Neuroblastoma pp 271-292 | Cite as

Prognostic Factors and Risk Stratification

  • Meredith S. IrwinEmail author


Neuroblastoma (NB), the third most common paediatric cancer, accounts for 7% of paediatric malignancies and 10–15% of cancer-related deaths in children. Prognosis and tailored treatments are determined by several clinical and biological risk factors. These factors have been used to create risk classifiers that predict the probability of recurrence. The estimated 5-year survival rates for patients with non-high risk and high-risk neuroblastoma are 90% and 50%, respectively. Recent clinical trials have continued to reduce therapy for patients with non-high risk neuroblastoma, including the most favourable subsets of patients, who are now often followed with observation approaches. In contrast, high-risk neuroblastoma patients are treated aggressively with chemotherapy, radiation, surgery, myeloablative and immunotherapies. Current prognostic factors used by most clinical trials cooperative groups and the International Risk Group (INRG) classification system include age, stage, histopathology, ploidy, status of MYCN and segmental chromosome aberrations (SCAs). In addition to these well-validated risk factors, research advances facilitated by large international collaborations and next generation sequencing (NGS) technologies have identified additional emerging prognostic factors at diagnosis and during treatment. These include specific genetic alterations of the ALK oncogene, aberrations of the telomerase pathway (including TERT fusions and ATRX mutations) and metastatic response. Standard prognostic factors together with these newer biomarkers will enable us to further refine risk categories as well as optimize treatment and enable precision medicine strategies.


Neuroblastoma Prognosis Risk stratification INRG MYCN Ploidy Segmental chromosome aberrations ALK Telomerase 


  1. 1.
    Irwin MS, Park JR. Neuroblastoma: pediatric paradigm for precision medicine. Pediatr Clin North Am. 2015;62:225–56.CrossRefGoogle Scholar
  2. 2.
    Pinto NR, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33:3008–17. Scholar
  3. 3.
    Brodeur GM, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11:1466–77.CrossRefGoogle Scholar
  4. 4.
    Cohn SL, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27:289–97.CrossRefGoogle Scholar
  5. 5.
    Cecchetto G, et al. Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol. 2005;23:8483–9.CrossRefGoogle Scholar
  6. 6.
    Monclair T, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009;27:298–303.CrossRefGoogle Scholar
  7. 7.
    Simon T, Hero B, Benz-Bohm G, von Schweinitz D, Berthold F. Review of image defined risk factors in localized neuroblastoma patients: results of the GPOH NB97 trial. Pediatr Blood Cancer. 2008;50:965–9. Scholar
  8. 8.
    Simon T, Spitz R, Faldum A, Hero B, Berthold F. New definition of low-risk neuroblastoma using stage, age, and 1p and MYCN status. J Pediatr Hematol Oncol. 2004;26:791–6.PubMedGoogle Scholar
  9. 9.
    Schmidt ML, et al. Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. J Clin Oncol. 2000;18:1260–8.CrossRefGoogle Scholar
  10. 10.
    George RE, et al. Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 2005;23:6466–73.CrossRefGoogle Scholar
  11. 11.
    London WB, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol. 2005;23:6459–65.CrossRefGoogle Scholar
  12. 12.
    Mosse YP, et al. Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer. 2014;61:627–35. Scholar
  13. 13.
    Schmidt ML, et al. Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children’s Cancer Group study. J Clin Oncol. 2005;23:6474–80.CrossRefGoogle Scholar
  14. 14.
    Schleiermacher G, et al. Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer. 2011;105:1940–8. Scholar
  15. 15.
    Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984;224:1121–4.CrossRefGoogle Scholar
  16. 16.
    Seeger RC, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313:1111–6.CrossRefGoogle Scholar
  17. 17.
    Moreau LA, et al. Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children’s Oncology Group study. Clin Cancer Res. 2006;12:5693–7.CrossRefGoogle Scholar
  18. 18.
