Disease Outcome May Be Predicted by Molecular Detection of Minimal Residual Disease in Bone Marrow in Advanced Neuroblastoma: A Pilot Study

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Abstract
This pilot study focussed on whether sequential molecular detection of minimal residual disease (MRD) in bone marrow (BM) could predict the outcome of patients with advanced neuroblastoma. Bone marrow samples from 21 patients older than age 12 months with stage IV neuroblastoma were sequentially examined for tumor cell contamination by detecting tyrosine hydroxylase (TH) messenger ribonucleic acid (mRNA) using reverse transcription-polymerase chain reaction (RT-PCR). Twenty patients received myeloablative therapy with hematopoietic stem cell transplantation after achieving complete remission. All BM samples of patients except that of one patient was cytologically positive for neuroblastoma cells at diagnosis, and they became negative for neuroblastoma cells within 3 months by cytologic examination. By RT-PCR analysis, BM samples of all patients were positive for TH mRNA at diagnosis, and samples of 19 patients became negative for TH mRNA 1 to 13 months after the start of chemotherapy. Six patients whose BM samples became negative for TH mRNA within 4 months after the start of chemotherapy remained alive without evidence of disease (median 76 mos, range 36-91). In contrast, out of 15 patients whose BM samples remained positive, 10 patients had relapse develop and 9 patients died from disease (median 15 mos, range 10-25). There was a statistically significant difference in disease-free survival between the two groups (P < 0.05). Persistence of MRD in BM may predict poor prognosis in advanced neuroblastoma.

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