Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group.
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SUBMITTER: Dubois SG
PROVIDER: S-EPMC3463166 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group.
Dubois Steven G SG Geier Ethan E Batra Vandana V Yee Sook Wah SW Neuhaus John J Segal Mark M Martinez Daniel D Pawel Bruce B Yanik Greg G Naranjo Arlene A London Wendy B WB Kreissman Susan S Baker David D Attiyeh Edward E Hogarty Michael D MD Maris John M JM Giacomini Kathleen K Matthay Katherine K KK
International journal of molecular imaging 20120925
Purpose. (123)I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performe ...[more]
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Project description:PurposeVesicular 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.MethodsWe 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.ResultsPatient 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.ConclusionVMAT1 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.
| S-EPMC4733400 | biostudies-literature
Project description: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.
| S-EPMC5868501 | biostudies-literature
Project description:The oncoprotein encoded by EWS-WT1, the hallmark diagnostic alteration in DSRCT, binds to FGFR4 and IGF2.
2020-08-15 | GSE156277 | GEO
Project description:BackgroundInduction 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.MethodsPatients 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.ResultsThe 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).ConclusionsImproved 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.
| S-EPMC6491235 | biostudies-literature
Project description:Clinical trials data from National Cancer Institute (NCI)-funded cooperative oncology group trials could be enhanced by merging with external data sources. Merging without direct patient identifiers would provide additional patient privacy protections. We sought to develop and validate a matching algorithm that uses only indirect patient identifiers.We merged the data from two Phase III Children's Oncology Group (COG) trials for de novo acute myeloid leukemia (AML) with the Pediatric Health Information Systems (PHIS). We developed a stepwise matching algorithm that used indirect identifiers including treatment site, gender, birth year, birth month, enrollment year and enrollment month. Results from the stepwise algorithm were compared against the direct merge method that used date of birth, treatment site, and gender. The indirect merge algorithm was developed on AAML0531 and validated on AAML1031.Of 415 patients enrolled on the AAML0531 trial at PHIS centers, we successfully matched 378 (91.1%) patients using the indirect stepwise algorithm. Comparison to the direct merge result suggested that 362 (95.7%) matches identified by the indirect merge algorithm were concordant with the direct merge result. When validating the indirect stepwise algorithm using the AAML1031 trial, we successfully matched 157 out of 165 patients (95.2%) and 150 (95.5%) of the indirectly merged matches were concordant with the directly merged matches.These data demonstrate that patients enrolled on COG clinical trials can be successfully merged with PHIS administrative data using a stepwise algorithm based on indirect patient identifiers. The merged data sets can be used as a platform for comparative effectiveness and cost effectiveness studies.
| S-EPMC4659568 | biostudies-other
Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration.
2009-06-25 | GSE11877 | GEO
Project description:PurposeInfants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm.Patients and methodsThe subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms.ResultsForty-nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biology) were assigned two cycles, 21 patients (any unfavorable biologic feature without 1p or 11q LOH) were assigned four cycles, and 11 patients (unfavorable biology including 1p and/or 11q LOH [n = 7] or symptomatic with unknown biology [n = 4]), were assigned eight cycles. The 3-year overall survival was 81.4% ± 5.8%. Eight of nine deaths were in patients younger than 2 months of age at diagnosis (median, 9 days [range, 1 to 68 days]): five acute deaths were a result of hepatomegaly and associated toxicities; two were a result of late relapse in patients with unfavorable biology; and two were a result of treatment complications. No deaths occurred after protocol-mandated pre-emptive treatment of infants younger than 2 months with hepatomegaly, regardless of symptoms. A new scoring algorithm for emergent chemotherapy in patients with 4S disease was developed on the basis of this experience.ConclusionThe outcome for 4S neuroblastoma can be improved with pre-emptive chemotherapy for evolving hepatomegaly or other baseline comorbidities in infants younger than 2 months of age.
| S-EPMC6325354 | biostudies-literature
Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration. Unsupervised clustering and supervised risk classification analyses of 207 diagnostic samples and associated clinical covariate data. See the Summary for greater details. The data were analyzed using Microarray Suite version 5.0 (MAS 5.0) in the Affymetrix Gene Chip Operating Software Version 1.4. Probe masking was used (see 9906_TT207_Affymetrix_probe_mask.msk, linked below as a supplementary file). Otherwise all Affymetrix default parameter settings were used. Global scaling as the normalization method, with the default target intensity of 500, was used.
2009-06-25 | E-GEOD-11877 | biostudies-arrayexpress
Project description:A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair young investigators (mentees) with established COG members (mentors). Despite the American Academy of Pediatrics policy statement promoting mentorship programs, there are no publications describing and evaluating national mentorship programs in pediatric subspecialties. In this study, a series of internal program evaluations were performed using surveys of both mentors and mentees. Responses were deidentified and analyzed to determine the utility of the program by both participant satisfaction and self-reported academic productivity. Results indicated that mentees were generally satisfied with the program. Mentor-mentee pairs that met at least quarterly demonstrated greater academic productivity than pairings that met less frequently. This formal mentorship program appeared to have subjective and objective utility for the development of academic pediatric subspecialists.
| S-EPMC3839621 | biostudies-literature
Project description:PurposeA primary objective of the Children's Oncology Group (COG) ANBL0532 phase III study was to assess the effect of increasing local dose of radiation to a residual primary tumor on the cumulative incidence of local progression (CILP) in patients with high-risk neuroblastoma.Patients and methodsNewly diagnosed patients with high-risk neuroblastoma were randomly assigned or assigned to receive single or tandem autologous stem-cell transplantation (SCT) after induction chemotherapy. Local control consisted of surgical resection during induction chemotherapy and radiotherapy after last SCT. Patients received 21.6 Gy to the preoperative primary tumor volume. For patients with incomplete surgical resection, an additional boost of 14.4 Gy was delivered to the gross residual tumor, for a total dose of 36 Gy. CILP (primary end point) and event-free (EFS) and overall survival (OS; secondary end points) were compared with the COG A3973 historical cohort, in which all patients received single SCT and 21.6 Gy without a boost.ResultsFor all patients in ANBL0532 receiving radiotherapy (n = 323), 5-year CILP, EFS, and OS rates were 11.2% ± 1.8%, 56.2% ± 3.4%, and 68.4% ± 3.2% compared with 7.1% ± 1.4% (P = .0590), 47.0% ± 3.5% (P = .0090), and 57.4% ± 3.5% (P = .0088) for all patients in A3973 receiving radiotherapy (n = 328), respectively. Five-year CILP, EFS, and OS rates for patients in A3973 with incomplete resection and radiotherapy (n = 47) were 10.6% ± 4.6%, 48.9% ± 10.1%, and 56.9% ± 10.0%, respectively. In comparison, 5-year CILP, EFS, and OS rates for patients in ANBL0532 who were randomly assigned or assigned to single SCT and received boost radiotherapy (n = 74) were 16.3% ± 4.3% (P = .4126), 50.9% ± 7.0% (P = .5084), and 68.1% ± 6.7% (P = .2835), respectively.ConclusionBoost radiotherapy to gross residual tumor present at the end of induction did not significantly improve 5-year CILP. These results highlight the need for new strategies to decrease the risk of locoregional failure.
| S-EPMC7430214 | biostudies-literature