    Ambros PF, et al. International consensus for neuroblastoma molecular diagnostics: report from the international Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009;100:1471–82.CrossRefGoogle Scholar
  19. 19.
    Campbell K, et al. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: a report from the Children’s Oncology Group. Cancer. 2017;123:4224–35. Scholar
  20. 20.
    Berbegall AP, et al. Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors. Oncogene. 2016;35:1423–32. Scholar
  21. 21.
    Marrano P, Irwin MS, Thorner PS. Heterogeneity of MYCN amplification in neuroblastoma at diagnosis, treatment, relapse, and metastasis. Genes Chromosomes Cancer. 2017;56:28–41. Scholar
  22. 22.
    Huang M, Weiss WA. Neuroblastoma and MYCN. Cold Spring Harb Perspect Med. 2013;3:a014415. Scholar
  23. 23.
    Ruiz-Perez MV, Henley AB, Arsenian-Henriksson M. The MYCN protein in health and disease. Genes (Basel). 2017;8 Scholar
  24. 24.
    Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16:2985–95.CrossRefGoogle Scholar
  25. 25.
    Zhu S, et al. Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell. 2012;21:362–73. Scholar
  26. 26.
    Berry T, et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell. 2012;22:117–30. Scholar
  27. 27.
    Valentijn LJ, et al. Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. Proc Natl Acad Sci U S A. 2012;109:19190–5. Scholar
  28. 28.
    Puissant A, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3:308–23. Scholar
  29. 29.
    Gustafson WC, et al. Drugging MYCN through an allosteric transition in Aurora Kinase A. Cancer Cell. 2014;26:414–27. Scholar
  30. 30.
    Brockmann M, et al. Small molecule inhibitors of Aurora-A induce proteasomal degradation of N-Myc in childhood neuroblastoma. Cancer Cell. 2013;24:75–89. Scholar
  31. 31.
    DuBois SG, et al. Phase I study of the Aurora A kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: a NANT (new approaches to neuroblastoma therapy) trial. J Clin Oncol. 2016;34:1368–75. Scholar
  32. 32.
    Wang LL, et al. Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children’s Oncology Group. Cancer. 2013;119:3718–26. Scholar
  33. 33.
    Wang LL, et al. Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children’s Oncology Group study. Br J Cancer. 2015;113:57–63. Scholar
  34. 34.
    Bagatell R, et al. Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol. 2009;27:365–70.CrossRefGoogle Scholar
  35. 35.
    Vo KT, et al. Clinical, biological and prognostic differences based on primary tumor site in neuroblastoma: a report from the International Neuroblastoma Risk Group (INRG) project. J Clin Oncol. 2014;32(28):3169–76.CrossRefGoogle Scholar
  36. 36.
    Thompson D, et al. Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: a report from the International Neuroblastoma Risk Group project. Cancer. 2016;122:935–45. Scholar
  37. 37.
    Teshiba R, et al. Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children’s Oncology Group. Pediatr Dev Pathol. 2014;17:441–9. Scholar
  38. 38.
    George RE, et al. Relationship between histopathological features, MYCN amplification, and prognosis: a UKCCSG study. United Kingdom Children Cancer Study Group. Med Pediatr Oncol. 2001;36:169–76.<169::AID-MPO1041>3.0.CO;2-U.CrossRefPubMedGoogle Scholar
  39. 39.
    Shimada H, et al. The international neuroblastoma pathology classification (the Shimada system). Cancer. 1999;86:364–72.CrossRefGoogle Scholar
  40. 40.
    Shimada H, et al. Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J Natl Cancer Inst. 1995;87:1470–6.CrossRefGoogle Scholar
  41. 41.
    Bowman LC, et al. Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst. 1997;89:373–80.CrossRefGoogle Scholar
  42. 42.
    Look AT, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1991;9:581–91.CrossRefGoogle Scholar
  43. 43.
    Oppedal BR, Storm-Mathisen I, Lie SO, Brandtzaeg P. Prognostic factors in neuroblastoma. Clinical, histopathologic, and immunohistochemical features and DNA ploidy in relation to prognosis. Cancer. 1988;62:772–80.CrossRefGoogle Scholar
  44. 44.
