Susan Cohn - Academia.edu (original) (raw)
Papers by Susan Cohn
Pediatric Blood & Cancer, Apr 1, 2019
Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to... more Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high-risk neuroblastoma (HR-NBL) have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an "ultra-highrisk" (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR-NBL and discusses the complex issues in defining UHR neuroblastoma.
Journal of Clinical Oncology, Jun 20, 2006
9013 Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and ... more 9013 Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and cyclophosphamide to a multi-agent chemotherapy induction regimen for treatment of newly diagnosed high-risk neuroblastoma. Methods: Patients received 2 cycles of topotecan (starting dose 1.2 mg/m2/day for 5 days) and cyclophosphamide (400 mg/m2/day for 5 days) (T/C) followed by an additional 4 cycles of chemotherapy; cisplatin, etoposide alternating with vincristine, doxorubicin, cyclophosphamide. Pharmacokinetically guided topotecan dosing (target systemic exposure of AUC 50 - 70 ng/ml*hr determined by single day topotecan lactone levels) was performed. Chemotherapy cycles were scheduled every 21 days, PBSC harvest occurred after T/C cycles and surgical resection of residual primary tumor after cycle 5. Results: Thirty-one patients, 3 with INSS Stage 3 and 28 with Stage 4, were enrolled between April 2004 and November 2005. Median age at diagnosis was 2.5 years (range 0.9 - 9.35 years). Ten of 25 patients had tumor cell MYCN amplification and 21 of 22 tumors were classified as unfavorable Shimada histology by central review. Targeted topotecan systemic exposure was achieved in 87% (27/31) of patients during T/C cycle 1 and in 85% (23/27) of patients during T/C cycle 2. PBSC collections occurred as intended in 95% of patients (21/22 patients), median harvest 30.8 × 106 CD34+cells cell/kg (range 2.24 - 542). No dose limiting toxicities occurred. All patients experienced Grade 3 or 4 hematopoietic toxicity. Febrile neutropenia occurred in 79% (19/24) of patients during T/C cycles and 78% (18/23) of patients during subsequent cycles of induction therapy. Documented infection occurred in 12.5% (3/24) patients during T/C cycles and 26% (6/23) during subsequent induction cycles. Dose intensity of all chemotherapy agents was maintained in 95.8% (23/24) of patients. Conclusions: This pilot induction regimen was well tolerated with expected and reversible toxicities. Dose intensity of standard induction chemotherapy agents was not limited by the addition of dose-intensive topotecan. These data support investigation of efficacy in a Phase III clinical trial for newly diagnosed high-risk neuroblastoma. [Table: see text]
Pediatric Blood & Cancer, Jul 25, 2020
Background: The 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to... more Background: The 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to include modern functional imaging studies and methods for quantifying disease in bone marrow. We hypothesized the 2017 INRC would enable more precise assessment of response to treatment and provide superior prognostic information compared to the 1993 criteria. Methods: High-risk (HR) neuroblastoma patients from two institutions in Chicago diagnosed between 2006 and 2016 were identified. Patients were assessed post induction chemotherapy via the 1993 and 2017 INRC and classified as responder (≥ mixed response (MXR) or ≥ minor response (MR), respectively) or non-responder (< MXR or < MR). Event free survival (EFS) and overall survival (OS) for responders versus non-responders were determined from end-induction and stratified by Cox regression. Patients with progressive disease at end-induction were eliminated from the EFS analyses but included in the OS analysis. Results: The 1993 criteria classified 52 of the 60 HR patients as responders, whereas 54 responders were identified using the 2017 criteria (Spearman correlation r=0.82, p<0.001). No statistically significant difference in EFS was observed for responders versus non-responders using either criteria (p=0.48 and p=0.08). However, superior OS was observed for responders (p=0.01) using either criteria. Both criteria were sensitive in identifying responders among those with good outcomes. The specificity to identify non-responders among those with poor outcomes was poor.
Journal of Clinical Oncology, Jun 20, 2007
9505 Background: Myeloablative consolidation improves outcome for HR-NB pts, especially for pts i... more 9505 Background: Myeloablative consolidation improves outcome for HR-NB pts, especially for pts in CR prior to consolidation. We assessed the toxicity and CR+VGPR rate of a dose-intensive multi-agent chemotherapy induction based upon the N7 regimen (JCO 22:4888, 2004) prior to myeloablative consolidation and peripheral blood autologous stem cell transplant (ASCT). Methods: Between 2/2001 and 3/2006, 489 eligible newly diagnosed HR- NB pts received the following induction consisting of 6 cycles of chemotherapy q 21 days. Cycles 1, 2, 4 & 6: cyclophosphamide 4.2 g/m2, doxorubicin 75 mg/m2, and vincristine 2 mg/m2 and Cycles 3 &5: cisplatin 200 mg/m2 and etoposide 600 mg/m2. Surgical resection of primary occurred after cycle 5. Following induction pts received purged or unpurged ASCT (as randomized), radiation, and then 13-cis-retinoic acid (13-cis-RA). Response was assessed after cycles 2 & 6 using the International Neuroblastoma Response Criteria and analyzed as intent-to-treat. Results: Median age was 3.1 yrs, 44% of 392 tumors tested had MYCN amplification. Fourteen pts (3%) died during induction (5 infection, 4 bleed into tumor, 4 compromised organ function from tumor, 1 unrelated to tumor/therapy). Patients experienced the following grade 3 & 4 toxicities at least once during induction: neutropenia 70%, thrombocytopenia 71%, hearing loss 6%, cardiac function 2% and renal function 3%. Documented infection occurred in 24% of cycles (90% bacterial, 3% viral, 7% fungal). Responses among the 489 pts at end of induction were CR 24%, VGPR 28%, PR 26%, SD 7%, and PD15%, with morphologically detectable bone marrow (BM) disease cleared in 87% and no disease remaining by MIBG scan in 55% of pts MIBG positive at baseline. Conclusions: Despite increased dose intensity of this regimen, toxicity was not excessive compared to prior HR-NB regimens. In a multi-center setting, the A3973 induction chemotherapy achieved morphologic BM clearance in 87% of pts prior to consolidation. The CR/VGPR rate of 52% is similar to that of prior less intensive regimens. The impact of this induction response on survival within the context of ASCT and 13-cis-RA on COG A3973 will be determined with longer follow-up. No significant financial relationships to disclose.
