Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Postoperative K-line conversion from (-) to (+) is a factor independently associated with a better surgical outcome. These slides can be retrieved under Electronic Supplementary material.

Previously, a rat model of chronic compressive myelopathy that uses a water-absorbing polymer inserted under a spinal lamina was reported. However, the best size and coefficient of expansion of the polymer sheet have not yet been established. The aim of the present study was to optimize these properties in an ideal rat model of cervical compressive myelopathy. Thirty rats were used in this study. A sheet of water-absorbing polymer was inserted under the cervical laminae. Rats were divided randomly into five experimental groups by the expansion rate (350 or 200%) and thickness (0.5 or 0.7 mm) and the control. After the surgery, the severity of paralysis was evaluated for 12 weeks. At 12 weeks after the surgery, cresyl violet staining was performed to assess the number of motor neurons in the anterior horn at the C4/C5 segment and Luxol Fast Blue staining was performed to assess demyelination in the corticospinal tract at the C7 segment. ‘Slow-progressive’ paralysis appeared at 4–8 weeks postoperatively in rat models using sheets with 200% expansion. By contrast, only temporary paralysis was observed in rat models using sheets with 350% expansion. A loss of motor neurons in the anterior horn was observed in all groups, except for the control. Demyelination in the corticospinal tract was observed in rat models using sheets with 200% expansion, but not rat models using sheets with 350% expansion. A polymer sheet that expands its volume by 200% is an ideal material for rat models of cervical compressive myelopathy.

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