    Janoueix-Lerosey I, et al. Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 2009;27:1026–33.CrossRefGoogle Scholar
  45. 45.
    Attiyeh EF, et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med. 2005;353:2243–53.CrossRefGoogle Scholar
  46. 46.
    Brodeur GM, et al. Molecular analysis and clinical significance of N-myc amplification and chromosome 1p monosomy in human neuroblastomas. Prog Clin Biol Res. 1988;271:3–15.PubMedGoogle Scholar
  47. 47.
    Maris JM, et al. Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children’s Cancer Group study. J Clin Oncol. 2000;18:1888–99.CrossRefGoogle Scholar
  48. 48.
    Mosse YP, et al. Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Genes Chromosomes Cancer. 2007;46:936–49. Scholar
  49. 49.
    Guo C, et al. Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene. 1999;18:4948–57.CrossRefGoogle Scholar
  50. 50.
    Tonini GP, et al. MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol. 1997;15:85–93.CrossRefGoogle Scholar
  51. 51.
    De Bernardi B, et al. Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol. 2009;27:1034–40. Scholar
  52. 52.
    Minard V, et al. Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer. 2000;83:973–9. Scholar
  53. 53.
    Katzenstein HM, et al. Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience—a pediatric oncology group study. J Clin Oncol. 1998;16:2007–17.CrossRefGoogle Scholar
  54. 54.
    Baker DL, et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med. 2010;363:1313–23. Scholar
  55. 55.
    Rubie H, et al. N-Myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL 90 study. Neuroblastoma Study Group of the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol. 1997;15:1171–82. Scholar
  56. 56.
    Shimada H, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984;73:405–16.CrossRefGoogle Scholar
  57. 57.
    Strother DR, et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol. 2012;30:1842–8. Scholar
  58. 58.
    Meany HJ, et al. Significance of clinical and biologic features in Stage 3 neuroblastoma: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer. 2014; Scholar
  59. 59.
    Look AT, Hayes FA, Nitschke R, McWilliams NB, Green AA. Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med. 1984;311:231–5. Scholar
  60. 60.
    Park JR, et al. Children’s Oncology Group’s 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer. 2013;60:985–93. Scholar
  61. 61.
    Bown N, et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med. 1999;340:1954–61.CrossRefGoogle Scholar
  62. 62.
    Meddeb M, et al. Additional copies of a 25 Mb chromosomal region originating from 17q23.1-17qter are present in 90% of high-grade neuroblastomas. Genes Chromosomes Cancer. 1996;17:156–65.<156::AID-GCC3>3.0.CO;2-3.CrossRefPubMedGoogle Scholar
  63. 63.
    Caron H, et al. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med. 1996;334:225–30.CrossRefGoogle Scholar
  64. 64.
    Riley RD, et al. A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res. 2004;10:4–12.CrossRefGoogle Scholar
  65. 65.
    Spitz R, Hero B, Simon T, Berthold F. Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res. 2006;12:3368–73. Scholar
  66. 66.
    Schleiermacher G, et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer. 2012;107:1418–22. Scholar
  67. 67.
    Defferrari R, et al. Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification. Br J Cancer. 2015;112:290–5. Scholar
  68. 68.
    Chicard M, et al. Genomic copy number profiling using circulating free tumor DNA highlights heterogeneity in neuroblastoma. Clin Cancer Res. 2016;22:5564–73. Scholar
  69. 69.
    Van Roy N, et al. Shallow whole genome sequencing on circulating cell-free DNA allows reliable noninvasive copy-number profiling in neuroblastoma patients. Clin Cancer Res. 2017;23:6305–14. Scholar
  70. 70.
    Campbell BB, et al. Comprehensive analysis of hypermutation in human cancer. Cell. 2017;171:1042–1056 e1010. Scholar
  71. 71.
    Pugh TJ, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013; Scholar
  72. 72.
