title: The prognostic value of fast molecular response of marrow disease in patients aged over 1 year with stage 4 neuroblastoma.
abstract: BACKGROUND
  Quantitative real-time (q)PCR for detection of minimal residual disease (MRD) in children with neuroblastoma (NB) can evaluate molecular bone marrow (BM) response to therapy, but the prognostic value of tumour kinetics in the BM during induction treatment remains to be established. The purpose of this study was to analyse at which time points MRD detection by sequential molecular assessment of BM was prognostic for overall survival (OS).
  
  
  METHODS
  In this single centre study, qPCR was performed with five NB-specific markers: PHOX2B, TH, DDC, GAP43 and CHRNA3, on 106 retrospectively analysed BM samples of 53 patients >1 year with stage 4 neuroblastoma. The prognostic impact of MRD at diagnosis (n = 39), at 3 months after diagnosis (n = 38) and after completing induction chemotherapy (n = 29) was assessed using univariate and bivariate Cox regression analyses.
  
  
  RESULTS
  There was no correlation between tumour load at diagnosis and outcome (p = 0.93). Molecular BM remission was observed in 11/38 (29%) of patients at 3 months after diagnosis and associated with favourable outcome (5-y-OS 62 ± 15.0% versus 19 ± 8%; p = 0.009). After completion of induction chemotherapy, BM of 41% (12/29) of the patients was still MRD positive, which was associated with poor outcome (5-y-OS 0% versus 52 ± 12%; p<0.001). For both time points, the prognostic value of molecular response remained significant in bivariate analysis.
  
  
  CONCLUSIONS
  MRD detection measured by a panel of NB specific-PCR targets could identify fast responders, who clear their BM early during treatment. Fast molecular response was a prognostic factor, associated with better outcome. Our data indicate that MRD analysis during induction therapy should be included in prospective MRD studies.
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Stutterheim
authors.forename: L
authors.initials: L
authors.lastname: Zappeij-Kannegieter
authors.forename: R
authors.initials: R
authors.lastname: Versteeg
authors.forename: H N
authors.initials: HN
authors.lastname: Caron
authors.forename: C E
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: G A M
authors.initials: GA
authors.lastname: Tytgat
mesh_terms: D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007700:Kinetics; D009447:Neuroblastoma / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome