Search

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., Koda et al. present the results of a randomized phase 3 trial comparing granulocyte colony-stimulating factor versus placebo in patients with acute spinal cord injury. While the primary endpoint was not met, a sub-analysis revealed a trend towards superior efficacy of G-CSF versus placebo in an elderly population.

Purpose To elucidate the independent preoperative factors that have a significant impact on poor surgical outcome after laminoplasty for K-line (+) ossification of the posterior longitudinal ligament (OPLL). Analyses in K-line (+) patient population can exclude the influence by mal-alignment and thick OPLL, both of which are well known two major factors that have significant impact on clinical outcome. Methods The present study included 72 patients (50 male and 22 female) who underwent laminoplasty for K-line (+) cervical OPLL and were followed-up for at least 1 year. Recovery of Japanese Orthopedic Association score (JOA score) for cervical myelopathy was used as the measure of clinical outcome. For radiographic assessment, the type of OPLL, the maximum OPLL occupation ratio, the C2-C7 angle, and the segmental range of motion at the peak of OPLL (segmental ROM) were assessed. To elucidate the factors that are significantly associated with a poor clinical outcome after laminoplasty for K-line (+) OPLL, statistical analyses were conducted. Results The mean preoperative JOA score was 8.9 points and improved to 12.8 points after surgery. The recovery of JOA score was 47 ± 35%. Stepwise logistic regression following univariate analyses revealed that preoperative segmental ROM at the peak of OPLL is an independent factor associated with a poor outcome (p = 0.04, odds ratio = 1.15). Conclusions Large preoperative segmental ROM at the peak of the OPLL is an independent factor that has significant impact on poor surgical outcome after laminoplasty for K-line (+) OPLL.

Background: Spontaneous epidural hematoma is a rare condition, which usually requires urgent surgical treatment. Objectives: To report two cases of spontaneous epidural hematoma, one of which was treated conservatively, and the other surgically, and discuss the possibility of unusual spontaneous recovery and treatment decision-making. Case Report: We encountered 2 patients with spontaneous spinal epidural hematoma, both of whom were taking an anti-platelet agent, producing severe paraplegia. One patient with a hematoma at C2–T3 experienced a rapid neurological recovery while a magnetic resonance imaging scan was being performed. A complete resolution of the hematoma and complete neurological recovery ensued without surgical intervention. A second patient with a hematoma at T10–12 showed no neurological recovery up to the time emergency surgery started and was treated surgically by T10–12 laminectomy and excision of the hematoma. Neurological function returned to normal in both patients. Conclusion: The occurrence of spontaneous recovery in some patients makes the decision for surgery difficult. Emergency physicians need to be aware of the possibility of spontaneous rapid neurological recovery in patients with spinal epidural hematoma. To avoid unnecessary surgery in patients who will spontaneously have neurological recovery, neurological evaluations need to be repeatedly performed up to the time the emergency surgery begins. However, unfortunately, there is no diagnostic tool at present to identify the patients who recover spontaneously, and the interval between onset and surgery is correlated with clinical results, therefore, conservative treatment should be prescribed only for those patients who exhibit improving neurological signs early in the clinical course.

Introduction Granulocyte 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 analysis The 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/m 2 /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 dissemination The 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 number UMIN000018752.

Study design A case report of 3 patients with posterior migration of bullet-shaped fusion cages after transforaminal lumbar interbody fusion (TLIF). One patient required emergency revision surgery; the other 2 patients are being observed during conservative treatment. Objective To review cases of posterior migration of fusion cages and report ensuing clinical courses. Summary of background data TLIF is a commonly used procedure; however, there are few reports describing cage migration after the procedure. In most cases, when posterior cage migration follows posterior lumbar interbody fusion, emergency revision surgery is required. One recent study reported a case of posterior cage migration after TLIF, which was treated conservatively. Methods Posterior migration of the bullet-shaped fusion cages occurred 1 to 2 months after TLIF in 3 patients. One of the 3 patients had isthmic spondylolisthesis treated by TLIF with bilateral pedicle screw fixation. The other 2 patients had degenerative scoliosis and were treated by TLIF with unilateral pedicle screw fixation. Results The patient with isthmic spondylolisthesis required revision surgery because the migrated cage caused nerve root irritation. The migrated cage was removed and a large-sized cage was employed to achieve stability. The other 2 patients had no pathologic symptoms after the posterior migration of the cage and were treated conservatively and observed. Conclusion Revision surgery after TLIF appears relatively safe because the migrated cage tends to locate more laterally than in patients with cage migration after posterior lumbar interbody fusion. Cage migration subsequent to TLIF may not cause compression of neural tissues, so conservative treatment may suffice for these patients. Unilateral pedicle screw fixation may not provide sufficient stability to prevent cage migration in patients with degenerative scoliosis. Further study is needed to clarify surgical indications for unilateral pedicle screw fixation in TLIF.