    Molenaar JJ, et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483:589–93. Scholar
  73. 73.
    Sausen M, et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet. 2013;45:12–7. Scholar
  74. 74.
    Bresler SC, et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014;26:682–94. Scholar
  75. 75.
    Suzuki M, et al. Treatment and outcome of adult-onset neuroblastoma. Int J Cancer. 2018; Scholar
  76. 76.
    Cheung NK, et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA. 2012;307:1062–71. Scholar
  77. 77.
    Bellini A, et al. Deep sequencing reveals occurrence of subclonal ALK mutations in neuroblastoma at diagnosis. Clin Cancer Res. 2015;21:4913–21. Scholar
  78. 78.
    Schleiermacher G, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014; Scholar
  79. 79.
    Eleveld TF, et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015;47:864–71. Scholar
  80. 80.
    Padovan-Merhar OM, et al. Enrichment of targetable mutations in the relapsed neuroblastoma genome. PLoS Genet. 2016;12:e1006501. Scholar
  81. 81.
    Schulte JH, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res. 2011;17:5082–92. Scholar
  82. 82.
    De Brouwer S, et al. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res. 2010;16:4353–62. Scholar
  83. 83.
    Duijkers FA, et al. High anaplastic lymphoma kinase immunohistochemical staining in neuroblastoma and ganglioneuroblastoma is an independent predictor of poor outcome. Am J Pathol. 2012;180:1223–31. Scholar
  84. 84.
    Bresler SC, et al. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med. 2011;3:108ra114. Scholar
  85. 85.
    Infarinato NR, et al. The ALK/ROS1 inhibitor PF-06463922 overcomes primary resistance to crizotinib in ALK-driven neuroblastoma. Cancer Discov. 2016;6:96–107. Scholar
  86. 86.
    Peifer M, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 2015;526:700–4. Scholar
  87. 87.
    Valentijn LJ, et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet. 2015;47:1411–4. Scholar
  88. 88.
    Hertwig F, Peifer M, Fischer M. Telomere maintenance is pivotal for high-risk neuroblastoma. Cell Cycle. 2016;15:311–2. Scholar
  89. 89.
    Henson JD, et al. The C-Circle Assay for alternative-lengthening-of-telomeres activity. Methods. 2017;114:74–84. Scholar
  90. 90.
    Mender I, Gryaznov S, Dikmen ZG, Wright WE, Shay JW. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer Discov. 2015;5:82–95. Scholar
  91. 91.
    Flynn RL, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015;347:273–7. Scholar
  92. 92.
    Vermeulen J, De Preter K, Laureys G, Speleman F, Vandesompele J. 59-Gene prognostic signature sub-stratifies high-risk neuroblastoma patients. Lancet Oncol. 2009;10:1030., S1470-2045(09)70325-0 [pii].CrossRefPubMedGoogle Scholar
  93. 93.
    De Preter K, et al. Accurate outcome prediction in neuroblastoma across independent data sets using a multigene signature. Clin Cancer Res. 2010;16:1532–41.CrossRefGoogle Scholar
  94. 94.
    Oberthuer A, et al. Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol. 2006;24:5070–8.CrossRefGoogle Scholar
  95. 95.
    Oberthuer A, et al. Prognostic impact of gene expression-based classification for neuroblastoma. J Clin Oncol. 2010;28:3506–15., JCO.2009.27.3367 [pii].CrossRefGoogle Scholar
  96. 96.
    Garcia I, et al. A three-gene expression signature model for risk stratification of patients with neuroblastoma. Clin Cancer Res. 2012–2023;18:2012. Scholar
  97. 97.
    Asgharzadeh S, et al. Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst. 2006;98:1193–203., 98/17/1193 [pii].CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Asgharzadeh S, et al. Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. J Clin Oncol. 2012;30:3525–32. Scholar
  99. 99.
    Hallett RM, Seong AB, Kaplan DR, Irwin MS. Transcript signatures that predict outcome and identify targetable pathways in MYCN-amplified neuroblastoma. Mol Oncol. 2016;10:1461–72. Scholar
  100. 100.
