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Kreissman, Susan Gail

Overview:

The emphasis of Dr Kreissman's clinical research involves the study of childhood neuroblastoma. Neuroblastoma is the most common extracranial solid tumor of childhood and this disease has a diverse clinical phenotype and prognosis. Dr Kreissman has developed, written, and served as national protocol chairman for 2 clinical trials designed to improve outcome for children with the high risk form of this disease through the Children's Oncology Group (COG). Results of this protocol have been published " A Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma" and established the new standard of using unpurged PBSC to support autologous transplant in high risk neuroblastoma. Dr. Kreissman also serves as a member of the Neuroblastoma committees for COG and is PI for COG studies at Duke. She is involved in designing and implimenting additional new protocols for the treatment of neuroblastoma.

Positions:

Professor of Pediatrics

Pediatrics, Hematology-Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

M.D. — Icahn School of Medicine at Mount Sinai

Intern, Pediatrics

Children's Hospital, Boston

Resident, Pediatrics

Children's Hospital, Boston

Clinical Fellow, Pediatric Hematology/Oncology, Pediatrics

Children's Hospital, Boston

Research Fellow, Pediatric Hematology/Oncology, Pediatrics

Children's Hospital, Boston

Grants:

COG Work Order AAML: 1031--Millennium Pharmaceuticals, Inc.

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
October 01, 2013
End Date
September 30, 2021

COG WORK ORDER: (PROJECT: EVERYCHILD (APEC14B1) PCR - COG FOUNDATION

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
October 26, 2015
End Date
February 29, 2020

COG Work Order: AALL1131: Ph III Clofarabine in High Risk B ALL

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
January 15, 2015
End Date
January 14, 2020

NCI Community Oncology Research Program (NCORP) Research Base Grant

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 31, 2019

COG WORK ORDER: (PROJECT: PEDIATRIC MATCH (APEC1621SC) PCR - COG FOUNDATION

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
July 01, 2017
End Date
June 30, 2019

COG WORK ORDER: BIQSFP AALL1131

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
March 01, 2016
End Date
February 28, 2019

Per Case Reimbursement : NIH National Clinical Trials Network (NCTN)

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
April 11, 2014
End Date
February 28, 2019

Workload Intensity NIH National Clinical Trials Network (NCTN)

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
April 01, 2014
End Date
February 28, 2019

ALTE15N2 STUDY

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
December 08, 2017
End Date
October 31, 2018

PBTC-043

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Principal Investigator
Start Date
September 15, 2015
End Date
October 19, 2017

Pediatric Brain Tumor Consortium

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Principal Investigator
Start Date
April 01, 2014
End Date
March 31, 2017

Stroma Biology Identifies Heparin as a Differentiating Agent in Neuroblastoma

Administered By
Medicine, Medical Oncology
Role
Co Investigator
Start Date
December 31, 2013
End Date
December 30, 2015

COG Work Order AALL07P1--Millennium Pharmaceuticals, Inc.

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Children's Hospital of Philadelphia
Role
Principal Investigator
Start Date
October 01, 2013
End Date
June 11, 2015
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Awards:

Leonard Palumbo Faculty Achievement Award . Duke University School of Medicine.

Type
School
Awarded By
Duke University School of Medicine
Date
May 01, 2019

Publications:

Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study.

PURPOSE: Neuroblastoma is the most common extracranial solid pediatric malignancy, with poor outcomes in high-risk disease. Standard treatment approaches employ an increasing array of aggressive multimodal therapies, of which local control with surgery and radiotherapy remains a backbone; however, the benefit of broad regional nodal irradiation remains controversial. We analyzed centrally reviewed radiation therapy data from patients enrolled on COG A3973 to evaluate the impact of primary site irradiation and the extent of regional nodal coverage stratified by extent of surgical resection. METHODS: Three hundred thirty high-risk neuroblastoma patients with centrally reviewed radiotherapy plans were analyzed. Outcome was evaluated by the extent of nodal irradiation. For the 171 patients who also underwent surgery (centrally reviewed), outcome was likewise analyzed according to the extent of resection. Overall survival (OS), event-free survival (EFS), and cumulative incidence of local progression (CILP) were examined by Kaplan-Meier, log-rank test (EFS, OS), and Grey test (CILP). RESULTS: The five-year CILP, EFS, and OS for all 330 patients receiving radiotherapy on A3973 were 8.5% ± 1.5%, 47.2% ± 3.0%, and 59.7% ± 3.0%, respectively. There were no significant differences in outcomes based on the extent of lymph node irradiation regardless of the degree of surgical resection (< 90% or ≥90%). CONCLUSION: Although local control remains a significant component of treatment of high-risk neuroblastoma, our results suggest there is no benefit of extensive lymph node irradiation, irrespective of the extent of surgical resection preceding stem cell transplant.

Authors
Braunstein, SE; London, WB; Kreissman, SG; Villablanca, JG; Davidoff, AM; DeSantes, K; Castleberry, RP; Murray, K; Diller, L; Matthay, K; Cohn, SL; Shulkin, B; von Allmen, D; Parisi, MT; Van Ryn, C; Park, JR; La Quaglia, MP; Haas-Kogan, DA
MLA Citation
Braunstein, Steve E., et al. “Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study..” Pediatr Blood Cancer, vol. 66, no. 7, July 2019. Pubmed, doi:10.1002/pbc.27736.
PMID
30968542
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
66
Issue
7
Publish Date
2019
Start Page
e27736
DOI
10.1002/pbc.27736

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

Authors
Fangusaro, J; Onar-Thomas, A; Young Poussaint, T; Wu, S; Ligon, AH; Lindeman, N; Banerjee, A; Packer, RJ; Kilburn, LB; Goldman, S; Pollack, IF; Qaddoumi, I; Jakacki, RI; Fisher, PG; Dhall, G; Baxter, P; Kreissman, SG; Stewart, CF; Jones, DTW; Pfister, SM; Vezina, G; Stern, JS; Panigrahy, A; Patay, Z; Tamrazi, B; Jones, JY; Haque, SS; Enterline, DS; Cha, S; Fisher, MJ; Doyle, LA; Smith, M; Dunkel, IJ; Fouladi, M
MLA Citation
Fangusaro, Jason, et al. “Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial..” Lancet Oncol, vol. 20, no. 7, July 2019, pp. 1011–22. Pubmed, doi:10.1016/S1470-2045(19)30277-3.
PMID
31151904
Source
pubmed
Published In
Lancet Oncol
Volume
20
Issue
7
Publish Date
2019
Start Page
1011
End Page
1022
DOI
10.1016/S1470-2045(19)30277-3

Predictors of differential response to induction therapy in high-risk neuroblastoma: A report from the Children's Oncology Group (COG).

BACKGROUND: Induction chemotherapy plays an important role in the management of patients with high-risk neuroblastoma. Predictors of response to induction therapy are largely lacking. We sought to describe clinical and biological features associated with induction response. METHODS: Patients from four consecutive COG high-risk trials were included. Response was evaluated by the 1993 International Neuroblastoma Response Criteria. The primary end-point was end-induction partial response (PR) or better. Univariate analyses were performed to compare response as a function of clinical or biologic predictors. A multivariate logistic regression model using significant predictors from univariate analyses was constructed to model PR or better. RESULTS: The analytic cohort included 1242 patients. End-induction response ≥PR was significantly associated with higher event-free and overall survival. Baseline factors associated with ≥PR included age <18 months (87.4% with ≥PR vs. 78.7% if older; p = 0.0103), International Neuroblastoma Staging System non-stage 4 (89.0% vs. 78.4% if stage 4; p = 0.0016), MYCN amplification (85.5% vs. 77.1% if non-amplified; p = 0.0006), 1p loss of heterozygosity (LOH; 85.6% vs. 76.0% if no LOH; p = 0.0085), no 11q LOH (84.8% vs. 70.9% if 11q LOH; p = 0.0004) and high mitosis-karyorrhexis index (MKI; 84.5% vs. 77.5% if low-intermediate MKI; p = 0.0098). On multivariable analysis (n = 407), the absence of 11q LOH was the only factor that remained significantly associated with ≥PR (odds ratio: 1.962 vs. 11q LOH; 95% confidence interval 1.104-3.487; p = 0.0216). CONCLUSIONS: Improved end-induction response in high-risk neuroblastoma is associated with longer survival. Patients with 11q LOH are less likely to respond to induction therapies and should be prioritised for novel approaches in future trials.

Authors
Pinto, N; Naranjo, A; Hibbitts, E; Kreissman, SG; Granger, MM; Irwin, MS; Bagatell, R; London, WB; Greengard, EG; Park, JR; DuBois, SG
MLA Citation
Pinto, Navin, et al. “Predictors of differential response to induction therapy in high-risk neuroblastoma: A report from the Children's Oncology Group (COG)..” Eur J Cancer, vol. 112, May 2019, pp. 66–79. Pubmed, doi:10.1016/j.ejca.2019.02.003.
PMID
30947024
Source
pubmed
Published In
Eur J Cancer
Volume
112
Publish Date
2019
Start Page
66
End Page
79
DOI
10.1016/j.ejca.2019.02.003

Improved contemporary outcomes of liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma.

PURPOSE:Improvement in outcomes of LT for pediatric HB and HCC has been reported in small series. We analyzed national outcomes and changes in donor, recipient, and perioperative factors over time that may contribute to survival differences. METHODS:The UNOS database was queried for patients age <21 years that underwent LT for a primary diagnosis of HB or HCC (1987-2017). Subjects were divided into historic (transplant before 2010) and contemporary (transplant after 2010) cohorts. Baseline characteristics were compiled and examined. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS:In total, 599 children with HB received LT (320 historic vs 279 contemporary). Concurrently, 141 children with HCC received LT (92 historic vs 49 contemporary). For both tumors, waitlist time decreased (HB 56.2 days historic vs 33.2 days contemporary, P = 0.017; HCC 189.3 days historic vs 71.7 days contemporary, P = 0.012). In the historic cohorts, patients with HB had a 1-year and 5-year OS of 84.6% and 75.1%, respectively. Survival for HCC was 84.4% and 59.9%, respectively. Outcomes improved in the contemporary era to 89.1% and 82.6% for HB, and 94.7% and 80.8% for HCC, respectively (both log-rank test P < 0.0001). CONCLUSION:Outcomes of LT have improved significantly, with contemporary survival now equivalent between these tumors and exceeding 80% 5-year OS. Future studies are needed to explore whether offering LT in patients that are resectable is justifiable.

Authors
Ezekian, B; Mulvihill, MS; Schroder, PM; Gilmore, BF; Leraas, HJ; Gulack, BC; Jane Commander, S; Mavis, AM; Kreissman, SG; Knechtle, SJ; Tracy, ET; Barbas, AS
MLA Citation
Ezekian, Brian, et al. “Improved contemporary outcomes of liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma..” Pediatric Transplantation, vol. 22, no. 8, Dec. 2018. Epmc, doi:10.1111/petr.13305.
PMID
30341782
Source
epmc
Published In
Pediatric Transplantation
Volume
22
Issue
8
Publish Date
2018
Start Page
e13305
DOI
10.1111/petr.13305

Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients.

Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001). Conclusions: Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.

Authors
Depuydt, P; Boeva, V; Hocking, TD; Cannoodt, R; Ambros, IM; Ambros, PF; Asgharzadeh, S; Attiyeh, EF; Combaret, V; Defferrari, R; Fischer, M; Hero, B; Hogarty, MD; Irwin, MS; Koster, J; Kreissman, S; Ladenstein, R; Lapouble, E; Laureys, G; London, WB; Mazzocco, K; Nakagawara, A; Noguera, R; Ohira, M; Park, JR; Pötschger, U; Theissen, J; Tonini, GP; Valteau-Couanet, D; Varesio, L; Versteeg, R; Speleman, F; Maris, JM; Schleiermacher, G; De Preter, K
MLA Citation
Depuydt, Pauline, et al. “Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients..” J Natl Cancer Inst, vol. 110, no. 10, Oct. 2018, pp. 1084–93. Pubmed, doi:10.1093/jnci/djy022.
PMID
29514301
Source
pubmed
Published In
J Natl Cancer Inst
Volume
110
Issue
10
Publish Date
2018
Start Page
1084
End Page
1093
DOI
10.1093/jnci/djy022

Predictors of differential response to induction chemotherapy in high-risk neuroblastoma: A report from the Children's Oncology Group (COG).