Journal of Clinical Oncology, Sep 20, 2005
To determine predictive strength of tumor cell ploidy and MYCN gene amplification on survival of ... more To determine predictive strength of tumor cell ploidy and MYCN gene amplification on survival of children older than 12 months with disseminated neuroblastoma (NB). Patients and Methods Of 648 children with stage D NB enrolled onto the Pediatric Oncology Group NB Biology Study 9047 (1990-2000), 560 children were assessable for ploidy and MYCN amplification. Treatment of patients older than 12 months varied; most receiving high-dose chemotherapy with stem-cell rescue. Infants received standard chemotherapy, depending on MYCN status and ploidy. Results Among stage D MYCN-amplified patients, 4-year event-free survival (EFS) Ϯ SE had no prognostic significance for tumor cell ploidy for patients either younger than 12 months or Ն 12 months old. However, among stage D nonamplified-MYCN patients, 4-year EFS for those with tumor hyperdiploidy (DNA index [DI] Ͼ 1) was clearly superior to those with diploidy (DI Յ 1): younger than 12 months, 83.7% Ϯ 4.4% (n ϭ 87) versus 46.2% Ϯ 13.8% (n ϭ 13; P ϭ .0003); and for 12-to 24-month-old children, 72.7% Ϯ 10.2% (n ϭ 22) versus 26.7% Ϯ 13.2% (n ϭ 16; P ϭ .0092). Further analysis suggested better prognoses in the 12to 18-month-old subgroup with hyperdiploid tumors (4-year EFS, 92.9% Ϯ 7.2%) compared with the 19-to 24-month-old subgroup (4-year EFS, 37.5% Ϯ 21.0%; P ϭ .0037). In children older than 24 months, outcome was dire (Ͻ 20% long-term survival), regardless of ploidy or MYCN status. Conclusion Children 12 to 18 months old with metastatic NB had favorable outcomes with high-dose therapy if their tumors were hyperdiploid and lacked MYCN amplification. This subgroup may respond well to contemporary chemotherapy, and could be spared intensive myeloablative therapy with stem-cell rescue.
Journal of Clinical Oncology, May 20, 2021
10036 Background: Biologic and socioeconomic factors contribute to health disparities among patie... more 10036 Background: Biologic and socioeconomic factors contribute to health disparities among patients with pediatric cancer. In an analysis of Children’s Oncology Group (COG) neuroblastoma (NBL) patients (pts) diagnosed between 2001-2009, non-Hispanic Black (Black) pts were previously shown to have a higher prevalence of high-risk disease and worse event-free survival (EFS) compared to non-Hispanic White (White) pts. Here, we analyzed data in the International Neuroblastoma Risk Group Data Commons (INRGdc) to validate these findings. Methods: Three-year EFS and overall survival (OS) of COG pts diagnosed between 2001-2009 (Cohort 1; n = 4,358) and 2010-2016 (Cohort 2; n = 3,689) in the INRGdc with known race and ethnicity were estimated by the Kaplan-Meier method. Cox proportional hazards regression models were used to evaluate differences in EFS and OS between racial/ethnic groups. The association of clinical characteristics and tumor biomarkers with racial/ethnic groups were analyzed using Chi-square tests. Results: The distribution of race/ethnicity for pts in Cohort 1 and Cohort 2 was as follows, respectively: White: 72% (n = 3,136) and 70% (n = 2,575); Black: 11.4% (n = 495) and 10.7% (n = 397); Hispanic: 12.2% (n = 532) and 14.1% (n = 522); Asian and Hawaiian: 4% (n = 178) and 4.6% (n = 172); Native American: 0.4% (n = 17) and 0.6% (n = 23). In both cohorts, a higher proportion of Black pts had INSS stage 4 disease, age ≥ 18mo, and unfavorable histology tumors when compared to White pts (Cohort 1: p = 0.003; p &lt; 0.001; p &lt; 0.001, respectively vs Cohort 2: p = 0.014; p &lt; 0.001; p &lt; 0.001, respectively). No significant differences in the proportion of pts with MYCN amplified or diploid tumors were detected between Black and White pts in either cohort. Black pts had a higher prevalence of high-risk disease compared to White pts in both Cohorts 1 and 2 (p &lt; 0.001 and p &lt; 0.001, respectively). Among all pts in Cohort 1, EFS was 73% and OS was 83%. In Cohort 1, Black pts had worse EFS (68% vs 73%; HR = 1.31, 95%CI 1.11-1.55, p = 0.002) and OS (78% vs 84%; HR = 1.41, 95% CI 1.16-1.70, p = 0.001) compared to White pts. Among all pts in Cohort 2, EFS was 81% and OS was 88%. Black pts in Cohort 2 also had worse EFS compared to White pts (76% vs 82%; HR = 1.35, 95% CI = 1.03-1.76, p = 0.027), although no significant difference in OS was observed (p = 0.21). In analyses restricted to high-risk pts, no statistically significant difference in EFS and OS in Black vs White pts was detected in either cohort. Conclusions: In the modern treatment era, Black NBL pts continue to have a higher prevalence of high-risk disease and inferior 3-year EFS compared to White pts. The lack of significant difference in survival among high-risk NBL pts by race suggests that Black and White pts are receiving comparable treatments and responding similarly. The socioeconomic and/or genomic factors contributing to the higher proportion of Black pts with high-risk disease requires further investigation.