    Oberthuer A, et al. Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers. Clin Cancer Res. 2015;21:1904–15. Scholar
  101. 101.
    Buckley PG, et al. Chromosomal and microRNA expression patterns reveal biologically distinct subgroups of 11q-neuroblastoma. Clin Cancer Res. 2010;16:2971–8., 1078-0432.CCR-09-3215 [pii].CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Chen Y, Stallings RL. Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. Cancer Res. 2007;67:976–83. Scholar
  103. 103.
    De Preter K, et al. miRNA expression profiling enables risk stratification in archived and fresh neuroblastoma tumor samples. Clin Cancer Res. 2011;17:7684–92. Scholar
  104. 104.
    Yanik GA, 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. 2013; Scholar
  105. 105.
    Matthay KK, et al. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol. 2003;21:2486–91. Scholar
  106. 106.
    Suc A, et al. Metastatic neuroblastoma in children older than one year: prognostic significance of the initial metaiodobenzylguanidine scan and proposal for a scoring system. Cancer. 1996;77:805–11.CrossRefGoogle Scholar
  107. 107.
    Ady N, et al. A new 123I-MIBG whole body scan scoring method—application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma. Eur J Cancer. 1995;31A:256–61.CrossRefGoogle Scholar
  108. 108.
    Ladenstein R, 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. 2018;45:292–305. Scholar
  109. 109.
    Brownhill SC, Burchill SA. PCR-based amplification of circulating RNAs as prognostic and predictive biomarkers – focus on neuroblastoma. Pract Lab Med. 2017;7:41–4. Scholar
  110. 110.
    Viprey VF, et al. Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study. J Clin Oncol. 2014;32:1074–83. Scholar
  111. 111.
    Corrias MV, et al. A novel syngeneic murine model for thoracic neuroblastoma obtained by intramediastinal injection of tumor cells. Cancer Detect Prev. 2002;26:468–75.CrossRefGoogle Scholar
  112. 112.
    Kreissman SG, et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013;14:999–1008. Scholar
  113. 113.
    Marachelian A, et al. Expression of five neuroblastoma genes in bone marrow or blood of patients with relapsed/refractory neuroblastoma provides a new biomarker for disease and prognosis. Clin Cancer Res. 2017;23:5374–83. Scholar
  114. 114.
    Alvarado CS, et al. Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group study. J Pediatr Hematol Oncol. 2000;22:197–205.CrossRefGoogle Scholar
  115. 115.
    Perez CA, et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a Children’s Cancer Group study. J Clin Oncol. 2000;18:18–26.CrossRefGoogle Scholar
  116. 116.
    Simon T, Spitz R, Hero B, Berthold F, Faldum A. Risk estimation in localized unresectable single copy MYCN neuroblastoma by the status of chromosomes 1p and 11q. Cancer Lett. 2006;237:215–22. Scholar
  117. 117.
    Nuchtern JG, et al. A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children’s Oncology Group study. Ann Surg. 2012;256:573–80. Scholar
  118. 118.
    Hero B, et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol. 2008;26:1504–10. Scholar
  119. 119.
    Kushner BH, et al. Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy. J Clin Oncol. 1996;14:373–81.CrossRefGoogle Scholar
  120. 120.
    Ladenstein R, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14. Scholar
  121. 121.
    Yu A, Gilman AL, Ozkaynak MF. A phase III randomized trial of the chimeric anti-GD2 antibody ch14.18 with GMCSF and IL2 as immunotherapy following dose intensive chemotherapy for high risk neuroblsatoma: Children’s Oncology Group (COG) study ANBL0032. J Clin Oncol. 2009;27Google Scholar
  122. 122.
    Depuydt P, et al. Genomic amplifications and distal 6q loss: novel markers for poor survival in high-risk neuroblastoma patients. J Natl Cancer Inst. 2018; Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Paediatrics, Hospital for Sick ChildrenUniversity of TorontoTorontoCanada

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