Authors
Pinto, NR; Hibbitts, E; Kreissman, SG; Granger, MP; Irwin, M; Bagatell, R; London, WB; Greengard, EG; Naranjo, A; Park, JR; DuBois, SG
MLA Citation
Pinto, Navin R., et al. “Predictors of differential response to induction chemotherapy in high-risk neuroblastoma: A report from the Children's Oncology Group (COG)..” Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. 10532–10532. Crossref, doi:10.1200/jco.2018.36.15_suppl.10532.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Issue
15_suppl
Publish Date
2018
Start Page
10532
End Page
10532
DOI
10.1200/jco.2018.36.15_suppl.10532

Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1.

A semiquantitative 123I-metaiodobenzylguanidine (123I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ≤ 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials.

Authors
Yanik, GA; Parisi, MT; Naranjo, A; Nadel, H; Gelfand, MJ; Park, JR; Ladenstein, RL; Poetschger, U; Boubaker, A; Valteau-Couanet, D; Lambert, B; Castellani, M-R; Bar-Sever, Z; Oudoux, A; Kaminska, A; Kreissman, SG; Shulkin, BL; Matthay, KK
MLA Citation
Yanik, Gregory A., et al. “Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1..” J Nucl Med, vol. 59, no. 3, Mar. 2018, pp. 502–08. Pubmed, doi:10.2967/jnumed.117.195883.
PMID
28887399
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
59
Issue
3
Publish Date
2018
Start Page
502
End Page
508
DOI
10.2967/jnumed.117.195883

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials.

BACKGROUND: Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations. RESULTS: The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response. CONCLUSIONS: Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

Authors
Ladenstein, R; Lambert, B; Pötschger, U; Castellani, M-R; Lewington, V; Bar-Sever, Z; Oudoux, A; Śliwińska, A; Taborska, K; Biassoni, L; Yanik, GA; Naranjo, A; Parisi, MT; Shulkin, BL; Nadel, H; Gelfand, MJ; Matthay, KK; Park, JR; Kreissman, SG; Valteau-Couanet, D; Boubaker, A
MLA Citation
Ladenstein, Ruth, et al. “Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials..” Eur J Nucl Med Mol Imaging, vol. 45, no. 2, Feb. 2018, pp. 292–305. Pubmed, doi:10.1007/s00259-017-3829-7.
PMID
28940046
Source
pubmed
Published In
Eur J Nucl Med Mol Imaging
Volume
45
Issue
2
Publish Date
2018
Start Page
292
End Page
305
DOI
10.1007/s00259-017-3829-7

MIBG avidity correlates with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group.

BACKGROUND: Prior studies suggest that neuroblastomas that do not accumulate metaiodobenzylguanidine (MIBG) on diagnostic imaging (MIBG non-avid) may have more favorable features compared with MIBG avid tumors. We compared clinical features, biologic features, and clinical outcomes between patients with MIBG nonavid and MIBG avid neuroblastoma. PROCEDURE: Patients had metastatic high- or intermediate-risk neuroblastoma and were treated on Children's Oncology Group protocols A3973 or A3961. Comparisons of clinical and biologic features according to MIBG avidity were made with chi-squared or Fisher exact tests. Event-free (EFS) and overall (OS) survival compared using log-rank tests and modeled using Cox models. RESULTS: Thirty of 343 patients (8.7%) had MIBG nonavid disease. Patients with nonavid tumors were less likely to have adrenal primary tumors (34.5 vs. 57.2%; P = 0.019), bone metastases (36.7 vs. 61.7%; P = 0.008), or positive urine catecholamines (66.7 vs. 91.0%; P < 0.001) compared with patients with MIBG avid tumors. Nonavid tumors were more likely to be MYCN amplified (53.8 vs. 32.6%; P = 0.030) and had lower norepinephrine transporter expression. Patients with MIBG nonavid disease had a 5-year EFS of 50.0% compared with 38.7% for patients with MIBG avid disease (P = 0.028). On multivariate testing in high-risk patients, MIBG avidity was the sole adverse prognostic factor for EFS identified (hazard ratio 1.77; 95% confidence interval 1.04-2.99; P = 0.034). CONCLUSIONS: Patients with MIBG nonavid neuroblastoma have lower rates of adrenal primary tumors, bone metastasis, and catecholamine secretion. Despite being more likely to have MYCN-amplified tumors, these patients have superior outcomes compared with patients with MIBG avid disease.

Authors
DuBois, SG; Mody, R; Naranjo, A; Van Ryn, C; Russ, D; Oldridge, D; Kreissman, S; Baker, DL; Parisi, M; Shulkin, BL; Bai, H; Diskin, SJ; Batra, V; Maris, JM; Park, JR; Matthay, KK; Yanik, G
MLA Citation
DuBois, Steven G., et al. “MIBG avidity correlates with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group..” Pediatr Blood Cancer, vol. 64, no. 11, Nov. 2017. Pubmed, doi:10.1002/pbc.26545.
PMID
28383813
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
64
Issue
11
Publish Date
2017
DOI
10.1002/pbc.26545

Reply to J. Stenman et al.

Authors
La Quaglia, MP; Haas-Kogan, D; Park, J; Kreissman, SG; von Allmen, D; Davidoff, A; London, WB; Khanna, G
MLA Citation
La Quaglia, Michael P., et al. “Reply to J. Stenman et al..” J Clin Oncol, vol. 35, no. 17, June 2017, pp. 1966–67. Pubmed, doi:10.1200/JCO.2017.72.2777.
PMID
28422554
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
35
Issue
17
Publish Date
2017
Start Page
1966
End Page
1967
DOI
10.1200/JCO.2017.72.2777

A PHASE II PROSPECTIVE STUDY OF SELUMETINIB IN CHILDREN WITH RECURRENT OR REFRACTORY LOW-GRADE GLIOMA (LGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

Authors
Fangusaro, J; Onar-Thomas, A; Poussaint, TY; Wu, S; Ligon, AH; Lindeman, N; Banerjee, A; Packer, RJ; Kilburn, LB; Pollack, IF; Jakacki, RI; Qaddoumi, I; Fisher, PG; Dhall, G; Baxter, P; Kreissman, SG; Stewart, CF; Pfister, SM; Jones, DTW; Vezina, G; Stern, J; Panigrahy, A; Jones, BV; Patay, Z; Tamrazi, B; Jones, JY; Haque, SS; Enterline, DS; Cha, S; Doyle, LA; Smith, M; Boyett, JM; Dunkel, IJ; Fouladi, M
MLA Citation
Fangusaro, Jason, et al. “A PHASE II PROSPECTIVE STUDY OF SELUMETINIB IN CHILDREN WITH RECURRENT OR REFRACTORY LOW-GRADE GLIOMA (LGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 34–35.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
34
End Page
35

A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

Authors
Fangusaro, JR; Onar-Thomas, A; Young-Poussaint, T; Wu, S; Ligon, AH; Lindeman, NI; Banerjee, A; Packer, R; Kilburn, LB; Pollack, I; Jakacki, R; Qaddoumi, IA; Fisher, PG; Dhall, G; Baxter, PA; Kreissman, SG; Doyle, LA; Smith, MA; Dunkel, IJ; Fouladi, M
MLA Citation
Fangusaro, Jason R., et al. “A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 10504–10504. Crossref, doi:10.1200/jco.2017.35.15_suppl.10504.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
10504
End Page
10504
DOI
10.1200/jco.2017.35.15_suppl.10504

Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma.

Purpose This analysis of patients in the Children's Oncology Group A3973 study evaluated the impact of extent of primary tumor resection on local progression and survival and assessed concordance between clinical and central imaging review-based assessments of resection extent. Patients and Methods The analytic cohort (n = 220) included patients who had both central surgery review and resection of the primary tumor site. For this analysis, resection categories of < 90% and ≥ 90% were used, with data on resection extent derived from operating surgeons' assessments (all patients), as well as blinded central imaging review of computed tomography scans for a subset of 84 patients; assessment results were compared for concordance. Treatment outcomes included event-free survival (EFS), overall survival (OS), and cumulative incidence of local progression (CILP). Results Surgeon-assessed extent of resection was ≥ 90% in 154 (70%) patients and < 90% in 66 (30%). Five-year EFS, OS, and CILP (± SE) were 43.5% ± 3.7%, 54.9% ± 3.7%, and 11.9% ± 2.2%, respectively. EFS was higher with ≥ 90% resection (45.9% ± 4.3%) than with < 90% resection (37.9% ± 7.2%; P = .04). Lower CILP ( P = .01) was associated with ≥ 90% resection (8.5% ± 2.3%) compared with < 90% resection (19.8% ± 5.0%). On multivariable analysis, ≥ 90% resection was associated with longer EFS after adjustment for MYCN amplification or diploidy but had no significant effect on OS. Concordance between surgeons' assessments of resection extent and central image-guided review was low, with agreement of 63% (< 90% v ≥ 90%; simple κ = -0.0301). Conclusion Despite discordance between clinical assessment of resection extent and assessment via central imaging review, a surgeon-assessed resection extent ≥ 90% was associated with significantly better EFS and lower CILP. Improving OS, however, remains a challenge in this disease. These findings support continued attempts at ≥ 90% resection of the primary tumor in high-risk neuroblastoma.

Authors
von Allmen, D; Davidoff, AM; London, WB; Van Ryn, C; Haas-Kogan, DA; Kreissman, SG; Khanna, G; Rosen, N; Park, JR; La Quaglia, MP
MLA Citation
von Allmen, Daniel, et al. “Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma..” J Clin Oncol, vol. 35, no. 2, Jan. 2017, pp. 208–16. Pubmed, doi:10.1200/JCO.2016.67.2642.
PMID
27870572
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
35
Issue
2
Publish Date
2017
Start Page
208
End Page
216
DOI
10.1200/JCO.2016.67.2642

The Way Towards an International MIBG Skeletal Score for High Risk Neuroblastoma: The Statistical Perspective

Authors
Poetschger, U; Naranjo, A; Yanik, G; Castellani, MR; Lambert, B; Lewington, V; Bar-Server, Z; Oudoux, A; Kaminska, A; Taborska, K; Biassoni, L; Parisi, MT; Shulkin, BL; Nadel, HR; Gelfand, M; Park, J; Kreissman, SG; Valteau-Couanet, D; Matthay, KK; Ladenstein, R
MLA Citation
Poetschger, U., et al. “The Way Towards an International MIBG Skeletal Score for High Risk Neuroblastoma: The Statistical Perspective.” Pediatric Blood & Cancer, vol. 63, WILEY-BLACKWELL, 2016, pp. S39–40.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
63
Publish Date
2016
Start Page
S39
End Page
S40

Erratum to: Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group.

Authors
Temple, W; Mendelsohn, L; Kim, GE; Nekritz, E; Gustafson, WC; Lin, L; Giacomini, K; Naranjo, A; Van Ryn, C; Parisi, MT; Shulkin, BL; Yanik, GA; Kreissman, SG; Hogarty, M; Matthay, KK; DuBois, SG
MLA Citation
Temple, William, et al. “Erratum to: Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group..” Eur J Nucl Med Mol Imaging, vol. 43, no. 7, July 2016. Pubmed, doi:10.1007/s00259-016-3381-x.
PMID
27044383
Source
pubmed
Published In
Eur J Nucl Med Mol Imaging
Volume
43
Issue
7
Publish Date
2016
Start Page
1396
DOI
10.1007/s00259-016-3381-x

A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children's Oncology Group (COG) study.

Authors
Park, JR; Kreissman, SG; London, WB; Naranjo, A; Cohn, SL; Hogarty, MD; Tenney, SC; Haas-Kogan, D; Shaw, PJ; Geiger, JD; Doski, JJ; Gorges, SW; Khanna, G; Voss, SD; Maris, JM; Grupp, SA; Diller, L
MLA Citation
Park, Julie R., et al. “A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children's Oncology Group (COG) study..” Journal of Clinical Oncology, vol. 34, no. 18, AMER SOC CLINICAL ONCOLOGY, 2016.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
18
Publish Date
2016

Clinical, biologic, and outcome differences according to MIBG avidity in children with neuroblastoma: A report from the Children’s Oncology Group (COG).

Authors
DuBois, SG; Mody, R; Van Ryn, C; Naranjo, A; Kreissman, SG; Baker, D; Parisi, MT; Shulkin, BL; Maris, JM; Batra, V; Park, JR; Matthay, KK; Yanik, GA
MLA Citation
DuBois, Steven G., et al. “Clinical, biologic, and outcome differences according to MIBG avidity in children with neuroblastoma: A report from the Children’s Oncology Group (COG)..” Journal of Clinical Oncology, vol. 34, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2016, pp. 10526–10526. Crossref, doi:10.1200/jco.2016.34.15_suppl.10526.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
15_suppl
Publish Date
2016
Start Page
10526
End Page
10526
DOI
10.1200/jco.2016.34.15_suppl.10526

Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group.

PURPOSE: Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features. METHODS: We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 - 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests. RESULTS: Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity. CONCLUSION: VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.

Authors
Temple, W; Mendelsohn, L; Kim, GE; Nekritz, E; Gustafson, WC; Lin, L; Giacomini, K; Naranjo, A; Van Ryn, C; Yanik, GA; Kreissman, SG; Hogarty, M; Matthay, KK; DuBois, SG
MLA Citation
Temple, William, et al. “Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group..” Eur J Nucl Med Mol Imaging, vol. 43, no. 3, Mar. 2016, pp. 474–81. Pubmed, doi:10.1007/s00259-015-3179-2.
PMID
26338179
Source
pubmed
Published In
Eur J Nucl Med Mol Imaging
Volume
43
Issue
3
Publish Date
2016
Start Page
474
End Page
481
DOI
10.1007/s00259-015-3179-2

Value of surgical resection in children with high-risk neuroblastoma.

BACKGROUND: The value of gross total resection (GTR) for children with high-risk neuroblastoma (NB) is controversial. We hypothesized that patients undergoing GTR would demonstrate improved overall survival (OS) compared those having 90% resection compared to <90% resection (P = 0.008). Multivariable Cox models confirmed these findings with improved survival in children undergoing >90% vs. <90% resection but no difference in GTR vs. 90% resection is associated with improved OS compared to less than 90% resection.

Authors
Englum, BR; Rialon, KL; Speicher, PJ; Gulack, B; Driscoll, TA; Kreissman, SG; Rice, HE
MLA Citation
Englum, Brian R., et al. “Value of surgical resection in children with high-risk neuroblastoma..” Pediatr Blood Cancer, vol. 62, no. 9, Sept. 2015, pp. 1529–35. Pubmed, doi:10.1002/pbc.25504.
PMID
25810376
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
62
Issue
9
Publish Date
2015
Start Page
1529
End Page
1535
DOI
10.1002/pbc.25504

Use of patient registries and administrative datasets for the study of pediatric cancer.

Analysis of data from large administrative databases and patient registries is increasingly being used to study childhood cancer care, although the value of these data sources remains unclear to many clinicians. Interpretation of large databases requires a thorough understanding of how the dataset was designed, how data were collected, and how to assess data quality. This review will detail the role of administrative databases and registry databases for the study of childhood cancer, tools to maximize information from these datasets, and recommendations to improve the use of these databases for the study of pediatric oncology.

Authors
Rice, HE; Englum, BR; Gulack, BC; Adibe, OO; Tracy, ET; Kreissman, SG; Routh, JC
MLA Citation
Rice, Henry E., et al. “Use of patient registries and administrative datasets for the study of pediatric cancer..” Pediatr Blood Cancer, vol. 62, no. 9, Sept. 2015, pp. 1495–500. Pubmed, doi:10.1002/pbc.25506.
PMID
25807938
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
62
Issue
9
Publish Date
2015
Start Page
1495
End Page
1500
DOI
10.1002/pbc.25506

Vesicular monoamine transporter protein expression in neuroblastoma: A report from the Children's Oncology Group.

Authors
DuBois, SG; Temple, W; Mendelsohn, L; Kim, GE; Nekritz, E; Gustafson, C; Lin, L; Giacomini, K; Naranjo, A; Van Ryn, C; Yanik, GA; Kreissman, SG; Hogarty, MD; Matthay, KK
MLA Citation
DuBois, Steven G., et al. “Vesicular monoamine transporter protein expression in neuroblastoma: A report from the Children's Oncology Group..” Journal of Clinical Oncology, vol. 33, no. 15, AMER SOC CLINICAL ONCOLOGY, 2015.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis.

PURPOSE: The aim of this study was to find clinically relevant MIBG-avid metastatic patterns in patients with newly diagnosed stage 4 neuroblastoma. METHODS: Diagnostic (123)I-MIBG scans from 249 patients (123 from a European and 126 from the COG cohort) were assessed for metastatic spread in 14 body segments and the form of the lesions: "focal" (clear margins distinguishable from adjacent background) or "diffuse" (indistinct margins, dispersed throughout the body segment). The total numbers of diffuse and focal lesions were recorded. Patients were then categorized as having lesions exclusively focal, lesions more focal than diffuse, lesions more diffuse than focal, or lesions exclusively diffuse. RESULTS: Diffuse lesions affected a median of seven body segments and focal lesions a median of two body segments (P < 0.001, both cohorts). Patients with a focal pattern had a median of 2 affected body segments and those with a diffuse pattern a median of 11 affected body segments (P < 0.001, both cohorts). Thus, two MIBG-avid metastatic patterns emerged: "limited-focal" and "extensive-diffuse". The median numbers of affected body segments in MYCN-amplified (MNA) tumours were 5 (European cohort) and 4 (COG cohort) compared to 9 and 11, respectively, in single-copy MYCN (MYCNsc) tumours (P < 0.001). Patients with exclusively focal metastases were more likely to have a MNA tumour (60% and 70%, respectively) than patients with the other types of metastases (23% and 28%, respectively; P < 0.001). In a multivariate Cox regression analysis, focal metastases were associated with a better event-free and overall survival than the other types of metastases in patients with MNA tumours in the COG cohort (P < 0.01). CONCLUSION: Two metastatic patterns were found: a "limited and focal" pattern found mainly in patients with MNA neuroblastoma that correlated with prognosis, and an "extensive and diffuse" pattern found mainly in patients with MYCNsc neuroblastoma.

Authors
Bleeker, G; van Eck-Smit, BL; Zwinderman, KH; Versteeg, R; van Noesel, MM; Kam, BL; Kaspers, GJ; van Schie, A; Kreissman, SG; Yanik, G; Hero, B; Schmidt, M; Laureys, G; Lambert, B; Øra, I; Schulte, JH; Caron, HN; Tytgat, GA
MLA Citation
Bleeker, Gitta, et al. “MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis..” Eur J Nucl Med Mol Imaging, vol. 42, no. 2, Feb. 2015, pp. 222–30. Pubmed, doi:10.1007/s00259-014-2909-1.
PMID
25267348
Source
pubmed
Published In
Eur J Nucl Med Mol Imaging
Volume
42
Issue
2
Publish Date
2015
Start Page
222
End Page
230
DOI
10.1007/s00259-014-2909-1

Impact of Post-Induction Curie Scores in High-Risk Neuroblastoma

Authors
Yanik, G; Naranjo, A; Parisi, MT; Shulkin, BL; Nadel, H; Gelfand, MJ; Ladenstein, R; Boubaker, A; Poetschger, U; Valteau-Couanet, D; Kreissman, SG; Park, JR; Matthay, KK
MLA Citation
Yanik, Gregory, et al. “Impact of Post-Induction Curie Scores in High-Risk Neuroblastoma.” Biology of Blood and Marrow Transplantation, vol. 21, no. 2, Elsevier BV, 2015, pp. S107–S107. Crossref, doi:10.1016/j.bbmt.2014.11.131.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
S107
End Page
S107
DOI
10.1016/j.bbmt.2014.11.131

MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis

© 2014, The Author(s). Methods: Diagnostic 123I-MIBG scans from 249 patients (123 from a European and 126 from the COG cohort) were assessed for metastatic spread in 14 body segments and the form of the lesions: “focal” (clear margins distinguishable from adjacent background) or “diffuse” (indistinct margins, dispersed throughout the body segment). The total numbers of diffuse and focal lesions were recorded. Patients were then categorized as having lesions exclusively focal, lesions more focal than diffuse, lesions more diffuse than focal, or lesions exclusively diffuse.Results: Diffuse lesions affected a median of seven body segments and focal lesions a median of two body segments (P < 0.001, both cohorts). Patients with a focal pattern had a median of 2 affected body segments and those with a diffuse pattern a median of 11 affected body segments (P < 0.001, both cohorts). Thus, two MIBG-avid metastatic patterns emerged: “limited-focal” and “extensive-diffuse”. The median numbers of affected body segments in MYCN-amplified (MNA) tumours were 5 (European cohort) and 4 (COG cohort) compared to 9 and 11, respectively, in single-copy MYCN (MYCNsc) tumours (P < 0.001). Patients with exclusively focal metastases were more likely to have a MNA tumour (60 % and 70 %, respectively) than patients with the other types of metastases (23 % and 28 %, respectively; P < 0.001). In a multivariate Cox regression analysis, focal metastases were associated with a better event-free and overall survival than the other types of metastases in patients with MNA tumours in the COG cohort (P < 0.01).Conclusion: Two metastatic patterns were found: a “limited and focal” pattern found mainly in patients with MNA neuroblastoma that correlated with prognosis, and an “extensive and diffuse” pattern found mainly in patients with MYCNsc neuroblastoma.Purpose: The aim of this study was to find clinically relevant MIBG-avid metastatic patterns in patients with newly diagnosed stage 4 neuroblastoma.

Authors
Bleeker, G; van Eck-Smit, BL; Zwinderman, KH; Versteeg, R; van Noesel, MM; Kam, BL; Kaspers, GJ; van Schie, A; Kreissman, SG; Yanik, G; Hero, B; Schmidt, M; Laureys, G; Lambert, B; Øra, I; Schulte, JH; Caron, HN; Tytgat, GA
MLA Citation
Bleeker, G., et al. “MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis.” European Journal of Nuclear Medicine and Molecular Imaging, vol. 42, no. 2, Jan. 2015, pp. 222–30. Scopus, doi:10.1007/s00259-014-2909-1.
Source
scopus
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
42
Issue
2
Publish Date
2015
Start Page
222
End Page
230
DOI
10.1007/s00259-014-2909-1

SIGNIFICANT PROGNOSTIC RESULTS OF THE SIOPEN MIBG SCORING METHOD IN 2 COOPERATIVE INDEPENDENT HIGH RISK NEUROBLASTOMA TRIALS

Authors
Ladenstein, R; Boubaker, A; Lambert, B; Castellani, MR; Bar-Sever, Z; Oudoux, A; Kaminska, A; Kreissman, SG; Matthay, KK; Poetschger, U
MLA Citation
Ladenstein, R., et al. “SIGNIFICANT PROGNOSTIC RESULTS OF THE SIOPEN MIBG SCORING METHOD IN 2 COOPERATIVE INDEPENDENT HIGH RISK NEUROBLASTOMA TRIALS.” Pediatric Blood & Cancer, vol. 61, WILEY-BLACKWELL, Dec. 2014, pp. S123–S123.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
61
Publish Date
2014
Start Page
S123
End Page
S123

Validation of the mIBG SIOPEN Scoring Method in 2 independent High Risk Neuroblastoma Trial Populations

Authors
Boubaker, A; Poetschger, U; Lambert, B; Castellani, MR; Bar-Sever, Z; Oudoux, A; Kaminska, A; Taborska, K; Kreissman, SG; Yanik, G; Matthay, KK; Naranjo, A; Park, JR; Valteau-Couanet, D; Ladenstein, R
MLA Citation
Boubaker, A., et al. “Validation of the mIBG SIOPEN Scoring Method in 2 independent High Risk Neuroblastoma Trial Populations.” European Journal of Nuclear Medicine and Molecular Imaging, vol. 41, SPRINGER, 2014, pp. S220–S220.
Source
wos
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
41
Publish Date
2014
Start Page
S220
End Page
S220

Extent of Lymph Node Radiation Coverage in High-Risk Neuroblastoma Does Not Affect Clinical Outcome: A Report From the COG A3973 Study

Authors
Haas-Kogan, D; Douglas, J; London, WB; McCauley Van Ryn, CJ; von Allmen, D; Davidoff, AM; Villablanca, JG; Matthay, KK; DuBois, SG; Kreissman, SG; La Quaglia, MP; Park, JR
MLA Citation
Haas-Kogan, D., et al. “Extent of Lymph Node Radiation Coverage in High-Risk Neuroblastoma Does Not Affect Clinical Outcome: A Report From the COG A3973 Study.” International Journal of Radiation Oncology*Biology*Physics, vol. 90, no. 1, Elsevier BV, 2014, pp. S114–S114. Crossref, doi:10.1016/j.ijrobp.2014.05.539.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
90
Issue
1
Publish Date
2014
Start Page
S114
End Page
S114
DOI
10.1016/j.ijrobp.2014.05.539

Validation of the MIBG SIOPEN scoring method in two independent high-risk neuroblastoma trials.

Authors
Boubaker, A; Poetschger, U; Lambert, B; Castellani, MR; Bar-Sever, Z; Oudoux, A; Kaminska, A; Taborska, K; Biassoni, L; Kreissman, SG; Yanik, GA; Naranjo, A; Parisi, MT; Shulkin, BL; Matthay, KK; Park, JR; Valteau-Couanet, D; Ladenstein, RL
MLA Citation
Boubaker, Ariane, et al. “Validation of the MIBG SIOPEN scoring method in two independent high-risk neuroblastoma trials..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. 10029–10029. Crossref, doi:10.1200/jco.2014.32.15_suppl.10029.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
10029
End Page
10029
DOI
10.1200/jco.2014.32.15_suppl.10029

Validation of postinduction Curie scores in high-risk neuroblastoma.

Authors
Yanik, GA; Naranjo, A; Parisi, MT; Shulkin, BL; Nadel, HR; Gelfand, MJ; Ladenstein, RL; Boubaker, A; Poetschger, U; Lambert, B; Castellani, MR; Valteau-Couanet, D; Kreissman, SG; Park, JR; Matthay, KK
MLA Citation
Yanik, Gregory A., et al. “Validation of postinduction Curie scores in high-risk neuroblastoma..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. 10031–10031. Crossref, doi:10.1200/jco.2014.32.15_suppl.10031.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
10031
End Page
10031
DOI
10.1200/jco.2014.32.15_suppl.10031

Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group.

PURPOSE: Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study. PATIENTS AND METHODS: Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m(2); exposure one) or after cisplatin (400 mg/m(2)) plus carboplatin (1,700 mg/m(2); exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]). RESULTS: Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection. CONCLUSION: Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.

Authors
Landier, W; Knight, K; Wong, FL; Lee, J; Thomas, O; Kim, H; Kreissman, SG; Schmidt, ML; Chen, L; London, WB; Gurney, JG; Bhatia, S
MLA Citation
Landier, Wendy, et al. “Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group..” J Clin Oncol, vol. 32, no. 6, Feb. 2014, pp. 527–34. Pubmed, doi:10.1200/JCO.2013.51.2038.
PMID
24419114
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
32
Issue
6
Publish Date
2014
Start Page
527
End Page
534
DOI
10.1200/JCO.2013.51.2038

Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial.

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 non-purged 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 meta-iodobenzylguanidine 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.

Authors
Kreissman, SG; Seeger, RC; Matthay, KK; London, WB; Sposto, R; Grupp, SA; Haas-Kogan, DA; Laquaglia, MP; Yu, AL; Diller, L; Buxton, A; Park, JR; Cohn, SL; Maris, JM; Reynolds, CP; Villablanca, JG
MLA Citation
Kreissman, Susan G., et al. “Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial..” Lancet Oncol, vol. 14, no. 10, Sept. 2013, pp. 999–1008. Pubmed, doi:10.1016/S1470-2045(13)70309-7.
PMID
23890779
Source
pubmed
Published In
Lancet Oncol
Volume
14
Issue
10
Publish Date
2013
Start Page
999
End Page
1008
DOI
10.1016/S1470-2045(13)70309-7

Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group.

UNLABELLED: Radiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease. METHODS: mIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children's Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178). Individual mIBG scans were evaluated at 10 different anatomic regions, with the scoring of each site (0-3) based on the extent of disease at that anatomic region. RESULTS: There was no correlation between CS at diagnosis and subsequent treatment outcome. Patients with a CS > 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores ≤ 2 (3-y EFS: 15.4% ± 5.3% vs. 44.9% ± 3.9%, respectively; P < 0.001). A postinduction CS > 2 identified a cohort of patients at greater risk for an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade. For MYCN-amplified tumors, the presence (CS > 0) versus absence (CS = 0) of residual mIBG avidity after induction was associated with a significantly worse outcome (3-y EFS: 11.8% ± 7.8% vs. 49.6% ± 7.7%, respectively; P = 0.003). After transplantation, patients with a CS > 0 had an EFS inferior to that of patients with a CS of 0 (3-y EFS: 28.9% ± 6.8% vs. 49.3% ± 4.9%, respectively [n = 133]; P = 0.009). CONCLUSION: Curie scoring carries prognostic significance in the management of patients with high-risk neuroblastoma. In particular, patients with CSs > 2 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies.

Authors
Yanik, GA; Parisi, MT; Shulkin, BL; Naranjo, A; Kreissman, SG; London, WB; Villablanca, JG; Maris, JM; Park, JR; Cohn, SL; McGrady, P; Matthay, KK
MLA Citation
Yanik, Gregory A., et al. “Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group..” J Nucl Med, vol. 54, no. 4, Apr. 2013, pp. 541–48. Pubmed, doi:10.2967/jnumed.112.112334.
PMID
23440556
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
54
Issue
4
Publish Date
2013
Start Page
541
End Page
548
DOI
10.2967/jnumed.112.112334

DISTINCT METASTATIC PATTERNS IN NEUROBLASTOMA ARE CORRELATED WITH MYCN AMPLIFICATION

Authors
Bleeker, G; Caron, HN; van Eck-Smit, BLF; Versteeg, R; Kreissman, SG; Yanik, G; Tytgat, GA
MLA Citation
Bleeker, Gitta, et al. “DISTINCT METASTATIC PATTERNS IN NEUROBLASTOMA ARE CORRELATED WITH MYCN AMPLIFICATION.” Pediatric Blood & Cancer, vol. 59, no. 6, WILEY PERIODICALS, INC, Dec. 2012, pp. 1057–58.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
59
Issue
6
Publish Date
2012
Start Page
1057
End Page
1058

Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma.

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.

Authors
Asgharzadeh, S; Salo, JA; Ji, L; Oberthuer, A; Fischer, M; Berthold, F; Hadjidaniel, M; Liu, CW-Y; Metelitsa, LS; Pique-Regi, R; Wakamatsu, P; Villablanca, JG; Kreissman, SG; Matthay, KK; Shimada, H; London, WB; Sposto, R; Seeger, RC
MLA Citation
Asgharzadeh, Shahab, et al. “Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma..” J Clin Oncol, vol. 30, no. 28, Oct. 2012, pp. 3525–32. Pubmed, doi:10.1200/JCO.2011.40.9169.
PMID
22927533
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
28
Publish Date
2012
Start Page
3525
End Page
3532
DOI
10.1200/JCO.2011.40.9169

Presentation and outcomes for children with bone marrow necrosis and acute lymphoblastic leukemia: a literature review.

Bone marrow necrosis is a rare histopathology finding with the majority of cases occurring in the setting of a hematologic malignancy. This article reports a case of diffuse marrow necrosis in a child secondary to acute lymphoblastic leukemia and summarizes the clinical features and outcomes for children with bone marrow necrosis secondary to leukemia from 20 published reports. This review demonstrated that the most common presenting features were bone pain, fever, pancytopenia, and that outcomes were less favorable when compared with those without necrosis. However, contemporary literature suggests that outcomes are similar for children who have bone marrow necrosis secondary to leukemia when compared with overall survival rates for pediatric leukemia.

Authors
Shah, NR; Landi, DB; Kreissman, SG; Kulbachi, E; Moran, C
MLA Citation
Shah, Nirmish R., et al. “Presentation and outcomes for children with bone marrow necrosis and acute lymphoblastic leukemia: a literature review..” J Pediatr Hematol Oncol, vol. 33, no. 7, Oct. 2011, pp. e316–19. Pubmed, doi:10.1097/MPH.0b013e318223fe9b.
PMID
21941136
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Volume
33
Issue
7
Publish Date
2011
Start Page
e316
End Page
e319
DOI
10.1097/MPH.0b013e318223fe9b

Comparison of ¹²³I-metaiodobenzylguanidine (MIBG) and ¹³¹I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group.

BACKGROUND: ¹²³I-metaiodobenzylguanidine (MIBG) scans are preferable to ¹³¹I-MIBG for neuroblastoma imaging as they deliver less patient radiation yet have greater sensitivity in disease detection. Both ¹²³I-MIBG and ¹³¹I-MIBG scans were used for disease assessments of neuroblastoma patients enrolled on Children's Oncology Group (COG) high-risk study A3973. The hypothesis was that ¹²³I-MIBG and ¹³¹I-MIBG scans were sufficiently similar for clinical purposes in terms of ability to predict survival. PROCEDURE: Patients enrolled on COG A3973 with stage 4 disease who completed ¹²³I-MIBG or ¹³¹I-MIBG scans at diagnosis, post-induction, post-transplant, or post-biotherapy were analyzed. The performance of the Curie score for each MIBG scan type in predicting survival was evaluated. At each time point, survival curves for ¹²³I-MIBG versus ¹³¹I-MIBG were compared using the log-rank test. RESULTS: Of the 413 patients on A3973 with at least one MIBG scan, 350 were stage 4. The 5-year event-free survival (EFS) and overall survival (OS) rates were 33.4 ± 3.6% and 45.6 ± 4.0% (N = 350). At post-induction, EFS (P = 0.3501) and OS (P = 0.5337) for ¹²³I-MIBG versus ¹³¹I-MIBG were not significantly different. Similarly, comparisons at the three other time points were non-significant. CONCLUSIONS: We found no evidence of a statistically significant difference in outcome by type of scan. For future survival analyses of MIBG Curie scores, ¹²³I-MIBG and ¹³¹I-MIBG results may be combined and analyzed overall, without adjustment for scan type.

Authors
Naranjo, A; Parisi, MT; Shulkin, BL; London, WB; Matthay, KK; Kreissman, SG; Yanik, GA
MLA Citation
Naranjo, Arlene, et al. “Comparison of ¹²³I-metaiodobenzylguanidine (MIBG) and ¹³¹I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group..” Pediatr Blood Cancer, vol. 56, no. 7, July 2011, pp. 1041–45. Pubmed, doi:10.1002/pbc.22991.
PMID
21328522
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
56
Issue
7
Publish Date
2011
Start Page
1041
End Page
1045
DOI
10.1002/pbc.22991

Ototoxicity in children with high-risk neuroblastoma: Prevalence, risk factors, and concordance of grading scales—A report from the Children's Oncology Group (COG).