Journal of Clinical Oncology, May 20, 2021
10039 Background: Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality use... more 10039 Background: Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality used to evaluate neuroblastoma stage at diagnosis and also determine disease response following therapy. Curie scoring is used to semi-quantitatively assess disease burden from an MIBG scan on a scale from none (0) to widespread throughout the body (30). While a Curie score ≤2 after six cycles of induction chemotherapy has been shown to be prognostic of outcome, there is no established correlation between diagnostic Curie score and outcome. Deep learning models, such as convolutional neural networks (CNN), have been shown to learn generalizable patterns within images for successful classification of metastases and detection of multiple adult cancers. We hypothesized a CNN could be developed to predict response to induction chemotherapy, a proxy for outcome, using diagnostic MIBG scans. Methods: DICOM MIBG scans and associated clinical data from a Children’s Oncology Group (COG) pilot study for children diagnosed with high-risk neuroblastoma (ANBL12P1; NCT1798004) were deidentified and linked to clinical data by the Pediatric Cancer Data Commons and obtained from the International Neuroblastoma Risk Group Data Commons. Patients were defined as having a poor response to induction chemotherapy if their Curie score after four cycles of induction chemotherapy was ≥2. An independent external validation cohort was comprised of 29 images from 26 high-risk patients treated at the University of Chicago with clinically-annotated diagnostic and post-cycle six induction DICOM MIBG scans. The CNN was trained using 2D whole body MIBG scans obtained at diagnosis. We developed the CNN using a transfer learning approach using the Xception architecture as the base layer. Hyperparameter optimization was performed using an 80%-20% train-validation strategy. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC). Results: Among 146 patients with high-risk neuroblastoma enrolled on ANBL12P1, 104 had available diagnostic and end-induction MIBG scans. There were no differences in clinical or biological characteristics between included and excluded patients. The base model CNN was able to predict which patients had a poor response to induction chemotherapy with an AUROC of 0.72 in the validation set from the ANBL12P1 cohort. Additionally, the CNN was able to predict patient response to therapy with an AUROC of 0.64 in an independent external dataset from University of Chicago. Conclusions: Our study suggests it is feasible to apply machine learning of diagnostic MIBG scans to predict response to chemotherapy for high-risk neuroblastoma patients. Given these promising results, further work to improve AUROC and performance within larger datasets is ongoing.
Journal of Clinical Oncology, May 20, 2012
9516 Background: An increased prevalence of high-risk disease and worse outcome are observed in c... more 9516 Background: An increased prevalence of high-risk disease and worse outcome are observed in children with neuroblastoma who self-report as black versus white. We sought to determine whether genetic variation would explain this racial disparity. Methods: After quality control, we analyzed 511,836 germline genetic variants in 2,709 ethnically diverse children with neuroblastoma enrolled on Children’s Oncology Group study ANBL00B1 from 2001 to 2009. Genetic variation was summarized by conducting principal components analysis. The first principal component (PC1) separated patients with African ancestry from all others. PC1 was used as a continuous variable for ordinal regression with risk group and a Cox proportional hazard model of EFS. To identify genetic mechanisms for the observed disparities, we developed a method using genome-wide variation data applied to high-risk versus non-high risk samples. We identified a comprehensive list of loci with significant divergence between the ancestral populations. We then tested each such locus for association with high-risk phenotype using logistic regression with the proportion of African ancestry estimated by ADMIXTURE as covariate. Finally, top SNPs were added to multivariate models of both risk and event-free survival to determine if any top associations could abrogate observed disparities. Results: PC1 was associated with both risk (p = 0.007) and EFS (p = 0.037). We identified 72 population-divergent SNPs nominally associated with high-risk disease (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). The risk allele for one of the top SNPs: rs9295536 (p = 9.2x10-8) was more common in the African ancestral population, was associated with high-risk phenotype and poor outcome in all patients and validated in a Caucasian-only subanalysis. In multivariate testing, this SNP abrogated the PC1 association with EFS (p = 0.18). Conclusions: A SNP with high divergence between ancestral populations on chromosome 6p22 accounts for the observed racial disparity in survival and is also a common genetic variant associated with survival in patients derived from either European or African ancestry (Bonferroni adjusted p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Studies to elucidate the function of this SNP are underway.
Journal of Clinical Oncology, May 20, 2012
9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term surviva... more 9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term survival, and at diagnosis, it is not possible to identify patients who will be cured. Microarray studies have proposed expression signatures associated with outcome within high-risk cohorts. However, integrating this technology as a clinical test has been difficult, in part due to the lack of available frozen tissue and high quality RNA. The nCounter overcomes this obstacle, using formalin-fixed paraffin embedded tissue (FFPE). Our objective is to test the correlation of a previously published “ultra high-risk” microarray gene signature developed in the MYCN nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 2006) with the gene expression signature obtained with the nCounter (NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified high-risk neuroblastoma samples. Methods: FFPE tumor samples linked to clinical outcome data were obtained from 6 collaborative institutions. Tumor content of each sample was assessed morphologically. RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding to the candidate genes were designed by NanoString. Hybridization reactions were performed in duplicate using 100 ng of RNA. Positive and negative control probes and housekeeping probes were included in every reaction and were used to normalize data for differences in purification, hybridization, and capture efficiencies Results: Forty-two MYCN nonamplified high-risk neuroblastoma samples were analyzed by the nCounter. The cohort 5-year event-free survival and overall survival were 44.6 +/- 8.0% and 53.8 +/- 8.4% respectively. Highly degraded RNA (RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle components analysis on normalized expression data showed differential expression of most of the genes with clustering of cases depending upon outcome (FDR = 0.05). Conclusions: Our results demonstrate that the nCounter can yield gene expression profiles that are similar to microarray gene signatures. Further investigation of the clinical utility the nCounter technology to prognosticate outcome in patients with high-risk neuroblastoma is warranted.
