC3810072  PMID: 23418018
Childhood cancer therapy; late effects; long-term follow-up
15.  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.
Purpose
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.
Results
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.
Conclusion
The lack of toxicity with this approach allowed dramatic dose intensification of 131I-MIBG, with minimal toxicity and promising activity.
doi:10.1200/JCO.2007.15.7628
PMCID: PMC2738616  PMID: 19171714
16.  Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children's Oncology Group Study 
Journal of Clinical Oncology  2009;27(7):1007-1013.
Purpose
We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or to receive chemotherapy, and subsequent treatment with 13-cis-retinoic acid (cis-RA).
Patients and Methods
Patients received the same induction chemotherapy, with random assignment (N = 379) to consolidation with myeloablative chemotherapy, total-body irradiation, and ABMT versus three cycles of intensive chemotherapy. Patients who completed consolidation without disease progression were randomly assigned to receive no further therapy or cis-RA for 6 months.
Results
The event-free survival (EFS) for patients randomly assigned to ABMT was significantly higher than those randomly assigned to chemotherapy; the 5-year EFS (mean ± SE) was 30% ± 4% versus 19% ± 3%, respectively (P = .04). The 5-year EFS (42% ± 5% v 31% ± 5%) from the time of second random assignment was higher for cis-RA than for no further therapy, though it was not significant. Overall survival (OS) was significantly higher for each random assignment by a test of the log(−log(.)) transformation of the survival estimates at 5 years (P < .01). The 5-year OS from the second random assignment of patients who underwent both random assignments and who were assigned to ABMT/cis-RA was 59% ± 8%; for ABMT/no cis-RA, it was 41% ± 7%; for continuing chemotherapy/cis-RA, it was 38% ± 7%; and for chemotherapy/no cis-RA, it was 36% ± 7%.
Conclusion
Myeloablative therapy and autologous hematopoietic cell rescue result in significantly better 5-year EFS and OS than nonmyeloablative chemotherapy; cis-RA given after consolidation independently results in significantly improved OS.
doi:10.1200/JCO.2007.13.8925
PMCID: PMC2738615  PMID: 19171716
17.  Radiolabeled Metaiodobenzylguanidine for the Treatment of Neuroblastoma 
Nuclear medicine and biology  2008;35(Suppl 1):S35-S48.
Introduction
Neuroblastoma is the most common pediatric extracranial solid cancer. This tumor is characterized by metaiodobenzylguanidine (MIBG) avidity in 90% of cases, prompting the use of radiolabeled MIBG for targeted radiotherapy in these tumors.
Methods
The available English language literature was reviewed for original research investigating in vitro, in vivo, and clinical applications of radiolabeled MIBG for neuroblastoma.
Results
MIBG is actively transported into neuroblastoma cells by the norepinephrine transporter. Preclinical studies demonstrate substantial activity of radiolabeled MIBG in neuroblastoma models, with 131I-MIBG showing enhanced activity in larger tumors compared to 125I-MIBG. Clinical studies of 131I-MIBG in patients with relapsed or refractory neuroblastoma have identified myelosuppression as the main dose-limiting toxicity, necessitating stem cell reinfusion at higher doses. Most studies report a response rate of 30–40% with 131I-MIBG in this population. More recent studies have focused on the use of 131I-MIBG in combination with chemotherapy or myeloablative regimens.
Conclusions
131I-MIBG is an active agent for the treatment of patients with neuroblastoma. Future studies will need to define the optimal role of this targeted radiopharmaceutical in the therapy of this disease.
doi:10.1016/j.nucmedbio.2008.05.002
PMCID: PMC2633223  PMID: 18707633
Metaiodobenzylguanidine; neuroblastoma; pediatric; radionuclide
18.  Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study 
BMC Research Notes  2014;7:256.
Background
Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.
Case presentation
On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.
Conclusions
After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.
doi:10.1186/1756-0500-7-256
PMCID: PMC4006848  PMID: 24755475
Ceftriaxone; Fenretinide; Acetaminophen; Drug interaction; Biliary sludge; Fulminant hepatic failure
19.  Characteristics and Outcomes of Patients with Ewing Sarcoma Over 40 Years of Age at Diagnosis 
Cancer epidemiology  2012;37(1):29-33.