Authors
Landier, W; Knight, KR; Wong, FL; Lee, JK; Thomas, O; Kim, H; Kreissman, SG; Schmidt, ML; Chen, L; London, WB; Bhatia, S; Gurney, JG
MLA Citation
Landier, W., et al. “Ototoxicity in children with high-risk neuroblastoma: Prevalence, risk factors, and concordance of grading scales—A report from the Children's Oncology Group (COG)..” Journal of Clinical Oncology, vol. 29, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2011, pp. 9515–9515. Crossref, doi:10.1200/jco.2011.29.15_suppl.9515.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
9515
End Page
9515
DOI
10.1200/jco.2011.29.15_suppl.9515

Ototoxicity in children with high-risk neuroblastoma: Prevalence, risk factors, and concordance of grading scales-A report from the Children's Oncology Group (COG).

9515 Background: Management of high-risk neuroblastoma relies on potentially ototoxic platinum-based therapy. In previous reports, the proportion of children with ototoxicity has ranged from 20-90%, with variability likely due to small samples and disparate grading scales. Currently there is no consensus regarding an optimal pediatric ototoxicity grading scale, and no reports of prevalence and risk factors for hearing loss (HL) in a large uniformly-treated cohort. We address these gaps using data from COG A3973. METHODS: Audiologic testing (AT) was completed after cisplatin (up to 400 mg/m(2): t1) and carboplatin (1700 mg/m(2): t2). HL was graded independently by 2 investigators using 3 grading scales (Brock, Chang, CTCv3). Concordance between scales was evaluated by McNemar's test, and risks for HL by logistic regression. RESULTS: Of 334 evaluable patients, 56% were male; median age at diagnosis was 3.3 yrs; the most recent evaluable AT was done at t1 for 20% and t2 for 80%. Cohen's kappa for inter-rater reliability was >0.95. HL was graded severe at t2 in 30% per Brock, 59% per Chang and 71% per CTCv3. In patients with hearing aids, HL was graded severe in 49% per Brock, 91% per Chang and 100% per CTCv3. Risk factors for severe HL included carboplatin conditioning and hospitalization for infection; scales were significantly discordant in detecting severe HL (p<.0001; Table). CONCLUSIONS: The study is the first to report conclusively that prevalence of severe hearing loss approaches 70% (CTCv3); risk is significantly increased after consolidation with carboplatin and hospitalization for infection; and the commonly-used Brock scale underestimates severe hearing loss, and should be used with caution in this setting. [Table: see text].

Authors
Landier, W; Knight, KR; Wong, FL; Lee, JK; Thomas, O; Kim, H; Kreissman, SG; Schmidt, ML; Chen, L; London, WB; Bhatia, S; Gurney, JG; Children's Oncology Group,
MLA Citation
Landier, W., et al. “Ototoxicity in children with high-risk neuroblastoma: Prevalence, risk factors, and concordance of grading scales-A report from the Children's Oncology Group (COG)..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28019812
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
9515

Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.

BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Authors
Yu, AL; Gilman, AL; Ozkaynak, MF; London, WB; Kreissman, SG; Chen, HX; Smith, M; Anderson, B; Villablanca, JG; Matthay, KK; Shimada, H; Grupp, SA; Seeger, R; Reynolds, CP; Buxton, A; Reisfeld, RA; Gillies, SD; Cohn, SL; Maris, JM; Sondel, PM; Children's Oncology Group,
MLA Citation
Yu, Alice L., et al. “Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma..” N Engl J Med, vol. 363, no. 14, Sept. 2010, pp. 1324–34. Pubmed, doi:10.1056/NEJMoa0911123.
PMID
20879881
Source
pubmed
Published In
The New England Journal of Medicine
Volume
363
Issue
14
Publish Date
2010
Start Page
1324
End Page
1334
DOI
10.1056/NEJMoa0911123

MIBG scoring as a prognostic indicator in patients with stage IV neuroblastoma: A COG study.

Authors
Yanik, GA; Parisi, MT; Naranjo, A; Matthay, KK; London, WB; McGrady, PW; Kreissman, SG; Shulkin, BL
MLA Citation
Yanik, G. A., et al. “MIBG scoring as a prognostic indicator in patients with stage IV neuroblastoma: A COG study..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 9516–9516. Crossref, doi:10.1200/jco.2010.28.15_suppl.9516.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
9516
End Page
9516
DOI
10.1200/jco.2010.28.15_suppl.9516

Peripheral blood stem cell support for multiple cycles of dose intensive induction therapy is feasible with little risk of tumor contamination in advanced stage neuroblastoma: a report from the Childrens Oncology Group.

BACKGROUND: Poor outcome in Stage 4 neuroblastoma may be improved with increased dose intensity of therapy. We investigated the feasibility of sequential collection and infusion of peripheral blood stem cells (PBSCs) as hematopoietic support for non-myeloablative dose intensive induction chemotherapy given every 21-28 days. METHODS: Twenty-two children with Stage 4 neuroblastoma (>or=1 year of age) received two cycles of high-dose cyclophosphamide (4 g/m(2)), doxorubicin (75 mg/m(2)), and vincristine (2 mg/m(2)) followed by three cycles of interpatient dose escalating carboplatin (Dose Level 0 = 800 mg/m(2); Dose Level 1 = 1,000 mg/m(2)), high-dose cyclophosphamide (4 g/m(2)), and etoposide (600 mg/m(2)). PBSC were harvested following cycle 2, 3, and 4 in Cohort 1 and infused after each subsequent cycle. In Cohort 2, PBSC were harvested after cycle 2 and split into three aliquots for infusion. Dose limiting toxicity (DLT) and ability to administer cycles within 28 days was assessed. RESULTS: Sufficient PBSC (>or=2 x 10(6) CD34 cells/kg per infusion) were collected from 17/21 eligible patients with minimal toxicity and no detectable neuroblastoma cells by immunocytology. Carboplatin at 1000 mg/m(2) resulted in DLT of delayed platelet recovery >28 days in 4/8 patients. Despite de-escalation to 800 mg/m(2), platelet DLT occurred in 4/7 Cohort 1 and 3/7 Cohort 2 patients. CONCLUSION: As defined in this protocol, doses of carboplatin were not tolerable with the PBSC dose administered. However, it was feasible to collect sufficient PBSC from small neuroblastoma patients to use as hematopoietic support with minimal risk of tumor contamination and toxicity.

Authors
Bensimhon, P; Villablanca, JG; Sender, LS; Matthay, KK; Park, JR; Seeger, R; London, WB; Yap, JSF; Kreissman, SG
MLA Citation
Bensimhon, Pamela, et al. “Peripheral blood stem cell support for multiple cycles of dose intensive induction therapy is feasible with little risk of tumor contamination in advanced stage neuroblastoma: a report from the Childrens Oncology Group..” Pediatr Blood Cancer, vol. 54, no. 4, Apr. 2010, pp. 596–602. Pubmed, doi:10.1002/pbc.22344.
PMID
20049927
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
54
Issue
4
Publish Date
2010
Start Page
596
End Page
602
DOI
10.1002/pbc.22344

A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children's Oncology Group study.

10011 Background: ASCT improves outcome for HR-NB, but potential risk of reinfusion of viable tumor in PBSC could affect event-free survival (EFS). We assessed the impact of ASCT with immunomagnetic purging of PBSC, compared to UP product, on EFS, PBSC tumor content, engraftment, and ASCT toxicity. METHODS: Between 2/2001 and 3/2006, 489 eligible newly diagnosed HR-NB pts were randomized at study entry to have P or UP PBSC obtained and cryopreserved after 2 cycles of induction chemotherapy. Purging was performed centrally using carbonyl iron depletion of phagocytes followed by 2 cycles of magnetic beads with 5 anti-NB monoclonal antibodies. After 6 chemotherapy cycles, pts received melphalan (180-210 mg/m(2)), carboplatin (AUC 4.1 to max 1700 mg/m(2)), and etoposide (800-1352 mg/m(2)) based on GFR followed by PBSC support. Post-ASCT pts had radiation to primary and MIBG+ sites, then 6 cycles of 13-cis-retinoic acid. EFS and overall survival (OS) from enrollment [primary endpoint] were analyzed as intent-to- treat. RESULTS: Median age at study entry was 3.1 yrs (range 91 days-29 years), 44% of 392 tumors tested had MYCN amplification and 424 were INSS stage 4. There were 368 pts transplanted (178 P and 190 UP). Crossover from P to UP arm occurred in 30 pts and from UP to P arm in 5 pts. Only 5 pts (1 P and 4 UP) had NB detected in PBSC by immunocytology at collection, none after purging. RT- PCR analysis of tumor in PBSC products is ongoing. The median time to ANC>500 was 13 days for P and 11 days for UP (p= 0.0001). Toxic death following ASCT was 3.2%, (8 P, 4 UP) mainly due to infection. There was no difference in toxicities between arms. CONCLUSIONS: Centralized immunomagnetic purging of PBSC in the context of dose-intensive chemoradiotherapy and biologic therapy in first response did not impact EFS or OS at 2 years. RT-PCR analyses of PBSC products will determine if purging of rare tumor cells occurred. [Table: see text] No significant financial relationships to disclose.

Authors
Kreissman, SG; Villablanca, JG; Seeger, RC; Grupp, SA; London, WB; Maris, JM; Park, JR; Cohn, SL; Matthay, KK; Reynolds, CP
MLA Citation
Kreissman, S. G., et al. “A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children's Oncology Group study..” J Clin Oncol, vol. 26, no. 15_suppl, May 2008.
PMID
27951329
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
10011

A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children’s Oncology Group study

Authors
Kreissman, SG; Villablanca, JG; Seeger, RC; Grupp, SA; London, WB; Maris, JM; Park, JR; Cohn, SL; Matthay, KK; Reynolds, CP
MLA Citation
Kreissman, S. G., et al. “A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children’s Oncology Group study.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 10011–10011. Crossref, doi:10.1200/jco.2008.26.15_suppl.10011.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
10011
End Page
10011
DOI
10.1200/jco.2008.26.15_suppl.10011

Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children's Oncology Group (COG A3973) study

Authors
Kreissman, SG; Villablanca, JG; Diller, L; London, WB; Maris, JM; Park, JR; Reynolds, CP; von Allmen, D; Cohn, SL; Matthay, KK
MLA Citation
Kreissman, S. G., et al. “Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children's Oncology Group (COG A3973) study.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase.

Administration of chemotherapy is often limited by myelosuppression. Expression of drug-resistance genes in hematopoietic cells has been proposed as a means to decrease the toxicity of cytotoxic agents. In this pilot study, we utilized a retroviral vector expressing methylguanine DNA methyltransferase (MGMT) to transduce hematopoietic progenitors, which were subsequently used in the setting of alkylator therapy (procarbazine, CCNU, vincristine (PCV)) for poor prognosis brain tumors. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells were collected by apheresis and enriched for CD34+ expression. Nine subjects were infused with CD34+-enriched cells treated in a transduction procedure involving a 4-day exposure to cytokines with vector exposure on days 3 and 4. No major adverse event was related to the gene therapy procedure. Importantly, the engraftment kinetics of the treated product was similar to unmanipulated peripheral blood stem cells, suggesting that the ex vivo manipulation did not significantly reduce engrafting progenitor cell function. Gene-transduced cells were detected in all subjects. Although the level and duration was limited, patients receiving cells transduced using fibronectin 'preloaded' with virus supernatant appeared to show improved in vivo marking frequency. These findings demonstrate the feasibility and safety of utilizing MGMT-transduced CD34+ peripheral blood progenitor cells in the setting of chemotherapy.

Authors
Cornetta, K; Croop, J; Dropcho, E; Abonour, R; Kieran, MW; Kreissman, S; Reeves, L; Erickson, LC; Williams, DA
MLA Citation
Cornetta, K., et al. “A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase..” Cancer Gene Ther, vol. 13, no. 9, Sept. 2006, pp. 886–95. Pubmed, doi:10.1038/sj.cgt.7700963.
PMID
16645619
Source
pubmed
Published In
Cancer Gene Therapy
Volume
13
Issue
9
Publish Date
2006
Start Page
886
End Page
895
DOI
10.1038/sj.cgt.7700963

A novel intensive induction therapy for high-risk neuroblastoma utilizing sequential peripheral blood stem cell collection and infusion as hematopoietic support.