JCO clinical cancer informatics, Dec 1, 2021
PURPOSE Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality that undergo ... more PURPOSE Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality that undergo Curie scoring to semiquantitatively assess neuroblastoma burden, which can be used as a marker of therapy response. We hypothesized that a convolutional neural network (CNN) could be developed that uses diagnostic MIBG scans to predict response to induction chemotherapy. METHODS We analyzed MIBG scans housed in the International Neuroblastoma Risk Group Data Commons from patients enrolled in the Children's Oncology Group high-risk neuroblastoma study ANBL12P1. The primary outcome was response to upfront chemotherapy, defined as a Curie score ≤ 2 after four cycles of induction chemotherapy. We derived and validated a CNN using two-dimensional whole-body MIBG scans from diagnosis and evaluated model performance using area under the receiver operating characteristic curve (AUC). We also developed a clinical classification model to predict response on the basis of age, stage, and MYCN amplification. RESULTS Among 103 patients with high-risk neuroblastoma included in the final cohort, 67 (65%) were responders. Performance in predicting response to upfront chemotherapy was equivalent using the CNN and the clinical model. Class-activation heatmaps verified that the CNN used areas of disease within the MIBG scans to make predictions. Furthermore, integrating predictions using a geometric mean approach improved detection of responders to upfront chemotherapy (geometric mean AUC 0.73 v CNN AUC 0.63, P < .05; v clinical model AUC 0.65, P < .05). CONCLUSION We demonstrate feasibility in using machine learning of diagnostic MIBG scans to predict response to induction chemotherapy for patients with high-risk neuroblastoma. We highlight improvements when clinical risk factors are also integrated, laying the foundation for using a multimodal approach to guiding treatment decisions for patients with high-risk neuroblastoma.
Supplementary Methods and Supplementary Table Legends
KIR/KIR-ligand genotypes that determine KIR-ligands present vs. KIR-ligand missing status for thi... more KIR/KIR-ligand genotypes that determine KIR-ligands present vs. KIR-ligand missing status for this report.
Incidence of KIR/KIR-ligand genotypes in the patients analyzed.
Clinical characteristics of COG patients, according to treatment group, for all patients and for ... more Clinical characteristics of COG patients, according to treatment group, for all patients and for those genotyped for KIR/KIR-ligand.
Journal for ImmunoTherapy of Cancer, 2021
BackgroundTumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis... more BackgroundTumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion.MethodsA defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by ...
Pediatric Blood & Cancer, 2020
BackgroundLong‐term outcome remains poor for children with high‐risk neuroblastoma (five‐year ove... more BackgroundLong‐term outcome remains poor for children with high‐risk neuroblastoma (five‐year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra‐high‐risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort.MethodsA total of 1820 high‐risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998‐2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three‐year OS. External validation was performed using the SIOPEN HR‐NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves.ResultsThe nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (...
Journal of Clinical Oncology, 2009
10010 Background: Neuroblastoma is a heterogeneous disease with variability in outcome among diff... more 10010 Background: Neuroblastoma is a heterogeneous disease with variability in outcome among different risk groups. Historically, INSS stage 4s neuroblastoma (age less than 12 months, stage 1 or 2 primary tumor with metastases limited to liver, skin and bone marrow) has a more favorable outcome than infant stage 4 disease. The aim was to determine if metastatic pattern (4 vs 4s) predicted favorable prognosis in infants < 12 months or in toddlers aged 12–18 months when stratifying by biology. Methods: Outcome was analyzed by log rank tests and Cox models for 656 infants with stage 4s neuroblastoma and 1,019 stage 4 patients < 18 months of age in the International Neuroblastoma Risk Group database (n=8,800). Prognostic factors (tumor ploidy, histology, grade, MKI, LDH, MYCN, 11q, 1p, primary site) were tested for association with age/stage subgroups (Fisher's exact test) and in Cox models. Results: MYCNamplification, 1p aberration, diploidy, and high MKI and LDH were more fr...
Pediatric Blood & Cancer, 2020
BackgroundThe 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to i... more BackgroundThe 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to include modern functional imaging studies and methods for quantifying disease in bone marrow. We hypothesized the 2017 INRC would enable more precise assessment of response to treatment and provide superior prognostic information compared with the 1993 criteria.MethodsHigh‐risk (HR) neuroblastoma patients from two institutions in Chicago diagnosed between 2006 and 2016 were identified. Patients were assessed post induction chemotherapy via the 1993 and 2017 INRC and classified as responder (≥ mixed response [MXR] or ≥ minor response [MR], respectively) or nonresponder (< MXR or < MR). Event‐free survival (EFS) and overall survival (OS) for responders versus nonresponders were determined from end induction and stratified by Cox regression. Patients with progressive disease at end induction were eliminated from the EFS analyses but included in the OS analysis.ResultsThe 1993 criteria ...
Journal of Clinical Oncology, 2007
9524 Background: We have previously shown, both retrospectively and prospectively, that high-leve... more 9524 Background: We have previously shown, both retrospectively and prospectively, that high-level expression of the multidrug transporter gene ABCC1/MRP1, is strongly predictive of poor outcome in the childhood cancer neuroblastoma (NEJM, 334:231–8, 1996; JCO, 24:1546–53, 2006), and that ABCC1/MRP1 can be regulated by the MYCN oncogene. The contribution of other ABCC family genes to clinical outcome in this disease has now been examined. Methods: Real-time quantitative PCR was used to determine ABCC gene expression in a large prospectively accrued cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Results: Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in the cohort. Amongst the ABCC family, high levels of ABCC1 and ABCC4, but low levels of ABCC3, were strongly associated with reduced survival and event-free survival (P<0.005) in the overall study population, and also in subgroups of pati...
