Outcome prediction by molecular detection of minimal residual disease in bone marrow for advanced neuroblastoma.
BACKGROUND
We have determined whether sequential molecular detection of minimal residual disease (MRD) in bone marrow (BM) could predict the outcome of patients with advanced neuroblastoma (NB).


METHODS
Bone marrow samples from 19 patients over 12 months of age with stage 4 neuroblastoma were sequentially examined for tumor cell contamination by detecting tyrosine hydroxylase (TH) mRNA using reverse transcription-polymerase chain reaction (RT-PCR). All patients received repetitive multi-drug chemotherapy including cisplatin, cyclophosphamide or ifosphamide, adriamycin, and etoposide or vincristine. Seventeen patients received myeloablative therapy with hematopoietic stem cell transplantation after achieving complete remission.


RESULTS
All but one patient were histologically positive for tumor cells in BM samples at diagnosis, and they became negative for tumor cells within 3 months histologically. By the RT-PCR analysis, all patients were positive for TH mRNA in BM samples at diagnosis, and they 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 61 months, range 20-76). In contrast, 12 of 13 patients whose BM samples remained positive at that time developed relapse and 10 of them died of disease (median 24 months, range 13-43). There was a statistically significant difference in survival between the two groups (P < 0.05). No significant difference of clinical characteristics by the MRD positivity at 4 months after the start of chemotherapy.


CONCLUSIONS
Persistence of MRD in BM at 4 months after the start of chemotherapy could predict poor prognosis in advanced neuroblastoma.
Horibe
K
K
Department of Pediatrics, Nagoya University School of Medicine, Japan. khoribe@med.nagoya-u.ac.jp
Fukuda
M
M
Miyajima
Y
Y
Matsumoto
K
K
Kondo
M
M
Inaba
J
J
Miyashita
Y
Y
D000310:Adrenal Gland Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001856:Bone Marrow Examination; D016026:Bone Marrow Transplantation; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005047:Etoposide / Q000008:administration & dosage; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D015993:Life Tables; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D018365:Neoplasm, Residual; D009447:Neuroblastoma / Q000737:chemistry / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis*; D012334:RNA, Neoplasm / Q000032:analysis*; D012186:Retroperitoneal Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016019:Survival Analysis; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D014750:Vincristine / Q000008:administration & dosage
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; C027260:pirarubicin; D014446:Tyrosine 3-Monooxygenase; D002945:Cisplatin; D007069:Ifosfamide