OBJECTIVE: To determine the feasibility, toxicities, and the response rate (RR) of a dose intensive, submyeloablative, induction chemotherapy protocol termed EPiC (etoposide, carboplatin, and intensive cyclophosphamide) utilizing sequential peripheral blood stem cell (PBSC) collection and infusion as hematopoietic support in children with newly diagnosed Stage 4 neuroblastoma. PATIENTS AND METHODS: Twenty-five children (age >1 year) with Stage 4 neuroblastoma were enrolled. First and third cycles consisted of cyclophosphamide (4 gm/m2) and carboplatin (400 mg/m2). Second and fourth cycles consisted of carboplatin (1 gm/m2), and etoposide (450 mg/m2). PBSC were collected following Cycles 1, 2, and 3 and reinfused in each subsequent cycle. Following EPiC and surgical resection of the primary tumor, patients proceeded to various consolidation therapies. RR was scored using the International Neuroblastoma Response Criteria. RESULTS: Using PBSC infusion following EPiC chemotherapy resulted in a dose intensity averaging 85% of intended dose intensity; and in early neutrophil but not platelet recovery. PBSC were adequately collected in all, but one patient. The protocol had minimal non-hematological toxicities. There was one toxic death. The overall RR was 78%, which included PR (partial response) and VGPR (very good partial response). The 5-year event-free survival and overall survival were 44% and 54%, respectively at a median follow-up of 58.6 months. CONCLUSION: EPiC is a feasible, well-tolerated, sub-myeloablative, induction chemotherapy protocol for children with high-risk neuroblastoma. RR is equivalent to prior published studies, however, with minimal toxicities. Sequential PBSC collection and infusion is feasible even in very young children.

Authors
Pradhan, KR; Johnson, CS; Vik, TA; Sender, LS; Kreissman, SG
MLA Citation
Pradhan, Kamnesh R., et al. “A novel intensive induction therapy for high-risk neuroblastoma utilizing sequential peripheral blood stem cell collection and infusion as hematopoietic support..” Pediatr Blood Cancer, vol. 46, no. 7, June 2006, pp. 793–802. Pubmed, doi:10.1002/pbc.20594.
PMID
16206215
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
46
Issue
7
Publish Date
2006
Start Page
793
End Page
802
DOI
10.1002/pbc.20594

Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: a clinical, haematological and biological study.

Thrombocytopenia remains the major dose-limiting toxicity of myelosuppressive chemotherapy in children with solid tumours. Recombinant human interleukin-11 (rhIL-11) has been approved by the Food and Drug Administration as treatment for adults with solid tumours and lymphomas with severe chemotherapy-induced thrombocytopenia. We conducted a phase I/II trial of rhIL-11 following ifosfamide, carboplatin and etoposide (ICE) chemotherapy in children with solid tumours or lymphomas. Patients received ifosfamide 1800 mg/m(2)/d for 5 d, carboplatin 400 mg/m(2)/d for 2 d and etoposide 100 mg/m(2)/d for 5 d with rhIL-11 subcutaneous (s.c.) at 25-125 microg/kg/d on days 6-33. Forty-seven patients with median age 10.5 years (range, 0.7-26 years) were studied. Median days to absolute neutrophil count >/=0.5 x 10(9)/l, platelet count >/=50 x 10(9)/l and platelet transfusions were 23, 18, 18, 16.5 and 18.5, 21, 20, 18 and 3, 3, 4, and 2 d at doses 25, 50, 75 and 100 Schulteg/kg respectively. There was a dose-dependent increase in C(max) (7.6-25.5 ng/ml), AUC(0-rho) (57-209 ng.h/ml) and T(1/2) (4-8.2 h) respectively. There was a 4% incidence of anti-IL-11 antibody formation. Clinically important adverse events to rhIL-11 were papilloedema and periosteal bone formation. In summary, rhIL-11 was well tolerated at doses of

Authors
Cairo, MS; Davenport, V; Bessmertny, O; Goldman, SC; Berg, SL; Kreissman, SG; Laver, J; Shen, V; Secola, R; van de Ven, C; Reaman, GH
MLA Citation
Cairo, Mitchell S., et al. “Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: a clinical, haematological and biological study..” Br J Haematol, vol. 128, no. 1, Jan. 2005, pp. 49–58. Pubmed, doi:10.1111/j.1365-2141.2004.05281.x.
PMID
15606549
Source
pubmed
Published In
British Journal of Haematology
Volume
128
Issue
1
Publish Date
2005
Start Page
49
End Page
58
DOI
10.1111/j.1365-2141.2004.05281.x

Peripheral blood stem cell support reduces the toxicity of intensive chemotherapy for children and adolescents with metastatic sarcomas.

BACKGROUND: To increase the dose intensity (DI) of chemotherapy for pediatric patients with metastatic sarcomas, including the Ewing sarcoma family of tumors (ESFT) and rhabdomyosarcoma (RMS), the authors tested the feasibility of an intensive regimen supported by granulocyte-colony stimulating factor (G-CSF) and peripheral blood stem cells (PBSC). METHODS: Twenty-three children and adolescents with metastatic sarcomas received vincristine, doxorubicin, cyclophosphamide, ifosfamide, sodium mercaptoethanesulfonate (mensa), and etoposide (VACIME) chemotherapy, consisting of 8 courses of vincristine 2 mg/m(2) on Day 0, doxorubicin 37.5 mg/m(2) per day on Days 0-1, cyclophosphamide 360 mg/m(2) per day on Days 0-4, ifosfamide 1800 mg/m(2) per day on Days 0-4, mesna 2400 mg/m(2) per day, and etoposide 100 mg/m(2) per day on Days 0-4. Doxorubicin was omitted in Courses 7 and 8. G-CSF was given after each course of therapy. Courses of therapy were repeated every 21 days or as soon as hematopoietic recovery permitted. PBSC were collected twice: first, after Course 2 (infused after Courses 3 and 4) and, second, after Course 4 (infused after Courses 5 and 6). Surgical resection followed Course 6, and radiotherapy followed Course 8. RESULTS: PBSC collections were adequate in 91% of all harvests. The mean DI was 82% (standard deviation, 14%) of the intended DI, which was greater than historic data without PBSC support. Seventeen patients (74%) achieved a complete response (CR), 12 patients with chemotherapy alone and 5 more patients after undergoing surgical resection. Fifteen patients developed progressive disease, with a 2-year event free survival (EFS) rate of 39% (95% confidence interval, 19-59%). Hematopoietic toxicity was severe and cumulative, although it was less than that seen previously without PBSC support. CONCLUSIONS: PBSC-supported multicycle chemotherapy is a feasible method to increase chemotherapy DI for pediatric patients with metastatic sarcomas. Although the CR rate compared favorably with previously reported response rates, the 2-year EFS rate was similar to that achieved with other intensive regimens.

Authors
Hawkins, DS; Felgenhauer, J; Park, J; Kreissman, S; Thomson, B; Douglas, J; Rowley, SD; Gooley, T; Sanders, JE; Pendergrass, TW
MLA Citation
Hawkins, Douglas S., et al. “Peripheral blood stem cell support reduces the toxicity of intensive chemotherapy for children and adolescents with metastatic sarcomas..” Cancer, vol. 95, no. 6, Sept. 2002, pp. 1354–65. Pubmed, doi:10.1002/cncr.10801.
PMID
12216105
Source
pubmed
Published In
Cancer
Volume
95
Issue
6
Publish Date
2002
Start Page
1354
End Page
1365
DOI
10.1002/cncr.10801

Mobilization and collection of peripheral blood CD34+ cells from patients with Fanconi anemia.

A potential therapeutic option for patients with Fanconi anemia is collection of peripheral blood stem cells prior to the development of severe pancytopenia. These hematopoietic cells potentially could be infused when symptomatic bone marrow failure develops, as autologous rescue after chemotherapy in the event of leukemic transformation, or as targets for gene therapy. Eight patients with Fanconi anemia were mobilized with 10 microg/kg per day of granulocyte colony-stimulating factor (median, 10 +/- 4 days) to determine the feasibility of collecting peripheral blood stem cells for future use. Six patients achieved a peripheral blood CD34+ count of > or = 6/microL and underwent apheresis. The collection goal was 2 x 10(6) CD34+ cells/kg based on a predicted weight 5 years from the date of collection. A mean of 2.6 +/- 0.9 x 10(6) CD34+ cells/kg of the weight at the time of collection were collected, which corresponded to 1.9 +/- 0.4 x 10(6) CD34+ cells/kg of the target weight. The collections required a mean of 4 +/- 3 days (range, 2-8 days) of apheresis. Six of the 8 subjects had > or = 1 x 10(6) CD34+ cells/kg cryopreserved based on both actual and target weights, and 4 subjects had > or = 2 x 10(6) CD34+ cells/kg cryopreserved based on the target weight. These results suggest that some patients with Fanconi anemia can have adequate numbers of CD34+ cells mobilized and collected from the peripheral blood prior to the onset of severe bone marrow failure, but they may require an extended mobilization and multiple days of collection.

Authors
Croop, JM; Cooper, R; Fernandez, C; Graves, V; Kreissman, S; Hanenberg, H; Smith, FO; Williams, DA
MLA Citation
Croop, J. M., et al. “Mobilization and collection of peripheral blood CD34+ cells from patients with Fanconi anemia..” Blood, vol. 98, no. 10, Nov. 2001, pp. 2917–21. Pubmed, doi:10.1182/blood.v98.10.2917.
PMID
11698271
Source
pubmed
Published In
Blood
Volume
98
Issue
10
Publish Date
2001
Start Page
2917
End Page
2921
DOI
10.1182/blood.v98.10.2917

A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis.

Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC(0-96)). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC(0-96) was 128 +/- 70 mg/dL.hour for the rasburicase group and 329 +/- 129 mg/dL.hour for the allopurinol group (P <.0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P <.0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy.

Authors
Goldman, SC; Holcenberg, JS; Finklestein, JZ; Hutchinson, R; Kreissman, S; Johnson, FL; Tou, C; Harvey, E; Morris, E; Cairo, MS
MLA Citation
Goldman, S. C., et al. “A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis..” Blood, vol. 97, no. 10, May 2001, pp. 2998–3003. Pubmed, doi:10.1182/blood.v97.10.2998.
PMID
11342423
Source
pubmed
Published In
Blood
Volume
97
Issue
10
Publish Date
2001
Start Page
2998
End Page
3003
DOI
10.1182/blood.v97.10.2998

Large-scale mobilization and isolation of CD34+ cells from normal donors.

We describe collection and purification of peripheral blood CD34+ cells from volunteer, normal donors and allogeneic stem cell donors. A total of 98 aphereses were performed on 68 volunteer donors using peripheral venous access. The mean number of nucleated cells collected was 4.6 x 10(10) which included 1.9 x 10(8) CD34+ cells corresponding to 2.7 x 10(6) CD34+ cells/kg. The number of CD34+ cells collected did not differ between males and females but did correlate with the donor's weight and the total number of nucleated cells collected. The Nexell Isolex 300i cell separator was used to isolate CD34+ cells from 30 of the collections. A mean of 0.36% of the total cells was recovered and included 43 +/- 18% of the CD34+ cells. CD34+ cells represented 85 +/- 11% of the recovered cells. The total number of CD34+ cells recovered was not influenced by the number of nucleated cells placed on the Isolex 300i. The percentage of CD34+ cells recovered was not related to the number of CD34+ cells placed on the Isolex 300i. The purity of the final product was influenced by the number of CD34+ cells but not the total number of nucleated cells. An additional 38 CD34+ cell isolations were performed on normal allogeneic stem cell donors with similar results. These observations further support the safety and feasibility of peripheral blood CD34+ cell collection and purification.