Pediatric Blood & Cancer, Apr 1, 2019
Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to... more Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high-risk neuroblastoma (HR-NBL) have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an "ultra-highrisk" (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR-NBL and discusses the complex issues in defining UHR neuroblastoma.
Journal of Clinical Oncology, Jun 20, 2006
9013 Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and ... more 9013 Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and cyclophosphamide to a multi-agent chemotherapy induction regimen for treatment of newly diagnosed high-risk neuroblastoma. Methods: Patients received 2 cycles of topotecan (starting dose 1.2 mg/m2/day for 5 days) and cyclophosphamide (400 mg/m2/day for 5 days) (T/C) followed by an additional 4 cycles of chemotherapy; cisplatin, etoposide alternating with vincristine, doxorubicin, cyclophosphamide. Pharmacokinetically guided topotecan dosing (target systemic exposure of AUC 50 - 70 ng/ml*hr determined by single day topotecan lactone levels) was performed. Chemotherapy cycles were scheduled every 21 days, PBSC harvest occurred after T/C cycles and surgical resection of residual primary tumor after cycle 5. Results: Thirty-one patients, 3 with INSS Stage 3 and 28 with Stage 4, were enrolled between April 2004 and November 2005. Median age at diagnosis was 2.5 years (range 0.9 - 9.35 years). Ten of 25 patients had tumor cell MYCN amplification and 21 of 22 tumors were classified as unfavorable Shimada histology by central review. Targeted topotecan systemic exposure was achieved in 87% (27/31) of patients during T/C cycle 1 and in 85% (23/27) of patients during T/C cycle 2. PBSC collections occurred as intended in 95% of patients (21/22 patients), median harvest 30.8 × 106 CD34+cells cell/kg (range 2.24 - 542). No dose limiting toxicities occurred. All patients experienced Grade 3 or 4 hematopoietic toxicity. Febrile neutropenia occurred in 79% (19/24) of patients during T/C cycles and 78% (18/23) of patients during subsequent cycles of induction therapy. Documented infection occurred in 12.5% (3/24) patients during T/C cycles and 26% (6/23) during subsequent induction cycles. Dose intensity of all chemotherapy agents was maintained in 95.8% (23/24) of patients. Conclusions: This pilot induction regimen was well tolerated with expected and reversible toxicities. Dose intensity of standard induction chemotherapy agents was not limited by the addition of dose-intensive topotecan. These data support investigation of efficacy in a Phase III clinical trial for newly diagnosed high-risk neuroblastoma. [Table: see text]
Pediatric Blood & Cancer, Jul 25, 2020
Background: The 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to... more Background: The 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to include modern functional imaging studies and methods for quantifying disease in bone marrow. We hypothesized the 2017 INRC would enable more precise assessment of response to treatment and provide superior prognostic information compared to the 1993 criteria. Methods: High-risk (HR) neuroblastoma patients from two institutions in Chicago diagnosed between 2006 and 2016 were identified. Patients were assessed post induction chemotherapy via the 1993 and 2017 INRC and classified as responder (≥ mixed response (MXR) or ≥ minor response (MR), respectively) or non-responder (< MXR or < MR). Event free survival (EFS) and overall survival (OS) for responders versus non-responders were determined from end-induction and stratified by Cox regression. Patients with progressive disease at end-induction were eliminated from the EFS analyses but included in the OS analysis. Results: The 1993 criteria classified 52 of the 60 HR patients as responders, whereas 54 responders were identified using the 2017 criteria (Spearman correlation r=0.82, p<0.001). No statistically significant difference in EFS was observed for responders versus non-responders using either criteria (p=0.48 and p=0.08). However, superior OS was observed for responders (p=0.01) using either criteria. Both criteria were sensitive in identifying responders among those with good outcomes. The specificity to identify non-responders among those with poor outcomes was poor.
Journal of Clinical Oncology, Jun 20, 2007
9505 Background: Myeloablative consolidation improves outcome for HR-NB pts, especially for pts i... more 9505 Background: Myeloablative consolidation improves outcome for HR-NB pts, especially for pts in CR prior to consolidation. We assessed the toxicity and CR+VGPR rate of a dose-intensive multi-agent chemotherapy induction based upon the N7 regimen (JCO 22:4888, 2004) prior to myeloablative consolidation and peripheral blood autologous stem cell transplant (ASCT). Methods: Between 2/2001 and 3/2006, 489 eligible newly diagnosed HR- NB pts received the following induction consisting of 6 cycles of chemotherapy q 21 days. Cycles 1, 2, 4 & 6: cyclophosphamide 4.2 g/m2, doxorubicin 75 mg/m2, and vincristine 2 mg/m2 and Cycles 3 &5: cisplatin 200 mg/m2 and etoposide 600 mg/m2. Surgical resection of primary occurred after cycle 5. Following induction pts received purged or unpurged ASCT (as randomized), radiation, and then 13-cis-retinoic acid (13-cis-RA). Response was assessed after cycles 2 & 6 using the International Neuroblastoma Response Criteria and analyzed as intent-to-treat. Results: Median age was 3.1 yrs, 44% of 392 tumors tested had MYCN amplification. Fourteen pts (3%) died during induction (5 infection, 4 bleed into tumor, 4 compromised organ function from tumor, 1 unrelated to tumor/therapy). Patients experienced the following grade 3 & 4 toxicities at least once during induction: neutropenia 70%, thrombocytopenia 71%, hearing loss 6%, cardiac function 2% and renal function 3%. Documented infection occurred in 24% of cycles (90% bacterial, 3% viral, 7% fungal). Responses among the 489 pts at end of induction were CR 24%, VGPR 28%, PR 26%, SD 7%, and PD15%, with morphologically detectable bone marrow (BM) disease cleared in 87% and no disease remaining by MIBG scan in 55% of pts MIBG positive at baseline. Conclusions: Despite increased dose intensity of this regimen, toxicity was not excessive compared to prior HR-NB regimens. In a multi-center setting, the A3973 induction chemotherapy achieved morphologic BM clearance in 87% of pts prior to consolidation. The CR/VGPR rate of 52% is similar to that of prior less intensive regimens. The impact of this induction response on survival within the context of ASCT and 13-cis-RA on COG A3973 will be determined with longer follow-up. No significant financial relationships to disclose.