Background
The peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥ 40 years at diagnosis. We describe the clinical characteristics and survival of this rare group.
Methods
This retrospective cohort study utilized the Surveillance Epidemiology and End Results database. 2780 patients were identified; including 383 patients diagnosed ≥ 40 years. Patient characteristics between age groups were compared using chi-squared tests. Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer.
Results
Patients ≥ 40 years of age were more likely to have extra-skeletal tumors (66.1% v 31.7%; p<0.001), axial tumors (64.0% v 57.2%; p=0.01), and metastatic disease at diagnosis (35.5% v 30.0%; p=0.04) compared to younger patients. Five-year survival for those age ≥ 40 and age < 40 were 40.6% and 54.3%, respectively (p<0.0001). A Cox multivariable model controlling for differences between groups confirmed inferior survival for older patients (hazard ratio for death of 2.04; 95% CI 1.63 - 2.54; p < 0.0001); though treatment data were unavailable and not controlled for in the model. A competing risks analysis confirmed increased risk of cancer-related death in older patients.
Conclusion
Patients ≥ 40 years at diagnosis with EWS are more likely to have extra-skeletal tumors, metastatic disease, and axial primary tumors suggesting a difference in tumor biology. Independent of differences in these characteristics, older patients also have a lower survival rate.
doi:10.1016/j.canep.2012.08.006
PMCID: PMC3543501  PMID: 22959474
Ewing sarcoma; pediatric cancers; adult; age; SEER
20.  Tumor dosimetry using [124I]m-iodobenzylguanidine microPET/CT for [131I]m- iodobenzylguanidine treatment of neuroblastoma in a murine xenograft model 
Purpose
[124I]m-iodobenzylguanidine (124I-mIBG) provides a quantitative tool for pretherapy tumor imaging and dosimetry when performed before [131I]m-iodobenzylguanidine (131I-mIBG) targeted radionuclide therapy of neuroblastoma. 124I (T1/2=4.2d) has a comparable half-life to that of 131I (T1/2=8.02d), and can be imaged by PET for accurate quantification of the radiotracer distribution. We estimated expected radiation dose in tumors from 131I-mIBG therapy using 124I-mIBG microPET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter (hNET).
Procedures
In order to enhance mIBG uptake for in vivo imaging and therapy, NB 1691-luciferase (NB1691) human neuroblastoma cells were engineered to express high levels of hNET protein by lentiviral transduction (NB1691-hNET). Both NB1691 and NB1691-hNET cells were implanted subcutaneously and into renal capsules in athymic mice. 124I-mIBG (4.2–6.5 MBq) was administered intravenously for microPET/CT imaging at 5 time points over 95 hours (0.5, 3–5, 24, 48, and 93–95 h median time points). In vivo biodistribution data in normal organs, tumors, and whole-body were collected from reconstructed PET images corrected for photon attenuation using the CT-based attenuation map. Organ and tumor dosimetry were determined for 124I-mIBG. Dose estimates for 131I-mIBG were made, assuming the same in vivo biodistribution as 124I-mIBG.
Results
All NB1691-hNET tumors had significant uptake and retention of 124I-mIBG, whereas unmodified NB1691 tumors did not demonstrate quantifiable mIBG uptake in vivo, despite in vitro uptake. 124I-mIBG with microPET/CT provided an accurate 3-dimensional tool for estimating the radiation dose that would be delivered with 131I-mIBG therapy. For example, in our model system, we estimated that the administration of 131I-mIBG in the range of 52.8 – 206 MBq would deliver 20 Gy to tumors.
Conclusion
The overexpression of hNET was found to be critical for 124I-mIBG uptake and retention in vivo. The quantitative 124I-mIBG PET/CT is a promising new tool to predict tumor radiation doses with 131I-mIBG therapy of neuroblastoma. This methodology may be applied to tumor dosimetry of 131I-mIBG therapy in human subjects using 124I-mIBG pretherapy PET/CT data.
doi:10.1007/s11307-012-0552-4
PMCID: PMC3369020  PMID: 22382618
neuroblastoma; m-iodobenzylguanidine; iodine-124; iodine-131; PET/CT; animal model; radiation dosimetry
21.  Predictors of Acute Chemotherapy-Associated Toxicity in Patients with Ewing Sarcoma 
Pediatric blood & cancer  2011;59(4):611-616.
