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.

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The receptor-interacting protein kinase 3 (RIPK3) is a key regulator of necroptosis and is involved in various pathologies of human diseases. We previously reported that RIPK3 expression is upregulated in various neural cells at the lesions and necroptosis contributed to secondary neural tissue damage after spinal cord injury (SCI). Interestingly, recent studies have shown that the B-RAFV600E inhibitor dabrafenib has a function to selectively inhibit RIPK3 and prevents necroptosis in various disease models. In the present study, using a mouse model of thoracic spinal cord contusion injury, we demonstrate that dabrafenib administration in the acute phase significantly inhibites RIPK3-mediated necroptosis in the injured spinal cord. The administration of dabrafenib attenuated secondary neural tissue damage, such as demyelination, neuronal loss, and axonal damage, following SCI. Importantly, the neuroprotective effect of dabrafenib dramatically improved the recovery of locomotor and sensory functions after SCI. Furthermore, the electrophysiological assessment of the injured spinal cord objectively confirmed that the functional recovery was enhanced by dabrafenib. These findings suggest that the B-RAFV600E inhibitor dabrafenib attenuates RIPK3-mediated necroptosis to provide a neuroprotective effect and promotes functional recovery after SCI. The administration of dabrafenib may be a novel therapeutic strategy for treating patients with SCI in the future.

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IntroductionGranulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial.Methods and analysisThe objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients).Ethics and disseminationThe study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper.Trial registration numberUMIN000018752.

Background This study examined the biomechanics of preventing excessive internal hip joint rotation related to the hip flexion angle. Method An intramedullary nail with a circular plate equipped with a protractor was installed in the femur of nine normal hips. The circular plate was pulled by 3.15 Nm of force in the internal rotation direction. The external rotators were individually resected, finally cutting the ischiofemoral ligament. The cutting order of the external rotators differed on each side to individually determine the internal rotation resistance. The external rotators were resected from the piriformis to the obturator externus in the right hips and the reverse order in the left hips. Traction was performed after excising each muscle and ischiofemoral ligament. Measurements were taken at 0°, 30°, and 60° of hip flexion, and the differences from baseline were calculated. Results For the right hip measurements, the piriformis and ischiofemoral ligament resection significantly differed at 0° of flexion (p = 0.02), each external rotator and the ischiofemoral ligament resections significantly differed at 30° of flexion (p < 0.01), and the ischiofemoral ligament and piriformis and inferior gemellus resections significantly differed at 60° of flexion (p = 0.04 and p = 0.02, respectively). In the left hips, the ischiofemoral ligament and obturator externus, inferior gemellus, and obturator internus resections significantly differed at 0° of flexion (p < 0.01, p < 0.01, and p = 0.01, respectively), as did each external rotator and the ischiofemoral ligament resections at 30° of flexion (p < 0.01). Conclusion The ischiofemoral ligament primarily restricted the internal rotation of the hip joint. The piriformis and obturator internus may restrict internal rotation at 0° and 60° of flexion.

BackgroundThe purpose of this study was to examine the magnitude of the impact of each external rotator muscle and ischiofemoral ligament on prevention of joint dislocation, depending on the hip flexion angle.MethodNine normal hips were studied; the pelvis was fixed in the lateral decubitus position. An intramedullary nail was inserted into the femur and fixed using screws. A circular plate with a protractor was fixed on the nail. The circular plate was pulled by 3.15 Nm force in the direction of internal rotation, and this angle was defined as the baseline angle. External rotators of the right hip were resected stepwise using the posterior approach; in contrast, external rotators of the left hip were resected stepwise in the reverse order, and finally the ischiofemoral ligament was cut. After each muscle and ischiofemoral ligament resection, the increase in the angle by the traction of was measured at the neutral and 30° and 60° hip flexion positions.ResultsIn posterior approach, there was a significant difference between measurements after piriformis and ischiofemoral ligament resection at 0° of flexion (p=0.02). At 30° of flexion, there were significant differences between measurements after each external rotator and ischiofemoral ligament resection (p<0.01). At 60° of flexion, there were significant differences between ischiofemoral ligament resection and piriformis or inferior gemellus resection (p=0.04, p=0.02, respectively). In the reverse order of the posterior approach, there were significant differences between ischiofemoral ligament resection and the obturator externus, inferior gemellus, or obturator internus at 0° of flexion (p<0.01, p<0.01, p=0.01, respectively). At 30° of flexion, there was a significant difference between the ischiofemoral ligament and each external rotator (p<0.01). ConclusionThe ischiofemoral ligament is the main restrictor of posterior dislocation. The combination of the piriformis and obturator internus may restrict internal rotation at 0°and 60° of flexion.