Journal of Clinical Oncology, Sep 20, 2005
To determine predictive strength of tumor cell ploidy and MYCN gene amplification on survival of ... more To determine predictive strength of tumor cell ploidy and MYCN gene amplification on survival of children older than 12 months with disseminated neuroblastoma (NB). Patients and Methods Of 648 children with stage D NB enrolled onto the Pediatric Oncology Group NB Biology Study 9047 (1990-2000), 560 children were assessable for ploidy and MYCN amplification. Treatment of patients older than 12 months varied; most receiving high-dose chemotherapy with stem-cell rescue. Infants received standard chemotherapy, depending on MYCN status and ploidy. Results Among stage D MYCN-amplified patients, 4-year event-free survival (EFS) Ϯ SE had no prognostic significance for tumor cell ploidy for patients either younger than 12 months or Ն 12 months old. However, among stage D nonamplified-MYCN patients, 4-year EFS for those with tumor hyperdiploidy (DNA index [DI] Ͼ 1) was clearly superior to those with diploidy (DI Յ 1): younger than 12 months, 83.7% Ϯ 4.4% (n ϭ 87) versus 46.2% Ϯ 13.8% (n ϭ 13; P ϭ .0003); and for 12-to 24-month-old children, 72.7% Ϯ 10.2% (n ϭ 22) versus 26.7% Ϯ 13.2% (n ϭ 16; P ϭ .0092). Further analysis suggested better prognoses in the 12to 18-month-old subgroup with hyperdiploid tumors (4-year EFS, 92.9% Ϯ 7.2%) compared with the 19-to 24-month-old subgroup (4-year EFS, 37.5% Ϯ 21.0%; P ϭ .0037). In children older than 24 months, outcome was dire (Ͻ 20% long-term survival), regardless of ploidy or MYCN status. Conclusion Children 12 to 18 months old with metastatic NB had favorable outcomes with high-dose therapy if their tumors were hyperdiploid and lacked MYCN amplification. This subgroup may respond well to contemporary chemotherapy, and could be spared intensive myeloablative therapy with stem-cell rescue.
Journal of Clinical Oncology, May 20, 2021
10036 Background: Biologic and socioeconomic factors contribute to health disparities among patie... more 10036 Background: Biologic and socioeconomic factors contribute to health disparities among patients with pediatric cancer. In an analysis of Children’s Oncology Group (COG) neuroblastoma (NBL) patients (pts) diagnosed between 2001-2009, non-Hispanic Black (Black) pts were previously shown to have a higher prevalence of high-risk disease and worse event-free survival (EFS) compared to non-Hispanic White (White) pts. Here, we analyzed data in the International Neuroblastoma Risk Group Data Commons (INRGdc) to validate these findings. Methods: Three-year EFS and overall survival (OS) of COG pts diagnosed between 2001-2009 (Cohort 1; n = 4,358) and 2010-2016 (Cohort 2; n = 3,689) in the INRGdc with known race and ethnicity were estimated by the Kaplan-Meier method. Cox proportional hazards regression models were used to evaluate differences in EFS and OS between racial/ethnic groups. The association of clinical characteristics and tumor biomarkers with racial/ethnic groups were analyzed using Chi-square tests. Results: The distribution of race/ethnicity for pts in Cohort 1 and Cohort 2 was as follows, respectively: White: 72% (n = 3,136) and 70% (n = 2,575); Black: 11.4% (n = 495) and 10.7% (n = 397); Hispanic: 12.2% (n = 532) and 14.1% (n = 522); Asian and Hawaiian: 4% (n = 178) and 4.6% (n = 172); Native American: 0.4% (n = 17) and 0.6% (n = 23). In both cohorts, a higher proportion of Black pts had INSS stage 4 disease, age ≥ 18mo, and unfavorable histology tumors when compared to White pts (Cohort 1: p = 0.003; p &lt; 0.001; p &lt; 0.001, respectively vs Cohort 2: p = 0.014; p &lt; 0.001; p &lt; 0.001, respectively). No significant differences in the proportion of pts with MYCN amplified or diploid tumors were detected between Black and White pts in either cohort. Black pts had a higher prevalence of high-risk disease compared to White pts in both Cohorts 1 and 2 (p &lt; 0.001 and p &lt; 0.001, respectively). Among all pts in Cohort 1, EFS was 73% and OS was 83%. In Cohort 1, Black pts had worse EFS (68% vs 73%; HR = 1.31, 95%CI 1.11-1.55, p = 0.002) and OS (78% vs 84%; HR = 1.41, 95% CI 1.16-1.70, p = 0.001) compared to White pts. Among all pts in Cohort 2, EFS was 81% and OS was 88%. Black pts in Cohort 2 also had worse EFS compared to White pts (76% vs 82%; HR = 1.35, 95% CI = 1.03-1.76, p = 0.027), although no significant difference in OS was observed (p = 0.21). In analyses restricted to high-risk pts, no statistically significant difference in EFS and OS in Black vs White pts was detected in either cohort. Conclusions: In the modern treatment era, Black NBL pts continue to have a higher prevalence of high-risk disease and inferior 3-year EFS compared to White pts. The lack of significant difference in survival among high-risk NBL pts by race suggests that Black and White pts are receiving comparable treatments and responding similarly. The socioeconomic and/or genomic factors contributing to the higher proportion of Black pts with high-risk disease requires further investigation.