Authors
Croop, JM; Cooper, R; Seshadri, R; Fernandez, C; Graves, V; Kreissman, S; Smith, FO; Cornetta, K; Williams, DA; Abonour, R
MLA Citation
Croop, J. M., et al. “Large-scale mobilization and isolation of CD34+ cells from normal donors..” Bone Marrow Transplant, vol. 26, no. 12, Dec. 2000, pp. 1271–79. Pubmed, doi:10.1038/sj.bmt.1702720.
PMID
11223966
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
26
Issue
12
Publish Date
2000
Start Page
1271
End Page
1279
DOI
10.1038/sj.bmt.1702720

A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia

In this double-blind study to compare safety of 2 lipid formulations of amphotericin B, neutropenic patients with unresolved fever after 3 days of antibacterial therapy were randomized (1:1:1) to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n = 78), liposomal amphotericin B (L Amph) at a dose of 3 mg/kg/d (n = 85), or L Amph at a dose of 5 mg/kg/d (n = 81). L Amph (3 mg/kg/d and 5 mg/kg/d) had lower rates of fever (23.5% and 19.8% vs. 57.7% on day 1; P < .001), chills/rigors (18.8% and 23.5% vs. 79.5% on day 1; P <.001), nephrotoxicity (14.1% and 14.8% vs. 42.3%; P<.01), and toxicity-related discontinuations of therapy (12.9% and 12.3% vs. 32.1%; P = .004). After day 1, infusional reactions were less frequent with ABLC, but chills/rigors were still higher (21.0% and 24.3% vs. 50,7%; P < .001). Therapeutic success was similar in all 3 groups.

Authors
Wingard, JR; White, MH; Anaissie, E; Raffalli, J; Goodman, J; Arrieta, A; Albano, E; Bodensteiner, D; Broun, ER; Cagnoni, P; Greenberg, R; Hiemenz, J; Holcenberg, JS; Sepkowitz, K; Kreissman, S; Longo, WR; Roy, V; Uberti, J; Vesole, D; Buell, D; Thuma, N; Roloff, B; Hodosh, E
MLA Citation
Wingard, J. R., et al. “A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia.” Clinical Infectious Diseases, vol. 31, no. 5, 2000, pp. 1155–63. Scival, doi:10.1086/317451.
Source
scival
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
31
Issue
5
Publish Date
2000
Start Page
1155
End Page
1163
DOI
10.1086/317451

Prognostic significance of early response to a single dose of asparaginase in childhood acute lymphoblastic leukemia.

PURPOSE: The in vitro and in vivo efficacy of a single dose of asparaginase in children with newly diagnosed acute lymphoblastic leukemia and the correlation between in vitro and in vivo antileukemic response and long-term outcome were prospectively evaluated. PATIENTS AND METHODS: Two hundred fifty-one patients were randomized to receive 1 of 3 asparaginase preparations (Escherichia coli, Erwinia chrysanthemi [Erwinia], or pegaspargase). In vitro assessment of efficacy was expressed as the percent total cell kill (TCK), based on the number of viable cells found after 5 days of culture in the presence of asparaginase. In vivo leukemia cell kill (LCK) was calculated by comparing bone marrow cellularity and percent leukemic blasts in marrow obtained before and 5 days after treatment with a single dose of asparaginase. Acute toxicity was determined by clinical and laboratory assessment. RESULTS: There was equivalent cell kill with all three types of asparaginase. The mean in vitro TCKs for E. coli, Erwinia, and pegaspargase were 31%, 39%, and 36%, respectively (P = 0.63). The mean LCKs in marrow of patients exposed to E. coli, Erwinia, and pegaspargase were 69%, 74%, and 65%, respectively (P = 0.88). The lack of response to asparaginase in vitro predicted a higher risk for clinical relapse regardless of risk assignment (12 leukemic events among 21 in vitro nonresponders; 57%, P < 0.001). There was no difference in acute toxicity among the three asparaginase preparations. CONCLUSIONS: All three asparaginase preparations produced equivalent LCKs in in vitro and in vivo analyses. In vitro response to asparaginase provided a risk group-independent prognostic factor.

Authors
Asselin, BL; Kreissman, S; Coppola, DJ; Bernal, SD; Leavitt, PR; Gelber, RD; Sallan, SE; Cohen, HJ
MLA Citation
Asselin, B. L., et al. “Prognostic significance of early response to a single dose of asparaginase in childhood acute lymphoblastic leukemia..” J Pediatr Hematol Oncol, vol. 21, no. 1, Jan. 1999, pp. 6–12.
PMID
10029805
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Volume
21
Issue
1
Publish Date
1999
Start Page
6
End Page
12

Platelet depletion during pediatric peripheral blood progenitor cell (PBPC) harvesting

Authors
McCarthy, L; Smith, FO; Emanuel, D; Orazi, A; Danielson, C; Thompson, C; Thomas, C; Kreissman, S
MLA Citation
McCarthy, L., et al. “Platelet depletion during pediatric peripheral blood progenitor cell (PBPC) harvesting.” Transfusion Science, vol. 19, no. 1, July 1998. Scopus, doi:10.1016/S0955-3886(98)00016-2.
Source
scopus
Published In
Transfusion Science
Volume
19
Issue
1
Publish Date
1998
Start Page
61
DOI
10.1016/S0955-3886(98)00016-2

High dose chemotherapy with autologous peripheral blood progenitor cell transplantation in an anephric child with multiply recurrent Wilms tumor.

PURPOSE: An autologous peripheral blood progenitor cell (APBPC) transplant in an anephric child with multiply recurrent Wilms tumor using a conditioning regimen of high dose chemotherapy in conjunction with hemodialysis (HD) and peritoneal dialysis is described. PATIENT AND METHODS: The child had a left nephrectomy at 9 months of age for a stage II Wilms tumor. At 6 years of age, she required a right nephrectomy because of progressive, recurrent disease unresponsive to treatment with doxorubicin, actinomycin, and vincristine. She was maintained on peritoneal dialysis. Salvage chemotherapy consisted of 5 cycles of carboplatin and cyclophosphamide after APBPCs were collected after granulocyte colony-stimulating factor mobilization. After a preparative regimen of carboplatin, cyclophosphamide, and etoposide with closely timed HD, peripheral blood progenitor cells were infused and peritoneal dialysis was resumed. RESULTS: No nonhematopoietic toxicity occurred. Pharmacokinetic studies demonstrated that HD effectively eliminated carboplatin and provided safe, effective plasma concentrations in this anephric patient. Trilineage engraftment occurred by day +10 and the child was discharged from the hospital on day +14. She had a local recurrence on day +194 and died of progressive disease on day +660. CONCLUSIONS: With dialysis support and dose modification, high-dose chemotherapy followed by APBPC transplantation can be successfully performed in the anephric child. Given the lack of organ toxicity in this patient, increased doses of the drugs used in this preparative regimen may be possible for anephric children.

Authors
Dagher, R; Kreissman, S; Robertson, KA; Provisor, A; Bergstein, J; Burke, K; Rodman, JH; Emanuel, D; Smith, FO
MLA Citation
Dagher, R., et al. “High dose chemotherapy with autologous peripheral blood progenitor cell transplantation in an anephric child with multiply recurrent Wilms tumor..” J Pediatr Hematol Oncol, vol. 20, no. 4, July 1998, pp. 357–60.
PMID
9703013
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Volume
20
Issue
4
Publish Date
1998
Start Page
357
End Page
360

Combination of rhIL-11 + G-CSF enhances platelet (PLT) and myeloid recovery following ifosfamide, carboplatin, and etoposdde (ICE) chemotherapy in children with solid tumors (ST): RML-11 is well tolerated at double the adult recommended dose

RhIL-11 has demonstrated in phase II adult trials to reduce PLT tranfusions (TX) at the recommended dose of 50 ug/kg/d.(Isaacs et al Blood 88:448a, 1996 and Tepler et al Blood 87:3607,1996) We are reporting a multi-center phase I/II trial of rhIL-11 + G-CSF following ICE (I: 1800 mg/m /d × 5d, C: 400 mg/m /d × 2d, E: 100 mg/m/d × 5d) in pédiatrie ST patients (pts). RhIL-11 + G-CSF (5u,g/kg) was administered sub-q starting on day 6 until the ANC and PLT recovered 2 IK/ mm and 2100K/mm, respectively. Twenty eight pts, median age 6 (8mos-26yrs), 12F-16M, received 25 Hg/kg (n=4), 50 ug/kg (n=14), 75 Hg/kg (n=4), and 100 ug/kg (n=6) rhIL-11. None of the 28 pts receiving rML-11 exhibited evidence of Grade III or IV toxicity attributable to rhIL-11. The percentage of pts recovering their PLT Z 100K/mm1 by day 21 during cycle 1 at rhIL-11 100 Ug/kg was 67%. These results compare favorably to previous ST pts who received identical ICE with G-CSF alone (table [median]). Cytokine ANC PLT pts PLT 2100k/mm3# PLT Ug/kg/d aiK/mm u100K/mm by day 21 TX G-CSF (10) 21d 27d 25% 12 IL-11(100) + G(5) 17.5d 19.5d 67% 2 We conclude that although the maximum tolerated dose has not been reached in children, rhIL-11 is well tolerated at double the adult recommended dose and there appears to be an enhancement of recovery of PLT CT ï100K/mm by day 21, % pts by day 21, and decrease in PLT TX compared to historical controls with G-CSF alone.

Authors
Goldman, S; Davenport, V; Reaman, G; Laver, J; Kreissman, S; Blazar, B; Berg, S; Kaye, J; Patterson, F; Cairo, MS
MLA Citation
Goldman, S., et al. “Combination of rhIL-11 + G-CSF enhances platelet (PLT) and myeloid recovery following ifosfamide, carboplatin, and etoposdde (ICE) chemotherapy in children with solid tumors (ST): RML-11 is well tolerated at double the adult recommended dose.” Experimental Hematology, vol. 25, no. 8, Dec. 1997.
Source
scopus
Published In
Experimental Hematology
Volume
25
Issue
8
Publish Date
1997
Start Page
786

High dose cyclophosphamide with carboplatin: a tolerable regimen suitable for dose intensification in children with solid tumors.

PURPOSE: To determine the hematopoietic and nonhematopoietic toxicity of a novel dose-intensive chemotherapy regimen for the treatment of children with relapsed solid tumors. PATIENTS AND METHODS: The time to hematopoietic recovery and toxicity experienced during 46 courses of high-dose cyclophosphamide (4.0 g/m2), MESNA, and carboplatin (400 mg/m2) with granulocyte colony stimulating factor (G-CSF) support in 14 children with recurrent solid tumors was reviewed. RESULTS: All patients developed grade 4 neutropenia and thrombocytopenia. Recovery to an absolute neutrophil count (ANC) of 500/microliter and platelet count of 50,000/microliter occurred at a median of 15 days and 23 days respectively. Median time to ANC > 1,000/microliter and platelets > 100,000/microliter was 27 days. Hospitalization for fever and neutropenia occurred during 35 of 46 courses, with documented bacteremia in six courses. There was no grade II or greater nonhematopoietic organ toxicity. Responses (CR + PR) were observed in 6 of 11 evaluable patients. CONCLUSIONS: These data suggest that this regimen is tolerable in heavily pretreated children with solid tumors with myelosuppression as the primary toxicity. Due to the lack of significant nonhematopoietic toxicity, this is a good candidate regimen for dose escalation using peripheral blood progenitor cell infusions and deserves further evaluation for efficacy in children with both recurrent and newly diagnosed high-risk solid tumors.

Authors
Kreissman, SG; Rackoff, W; Lee, M; Breitfeld, PP
MLA Citation
Kreissman, S. G., et al. “High dose cyclophosphamide with carboplatin: a tolerable regimen suitable for dose intensification in children with solid tumors..” J Pediatr Hematol Oncol, vol. 19, no. 4, July 1997, pp. 309–12.
PMID
9256829
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Volume
19
Issue
4
Publish Date
1997
Start Page
309
End Page
312

Coming to terms: parents' response to a first cancer recurrence in their child.

