title: Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study.
abstract: We performed a randomized, double-blind, cross-over study to assess the neuroregenerative potential of intravenous granulocyte colony-stimulating factor (G-CSF) followed by infusion of mobilized peripheral blood mononuclear cells (mPBMCs) in children with cerebral palsy (CP).
  
  
  
  Children with non-severe CP were enrolled in this study. G-CSF was administered for 5 days, then mPBMCs were collected by apheresis and cryopreserved. One month later (M1), recipients were randomized to receive either mPBMCs or a placebo infusion, and these treatment groups were switched at 7 months (M7) and observed for another 6 months (M13). We assessed the efficacy of treatment by evaluating neurodevelopmental tests, as well as by brain magnetic resonance imaging-diffusion tensor imaging (MRI-DTI) and18F-fluorodeoxyglucose (FDG) brain positron emission tomography-computed tomography (PET-CT) scanning to evaluate the anatomical and functional changes in the brain.
  
  
  
  Fifty-seven patients aged 4.3 ± 1.9 (range 2-10) years and weighing 16.6 ± 4.9 (range 11.6-56.0) kg were enrolled in this study. The administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. The yield of mPBMCs was comparable to that reported in studies of pediatric donors without CP and patients with nonhematologic diseases. 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. In addition, larger changes in neurodevelopment test scores were observed in the 1 month after G-CSF administration (M0-M1) than during the 6 months after reinfusion with mPBMCs or placebo (M1-M7 or M7-M13). Patients who received G-CSF followed by mPBMC infusion at 7 months (T7 group) demonstrated significantly more neurodevelopmental improvement than patients who received G-CSF followed by mPBMC infusion at 1 month (T1 group). In contrast to the results of neurodevelopment tests, the results of MRI-DTI at the end of this study showed greater improvement in the T1 group. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo group or between the T1 and T7 group.
  
  
  
  Neurodevelopmental improvement was seen in response to intravenous G-CSF followed by mPBMC reinfusion, particularly to the G-CSF alone even without mPBMC reinfusion. Further studies using a larger number of mPBMCs for the infusion which could be collected by repeated cycles of apheresis or using repeated cycles of G-CSF alone, are needed to clarify the effect of mPBMC reinfusion or G-CSF alone (Trial registration: ClinicalTrials.gov, NCT02983708. Registered 5 December, 2016, retrospectively registered).
authors.affiliation: Department of Pediatrics, Hanyang University Medical Center, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.
authors.forename: Wee-Jin
authors.initials: WJ
authors.lastname: Rah
authors.affiliation: Department of Pediatrics, Hanyang University Medical Center, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea. cord@hanyang.ac.kr.|Blood and Marrow Transplantation Center, Hanyang University Medical Center, Seoul, South Korea. cord@hanyang.ac.kr.|Cell Therapy Center, Hanyang University Medical Center, Seoul, South Korea. cord@hanyang.ac.kr.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Hanyang University Medical Center, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.
authors.forename: Jin-Hwa
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Department of Pediatrics, Hanyang University Medical Center, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Jun
authors.affiliation: Department of Pediatrics, Hanyang University Medical Center, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.
authors.forename: Hye-Ryeong
authors.initials: HR
authors.lastname: Kang
authors.affiliation: Department of Pediatrics, Hanyang University Medical Center, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.|Blood and Marrow Transplantation Center, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Hani
authors.initials: H
authors.lastname: Koh
authors.affiliation: Blood and Marrow Transplantation Center, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Eom
authors.affiliation: Department of Radiology, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Radiology, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Yun-Young
authors.initials: YY
authors.lastname: Choi
authors.affiliation: Department of Rehabilitation Medicine, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Kyeongil
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Rehabilitation Medicine, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Cell Therapy Center, Hanyang University Medical Center, Seoul, South Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D016880:Anisotropy; D001921:Brain / Q000473:pathology; D002452:Cell Count; D002547:Cerebral Palsy / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D015925:Cryopreservation; D003710:Demography; D004311:Double-Blind Method; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D009416:Nerve Regeneration / Q000187:drug effects; D009483:Neuropsychological Tests; D010290:Parents; D036102:Peripheral Blood Stem Cell Transplantation; D000072916:Peripheral Blood Stem Cells / Q000166:cytology* / Q000187:drug effects; D000072078:Positron Emission Tomography Computed Tomography; D020127:Recovery of Function / Q000187:drug effects; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D016179:Granulocyte Colony-Stimulating Factor
keywords: Cerebral palsy; Granulocyte colony-stimulating factor; Mobilized peripheral blood mononuclear cells; Neuroregeneration