Journal of Clinical Oncology, May 20, 2021
10039 Background: Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality use... more 10039 Background: Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality used to evaluate neuroblastoma stage at diagnosis and also determine disease response following therapy. Curie scoring is used to semi-quantitatively assess disease burden from an MIBG scan on a scale from none (0) to widespread throughout the body (30). While a Curie score ≤2 after six cycles of induction chemotherapy has been shown to be prognostic of outcome, there is no established correlation between diagnostic Curie score and outcome. Deep learning models, such as convolutional neural networks (CNN), have been shown to learn generalizable patterns within images for successful classification of metastases and detection of multiple adult cancers. We hypothesized a CNN could be developed to predict response to induction chemotherapy, a proxy for outcome, using diagnostic MIBG scans. Methods: DICOM MIBG scans and associated clinical data from a Children’s Oncology Group (COG) pilot study for children diagnosed with high-risk neuroblastoma (ANBL12P1; NCT1798004) were deidentified and linked to clinical data by the Pediatric Cancer Data Commons and obtained from the International Neuroblastoma Risk Group Data Commons. Patients were defined as having a poor response to induction chemotherapy if their Curie score after four cycles of induction chemotherapy was ≥2. An independent external validation cohort was comprised of 29 images from 26 high-risk patients treated at the University of Chicago with clinically-annotated diagnostic and post-cycle six induction DICOM MIBG scans. The CNN was trained using 2D whole body MIBG scans obtained at diagnosis. We developed the CNN using a transfer learning approach using the Xception architecture as the base layer. Hyperparameter optimization was performed using an 80%-20% train-validation strategy. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC). Results: Among 146 patients with high-risk neuroblastoma enrolled on ANBL12P1, 104 had available diagnostic and end-induction MIBG scans. There were no differences in clinical or biological characteristics between included and excluded patients. The base model CNN was able to predict which patients had a poor response to induction chemotherapy with an AUROC of 0.72 in the validation set from the ANBL12P1 cohort. Additionally, the CNN was able to predict patient response to therapy with an AUROC of 0.64 in an independent external dataset from University of Chicago. Conclusions: Our study suggests it is feasible to apply machine learning of diagnostic MIBG scans to predict response to chemotherapy for high-risk neuroblastoma patients. Given these promising results, further work to improve AUROC and performance within larger datasets is ongoing.
Journal of Clinical Oncology, May 20, 2012
9516 Background: An increased prevalence of high-risk disease and worse outcome are observed in c... more 9516 Background: An increased prevalence of high-risk disease and worse outcome are observed in children with neuroblastoma who self-report as black versus white. We sought to determine whether genetic variation would explain this racial disparity. Methods: After quality control, we analyzed 511,836 germline genetic variants in 2,709 ethnically diverse children with neuroblastoma enrolled on Children’s Oncology Group study ANBL00B1 from 2001 to 2009. Genetic variation was summarized by conducting principal components analysis. The first principal component (PC1) separated patients with African ancestry from all others. PC1 was used as a continuous variable for ordinal regression with risk group and a Cox proportional hazard model of EFS. To identify genetic mechanisms for the observed disparities, we developed a method using genome-wide variation data applied to high-risk versus non-high risk samples. We identified a comprehensive list of loci with significant divergence between the ancestral populations. We then tested each such locus for association with high-risk phenotype using logistic regression with the proportion of African ancestry estimated by ADMIXTURE as covariate. Finally, top SNPs were added to multivariate models of both risk and event-free survival to determine if any top associations could abrogate observed disparities. Results: PC1 was associated with both risk (p = 0.007) and EFS (p = 0.037). We identified 72 population-divergent SNPs nominally associated with high-risk disease (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). The risk allele for one of the top SNPs: rs9295536 (p = 9.2x10-8) was more common in the African ancestral population, was associated with high-risk phenotype and poor outcome in all patients and validated in a Caucasian-only subanalysis. In multivariate testing, this SNP abrogated the PC1 association with EFS (p = 0.18). Conclusions: A SNP with high divergence between ancestral populations on chromosome 6p22 accounts for the observed racial disparity in survival and is also a common genetic variant associated with survival in patients derived from either European or African ancestry (Bonferroni adjusted p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Studies to elucidate the function of this SNP are underway.
Journal of Clinical Oncology, May 20, 2012
9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term surviva... more 9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term survival, and at diagnosis, it is not possible to identify patients who will be cured. Microarray studies have proposed expression signatures associated with outcome within high-risk cohorts. However, integrating this technology as a clinical test has been difficult, in part due to the lack of available frozen tissue and high quality RNA. The nCounter overcomes this obstacle, using formalin-fixed paraffin embedded tissue (FFPE). Our objective is to test the correlation of a previously published “ultra high-risk” microarray gene signature developed in the MYCN nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 2006) with the gene expression signature obtained with the nCounter (NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified high-risk neuroblastoma samples. Methods: FFPE tumor samples linked to clinical outcome data were obtained from 6 collaborative institutions. Tumor content of each sample was assessed morphologically. RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding to the candidate genes were designed by NanoString. Hybridization reactions were performed in duplicate using 100 ng of RNA. Positive and negative control probes and housekeeping probes were included in every reaction and were used to normalize data for differences in purification, hybridization, and capture efficiencies Results: Forty-two MYCN nonamplified high-risk neuroblastoma samples were analyzed by the nCounter. The cohort 5-year event-free survival and overall survival were 44.6 +/- 8.0% and 53.8 +/- 8.4% respectively. Highly degraded RNA (RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle components analysis on normalized expression data showed differential expression of most of the genes with clustering of cases depending upon outcome (FDR = 0.05). Conclusions: Our results demonstrate that the nCounter can yield gene expression profiles that are similar to microarray gene signatures. Further investigation of the clinical utility the nCounter technology to prognosticate outcome in patients with high-risk neuroblastoma is warranted.