Background
Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population.
Procedure
In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression.
Results
The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (p <0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% CI 1.9–13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2–10.9), pelvic tumor site (OR 3.88, 95% CI 1.17–12.88), and age <12 years (OR 2.8, 95% CI 1.0–7.5) were independent predictors of toxicity.
Conclusion
ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.
doi:10.1002/pbc.24031
PMCID: PMC3310949  PMID: 22180320
Ewing sarcoma; toxicity; income; ethnicity; age
22.  Evaluation of Polymorphisms in EWSR1 and Risk of Ewing Sarcoma: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;59(1):52-56.
Background
Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology.
Procedure
Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests.
Results
One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79 – 21.7; p = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%.
Conclusions
Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be a Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown.
doi:10.1002/pbc.23263
PMCID: PMC3204324  PMID: 21793187
Ewing sarcoma; EWSR1; single nucleotide polymorphism; genetic epidemiology
23.  Poly (ADP-Ribose) Polymerase Inhibitor MK-4827 together with Radiation as a Novel Therapy for Metastatic Neuroblastoma 
Anticancer research  2013;33(3):755-762.
Background/Aim
To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the treatment of neuroblastoma.
Material and Methods
Clonogenic survival assays were used to assess MK-4827, radiation and combination thereof in four neuroblastoma cell lines. In vivo efficacy was tested in a murine xenograft model of metastatic neuroblastoma. In vivo targeted inhibition and biological effects included measurement of cleaved caspase-3, gamma-H2AX, and Ki 67 by immunohistochemistry (IHC) and poly-ADP-ribose by Enzyme-Linked Immunosorbent Assay.
Results
Treatment of neuroblastoma cell lines reduced clonogenicity and resulted in additive effects with radiation. In vivo treatment with MK-4827 and radiation prolonged survival (p<0.01) compared to single modalities. In vivo superiority of MK-4827 plus radiation was further documented by significant elevations of cleaved caspase-3 and γ-H2AX in tumors from the combination group compared to single modality cohorts.
Conclusion
Combination of MK-4827 and radiation might provide effective therapy for children with high-risk neuroblastoma.
PMCID: PMC3684561  PMID: 23482742
24.  Symptom Cluster Analyses Based on Symptom Occurrence and Severity Ratings Among Pediatric Oncology Patients During Myelosuppressive Chemotherapy 
Cancer nursing  2012;35(1):19-28.
Background
Symptom cluster research is an emerging field in symptom management. The ability to identify symptom clusters that are specific to pediatric oncology patients may lead to improved understanding of symptoms’ underlying mechanisms among patients of all ages.
Objective
The purpose of this study, in a sample of children and adolescents with cancer who underwent a cycle of myelosuppressive chemotherapy, was to compare the number and types of symptom clusters identified using patients’ ratings of symptom occurrence and symptom severity.
Interventions/Methods
Children and adolescents with cancer (10 to 18 years of age; N=131) completed the Memorial Symptom Assessment Scale 10–18 on the day they started a cycle of myelosuppressive chemotherapy, using a one week recall of experiences. Symptom data based on occurrence and severity ratings were examined using Exploratory Factor Analysis (EFA). The defined measurement model suggested by the best EFA model was then examined with a latent variable analysis.
Results
Three clusters were identified when symptom occurrence ratings were evaluated which were classified as a chemotherapy sequelae cluster, mood disturbance cluster, and a neuropsychological discomforts cluster. Analysis of symptom severity ratings yielded similar cluster configurations.
Conclusions
Cluster configurations remained relatively stable between symptom occurrence and severity ratings. The evaluation of patients at a common point in the chemotherapy cycle may have contributed to these findings.
Implications for Practice
Additional uniformity in symptom clusters investigations is needed to allow appropriate comparisons among studies. The dissemination of symptom clusters research methodology through publication and presentation may promote uniformity in this field.
doi:10.1097/NCC.0b013e31822909fd
PMCID: PMC3237960  PMID: 21921793
25.  Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group 
Purpose. 123I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6–73.7%) versus 5.9% (range 0.6–110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0–100%) in MIBG avid patients compared to 10% (range 0–80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.
doi:10.1155/2012/250834
PMCID: PMC3463166  PMID: 23050139

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