The purpose of this study was to explore, using grounded theory, the process experienced by parents who are dealing with the first recurrence of cancer in their child. The sample of 33 guardians (27 mothers, 1 grandmother, and 5 fathers) was drawn from three pediatric oncology settings. Data were collected through interviews, observations, and medical record review. Thirteen parents were interviewed to validate first the evolving and, later, the complete study findings. Four interactive components emerged: regulating shock, situation monitoring, alternating realizations, and eyeing care-limiting decisions. The overall organizing construct induced from these components was labeled "coming to terms." This construct represents the parents' efforts to overcome shock and despair to make wise decisions about treatment while accepting that the outcome if beyond their control, and to help their child have the optimal chance for cure while preparing for the child's possible death.

Authors
Hinds, PS; Birenbaum, LK; Clarke-Steffen, L; Quargnenti, A; Kreissman, S; Kazak, A; Meyer, W; Mulhern, R; Pratt, C; Wilimas, J
MLA Citation
Hinds, P. S., et al. “Coming to terms: parents' response to a first cancer recurrence in their child..” Nurs Res, vol. 45, no. 3, May 1996, pp. 148–53.
PMID
8637795
Source
pubmed
Published In
Nursing Research
Volume
45
Issue
3
Publish Date
1996
Start Page
148
End Page
153

Predicting the risk of bacteremia in childen with fever and neutropenia.

PURPOSE: We sought to identify factors assessable at the time of admission for fever and neutropenia that predict bacteremia in children with cancer. PATIENTS AND METHODS: One hundred fifteen consecutive episodes of fever and absolute neutrophil count (ANC) less than 500/microliter in 72 children with cancer were studied prospectively to determine the risk of bacteremia using data assessable at the time of presentation. After exploratory analysis identified admission temperature and absolute monocyte count (AMoC) as the strongest predictive factors, recursive partitioning was used to determine cutpoints for these variables that resulted in discrimination between episodes associated with a lower or higher risk of bacteremia. RESULTS: There were 24 episodes of bacteremia (21% of episodes). Episodes were grouped using the cutpoints for AMoC and temperature: 17% were classified as low risk for bacteremia (AMoC > or = 100/microliter), 65% as intermediate risk (AMoC < 100/microliter and temperature < 39.0 degrees C), and 18% as high risk (AMoC < 100/microliter and temperature > or = 39.0 degrees C). No episodes classified as low risk were associated with bacteremia; 19% of intermediate-risk and 48% of high-risk episodes were associated with bacteremia. The odds ratio of bacteremia for the high-risk versus the intermediate-risk group is 4.4 (95% confidence interval, 1.6 to 12.9). The risk classification was validated using data from 57 different episodes of fever and neutropenia treated in the same hospital. CONCLUSION: Three levels of risk for bacteremia are defined using the AMoC and temperature at the time of admission for fever and neutropenia. Trials now should be conducted to test whether these factors may be used to assign some children to less intensive or outpatient antibiotic therapy at the time of presentation with fever and neutropenia.

Authors
Rackoff, WR; Gonin, R; Robinson, C; Kreissman, SG; Breitfeld, PB
MLA Citation
Rackoff, W. R., et al. “Predicting the risk of bacteremia in childen with fever and neutropenia..” J Clin Oncol, vol. 14, no. 3, Mar. 1996, pp. 919–24. Pubmed, doi:10.1200/JCO.1996.14.3.919.
PMID
8622040
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
14
Issue
3
Publish Date
1996
Start Page
919
End Page
924
DOI
10.1200/JCO.1996.14.3.919

Molecular genetics: toward an understanding of childhood cancer.

Investigation in cellular and molecular genetics has yielded a wealth of new information regarding the role of genetic alterations in the etiology of childhood cancer. The recent advancement of molecular biologic techniques has allowed researchers to bridge the gap from the description of chromosomal aberrations in tumor cells to the current identification of oncogenes and tumor suppressor genes involved in malignant transformation. This article reviews the advances in molecular genetics of childhood cancer, briefly outlines the history, and details the current knowledge of the use of cytogenetics, oncogenes, and other tools in the diagnosis, management, and further understanding of pediatric malignancies.

Authors
Kreissman, SG
MLA Citation
Kreissman, S. G. “Molecular genetics: toward an understanding of childhood cancer..” Semin Pediatr Surg, vol. 2, no. 1, Feb. 1993, pp. 2–10.
PMID
8062019
Source
pubmed
Published In
Seminars in Pediatric Surgery
Volume
2
Issue
1
Publish Date
1993
Start Page
2
End Page
10

LOCAL-CONTROL IN STAGE-III NEUROBLASTOMA PATIENTS OVER ONE-YEAR OF AGE - THE JOINT CENTER CHILDRENS-HOSPITAL DANA-FARBER-CANCER-INSTITUTE EXPERIENCE

Authors
MACKLIS, RM; WEST, DC; SHAMBERGER, RC; KOZAKEWICH, HP; KREISSMAN, SG; GRIER, HE
MLA Citation
MACKLIS, R. M., et al. “LOCAL-CONTROL IN STAGE-III NEUROBLASTOMA PATIENTS OVER ONE-YEAR OF AGE - THE JOINT CENTER CHILDRENS-HOSPITAL DANA-FARBER-CANCER-INSTITUTE EXPERIENCE.” International Journal of Radiation Oncology Biology Physics, vol. 27, PERGAMON-ELSEVIER SCIENCE LTD, Jan. 1993, pp. 131–32.
Source
wos
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
27
Publish Date
1993
Start Page
131
End Page
132

Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents.

PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis. PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors. RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS. CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.

Authors
West, DC; Shamberger, RC; Macklis, RM; Kozakewich, HP; Wayne, AS; Kreissman, SG; Korf, BR; Lavally, B; Grier, HE
MLA Citation
West, D. C., et al. “Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents..” J Clin Oncol, vol. 11, no. 1, Jan. 1993, pp. 84–90. Pubmed, doi:10.1200/JCO.1993.11.1.84.
PMID
8418247
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
11
Issue
1
Publish Date
1993
Start Page
84
End Page
90
DOI
10.1200/JCO.1993.11.1.84

Incidence of secondary acute myelogenous leukemia after treatment of childhood acute lymphoblastic leukemia.

BACKGROUND: Recent reports of secondary acute myelogenous leukemia (AML) occurring in children previously treated for acute lymphoblastic leukemia (ALL) prompted a review of patients with ALL treated at the Dana Farber Cancer Institute consortium (DFCI) between 1973 and 1987. Seven hundred fifty-two of 779 children treated for ALL entered complete remission. The mean follow-up time for the 752 patients was 4.4 years. Two children had AML develop 12 and 13 months after the diagnosis of ALL, respectively. METHODS: The estimated overall risk of secondary AML was calculated for the patient population as instances per 1000 patient-years of follow-up. This was compared with recent reported cases from another institution. RESULTS: The estimated overall risk of secondary AML was 0.61 instances per 1000 patient-years of follow-up (95% confidence interval: 0.15, 4.4). The difference between the risk of 0.61 among DFCI patients versus previously reported risk of 5.8 among a differently treated group of patients with ALL was statistically significant (P = 0.0008). No epipodophyllotoxin was used in the patients in the DFCI consortium. In contrast, an epipodophyllotoxin was used in 12 of 13 previously reported patients who had secondary AML develop. CONCLUSIONS: The authors concluded that the use of epipodophyllotoxins may be associated with an increased risk of having secondary AML develop in patients with ALL.

Authors
Kreissman, SG; Gelber, RD; Cohen, HJ; Clavell, LA; Leavitt, P; Sallan, SE
MLA Citation
Kreissman, S. G., et al. “Incidence of secondary acute myelogenous leukemia after treatment of childhood acute lymphoblastic leukemia..” Cancer, vol. 70, no. 8, Oct. 1992, pp. 2208–13. Pubmed, doi:10.1002/1097-0142(19921015)70:8<2208::aid-cncr2820700832>3.0.co;2-p.
PMID
1394053
Source
pubmed
Published In
Cancer
Volume
70
Issue
8
Publish Date
1992
Start Page
2208
End Page
2213
DOI
10.1002/1097-0142(19921015)70:8<2208::aid-cncr2820700832>3.0.co;2-p

Positive and negative elements regulate human interleukin 3 expression.

The human interleukin 3 (IL-3) promoter is comprised of several cis-acting DNA sequences that modulate T-cell expression of IL-3. These are located within 315 nucleotides upstream of the mRNA start site. Transient expression of reporter genes linked to serially deleted sequences of the IL-3 promoter has allowed mapping of two activator sequences and an interposed repressor sequence. The proximal regulatory region is specific to IL-3 and prerequisite for efficient transcription. Its effect is enhanced by a second, more distal activating sequence consisting of an AP-1 binding site. Between the two activators lies a transcriptional silencer, which is a potent repressor in the absence of the AP-1 site. DNA-nuclear protein binding experiments demonstrate specific complex formation within each of these functional regions. Thus, both positive and negative regulatory elements appear to control expression of the human IL-3 gene in activated T cells.

Authors
Mathey-Prevot, B; Andrews, NC; Murphy, HS; Kreissman, SG; Nathan, DG
MLA Citation
Mathey-Prevot, B., et al. “Positive and negative elements regulate human interleukin 3 expression..” Proc Natl Acad Sci U S A, vol. 87, no. 13, July 1990, pp. 5046–50. Pubmed, doi:10.1073/pnas.87.13.5046.
PMID
1695008
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
87
Issue
13
Publish Date
1990
Start Page
5046
End Page
5050
DOI
10.1073/pnas.87.13.5046

NUCLEAR FACTOR BINDING-SITES IN THE INTERLEUKIN (IL-3) PROMOTER

Authors
ANDREWS, NC; MATHEYPREVOT, B; KREISSMAN, SG; NATHAN, DG
MLA Citation
ANDREWS, N. C., et al. “NUCLEAR FACTOR BINDING-SITES IN THE INTERLEUKIN (IL-3) PROMOTER.” Pediatric Research, vol. 27, no. 4, WILLIAMS & WILKINS, Apr. 1990, pp. A138–A138.
Source
wos
Published In
Pediatric Research
Volume
27
Issue
4
Publish Date
1990
Start Page
A138
End Page
A138

The isolation of ecdysterone inducible genes by hybridization subtraction chromatography.

We have developed a procedure for selectively enriching a mRNA population for inducible sequences. Other than the induced mRNA species, the population of mRNA in control cells is approximately the same as the mRNA population in induced cells. Cytoplasmic mRNA from control cells is bound to oligo (dT)-cellulose and used as a template for reverse transcriptase, the oligo (dT) serving as a primer. After removing the template mRNAs, the cDNA-cellulose column is used to hybridize a population of mRNAs from induced cells. The non-hybridized poly A+ RNAs are greatly enriched in the inducible sequences. We have used this technique of hybridization subtraction chromatography to select a mRNA population enriched for the mRNAs inducible by ecdysterone in Schneider's Line 2 Drosophila cells. This population of RNAs was used to screen a recombinant library. Preliminary results indicate that approximately 10% of the RNA in the probe population represents ecdysterone inducible sequences. Methods are described for optimizing the cDNA synthesis reaction (we obtain greater than or equal to 30% efficiency) and hybridizing RNA to the cDNA-cellulose resin. This method can be used to select induced mRNAs regardless of the way in which the induction is brought about.

Authors
Vitek, MP; Kreissman, SG; Gross, RH
MLA Citation
Vitek, M. P., et al. “The isolation of ecdysterone inducible genes by hybridization subtraction chromatography..” Nucleic Acids Res, vol. 9, no. 5, Mar. 1981, pp. 1191–202. Pubmed, doi:10.1093/nar/9.5.1191.
PMID
6894489
Source
pubmed
Published In
Nucleic Acids Research
Volume
9
Issue
5
Publish Date
1981
Start Page
1191
End Page
1202
DOI
10.1093/nar/9.5.1191
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