JCO clinical cancer informatics, Dec 1, 2021
PURPOSE Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality that undergo ... more PURPOSE Metaiodobenzylguanidine (MIBG) scans are a radionucleotide imaging modality that undergo Curie scoring to semiquantitatively assess neuroblastoma burden, which can be used as a marker of therapy response. We hypothesized that a convolutional neural network (CNN) could be developed that uses diagnostic MIBG scans to predict response to induction chemotherapy. METHODS We analyzed MIBG scans housed in the International Neuroblastoma Risk Group Data Commons from patients enrolled in the Children's Oncology Group high-risk neuroblastoma study ANBL12P1. The primary outcome was response to upfront chemotherapy, defined as a Curie score ≤ 2 after four cycles of induction chemotherapy. We derived and validated a CNN using two-dimensional whole-body MIBG scans from diagnosis and evaluated model performance using area under the receiver operating characteristic curve (AUC). We also developed a clinical classification model to predict response on the basis of age, stage, and MYCN amplification. RESULTS Among 103 patients with high-risk neuroblastoma included in the final cohort, 67 (65%) were responders. Performance in predicting response to upfront chemotherapy was equivalent using the CNN and the clinical model. Class-activation heatmaps verified that the CNN used areas of disease within the MIBG scans to make predictions. Furthermore, integrating predictions using a geometric mean approach improved detection of responders to upfront chemotherapy (geometric mean AUC 0.73 v CNN AUC 0.63, P < .05; v clinical model AUC 0.65, P < .05). CONCLUSION We demonstrate feasibility in using machine learning of diagnostic MIBG scans to predict response to induction chemotherapy for patients with high-risk neuroblastoma. We highlight improvements when clinical risk factors are also integrated, laying the foundation for using a multimodal approach to guiding treatment decisions for patients with high-risk neuroblastoma.
Supplementary Methods and Supplementary Table Legends
KIR/KIR-ligand genotypes that determine KIR-ligands present vs. KIR-ligand missing status for thi... more KIR/KIR-ligand genotypes that determine KIR-ligands present vs. KIR-ligand missing status for this report.
Incidence of KIR/KIR-ligand genotypes in the patients analyzed.
Clinical characteristics of COG patients, according to treatment group, for all patients and for ... more Clinical characteristics of COG patients, according to treatment group, for all patients and for those genotyped for KIR/KIR-ligand.
Journal for ImmunoTherapy of Cancer, 2021
BackgroundTumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis... more BackgroundTumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion.MethodsA defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by ...
Pediatric Blood & Cancer, 2020
BackgroundLong‐term outcome remains poor for children with high‐risk neuroblastoma (five‐year ove... more BackgroundLong‐term outcome remains poor for children with high‐risk neuroblastoma (five‐year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra‐high‐risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort.MethodsA total of 1820 high‐risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998‐2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three‐year OS. External validation was performed using the SIOPEN HR‐NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves.ResultsThe nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (...
Journal of Clinical Oncology, 2009
10010 Background: Neuroblastoma is a heterogeneous disease with variability in outcome among diff... more 10010 Background: Neuroblastoma is a heterogeneous disease with variability in outcome among different risk groups. Historically, INSS stage 4s neuroblastoma (age less than 12 months, stage 1 or 2 primary tumor with metastases limited to liver, skin and bone marrow) has a more favorable outcome than infant stage 4 disease. The aim was to determine if metastatic pattern (4 vs 4s) predicted favorable prognosis in infants < 12 months or in toddlers aged 12–18 months when stratifying by biology. Methods: Outcome was analyzed by log rank tests and Cox models for 656 infants with stage 4s neuroblastoma and 1,019 stage 4 patients < 18 months of age in the International Neuroblastoma Risk Group database (n=8,800). Prognostic factors (tumor ploidy, histology, grade, MKI, LDH, MYCN, 11q, 1p, primary site) were tested for association with age/stage subgroups (Fisher's exact test) and in Cox models. Results: MYCNamplification, 1p aberration, diploidy, and high MKI and LDH were more fr...
Pediatric Blood & Cancer, 2020
BackgroundThe 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to i... more BackgroundThe 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to include modern functional imaging studies and methods for quantifying disease in bone marrow. We hypothesized the 2017 INRC would enable more precise assessment of response to treatment and provide superior prognostic information compared with the 1993 criteria.MethodsHigh‐risk (HR) neuroblastoma patients from two institutions in Chicago diagnosed between 2006 and 2016 were identified. Patients were assessed post induction chemotherapy via the 1993 and 2017 INRC and classified as responder (≥ mixed response [MXR] or ≥ minor response [MR], respectively) or nonresponder (< MXR or < MR). Event‐free survival (EFS) and overall survival (OS) for responders versus nonresponders were determined from end induction and stratified by Cox regression. Patients with progressive disease at end induction were eliminated from the EFS analyses but included in the OS analysis.ResultsThe 1993 criteria ...
Journal of Clinical Oncology, 2007
9524 Background: We have previously shown, both retrospectively and prospectively, that high-leve... more 9524 Background: We have previously shown, both retrospectively and prospectively, that high-level expression of the multidrug transporter gene ABCC1/MRP1, is strongly predictive of poor outcome in the childhood cancer neuroblastoma (NEJM, 334:231–8, 1996; JCO, 24:1546–53, 2006), and that ABCC1/MRP1 can be regulated by the MYCN oncogene. The contribution of other ABCC family genes to clinical outcome in this disease has now been examined. Methods: Real-time quantitative PCR was used to determine ABCC gene expression in a large prospectively accrued cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Results: Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in the cohort. Amongst the ABCC family, high levels of ABCC1 and ABCC4, but low levels of ABCC3, were strongly associated with reduced survival and event-free survival (P<0.005) in the overall study population, and also in subgroups of pati...