Chondrogenesis is an essential component of endochondral fracture healing, though the molecular and cellular events by which it is regulated have not been fully elucidated. In this study, we used a rat model of closed fracture healing to determine the spatial and temporal expression of genes for cartilage-specific collagens. Furthermore, to determine the effects of basic fibroblast growth factor (bFGF) on chondrogenesis in fracture healing, we injected 100 microg recombinant human bFGF into the fracture site immediately after fracture. In normal calluses, pro-alpha1(II) collagen mRNA (COL2A1) was detected in proliferative chondrocytes beginning on day 4 after the fracture, and pro-alpha1(X) collagen mRNA (COL10A1) in hypertrophic chondrocytes beginning on day 7. In FGF-injected calluses, the cartilage enlarged in size significantly. On day 14, both COL2A1- and COL10A1-expressing cells were more widely distributed, and the amounts of COL2A1 and COL10A1 mRNAs were both approximately 2-fold increased when compared with uninjected fractures. Temporal patterns of expression for these genes were, however, identical to those found in normal calluses. The number of proliferating cell nuclear antigen-positive cells was increased in the non-cartilaginous area in the bFGF-injected calluses by day 4. The present molecular analyses demonstrate that a single injection of bFGF enhances the proliferation of chondroprogenitor cells in fracture callus, and thus contributes to the formation of a larger cartilage. However, maturation of chondrocytes and replacement of the cartilage by osseous tissue are not enhanced by exogenous bFGF, and this results in the prolonged cartilaginous callus phase. We conclude that, in the healing of closed fractures of long bones, exogenous bFGF has a capacity to enlarge the cartilaginous calluses, but not to induce more rapid healing.

Object Many surgeons currently prefer to use transforaminal lumbar interbody fusion (TLIF), placing 1 unilateral pedicle screw (PS) and 1 cage. However, no study has examined whether unilateral fixation improves surgical outcome. The authors conducted a prospective randomized controlled trial with a minimum 2-year follow-up to analyze TLIF outcomes for 2 techniques: placement of a unilateral PS and a cage compared with placement of bilateral PSs and 2 cages. Methods Fifty patients with degenerative spondylolisthesis undergoing single-level TLIF were randomly assigned to receive either unilateral or bilateral fixation. Parameters compared between the groups were surgical invasiveness, severity of intermittent claudication, pre- and postoperative visual analog scale (VAS) scores (from 0 to 10 for back pain, lower-extremity pain, and lower-extremity numbness), postoperative disability scores for lumbar spinal disorders (Japanese Orthopaedic Association Back Pain Evaluation Questionnaire [JOABPEQ]), and fusion rates. Results The mean operative time for TLIF was significantly (p = 0.05) shorter and mean estimated blood loss was significantly lower in the unilateral than in the bilateral group. Intermittent claudication improved in response to each technique, but there was no significant intergroup difference. The unilateral group had a nonsignificant tendency toward less improvement in VAS score for back pain (1.5 vs 3.7 for the bilateral group) and exhibited significantly less improvement in VAS score for lower-extremity pain (2.1 vs 5.1, respectively) and numbness (1.7 vs 4.4). There were no significant differences between the groups in postsurgical scores for all 5 items of the JOABPEQ. The fusion rates were 87.5% (21 of 24 patients) in the unilateral group and 95.7% (22 of 23) in the bilateral group. Conclusions Transforaminal lumbar interbody fusion involving unilateral PS fixation and a single-cage technique is less invasive than a 2-cage technique and bilateral fixation, and it improved patients' symptoms. However, it resulted in less improvement in back pain, lower-extremity pain, and lower-extremity numbness. When considering unilateral PS fixation and a single cage, the surgeon should be aware of the potential limitations of this technique. Clinical trial registration no.: UMIN000007833 (UMIN).

Patients with ankylosing spondylitis (AS) are prone to spinal fracture after even minor trauma. We report a case of thoracic spinal fracture in a patient with AS who developed a secondary neurological deficit due to delayed diagnosis and prolonged conservative treatment. When the neurological deficit occurred, the fractured segment showed no displacement, but a spinal epidural hematoma was present. Surgical treatment produced significant neurological improvement, although incomplete paralysis persisted.

Object Because the authors encountered 4 cases of hardware migration following transforaminal lumbar interbody fusion, a retrospective study was conducted to identify factors influencing the posterior migration of fusion cages. Methods Patients with lumbar degenerative disc disease (125 individuals; 144 disc levels) were treated using transforaminal lumbar interbody fusion and followed for 12–33 months. Medical records and pre- and postoperative radiographs were reviewed, and factors influencing the incidence of cage migration were analyzed. Results Postoperative cage migration was found in 4 patients at or before 3 months. Because all the cages that migrated postoperatively were bullet-shaped (Capstone), only these cages were analyzed. The analysis of preoperative radiographs revealed that higher posterior disc height ([PDH] ≥ 6 mm) significantly increased the incidence of postoperative cage migration, but percent slippage, translation, range of motion, and Cobb angle did not. The incidence of cage migration in patients with unilateral fixation (3 [8.3%] of 36) was not significantly different from that in patients with bilateral fixation (1 [2.1%] of 48). Patients who had scoliotic curvature with a Cobb angle > 10° when treated with unilateral fixation demonstrated a tendency to have more frequent postoperative cage migration than patients treated with bilateral fixation. To examine the influence of the height of fusion cages, a value obtained by subtracting preoperative anterior disc height (ADH) or PDH from cage height was defined as “Cage height – ADH” (or “Cage height –PDH”). The analysis revealed that the value for “Cage height –ADH” as well as “Cage height –PDH” was significantly lower in migrated levels than in nonmigrated levels, suggesting that the choice of undersized cages may increase the incidence of cage migration. Conclusions The results suggest that the use of a bullet-shaped cage, higher PDH, the presence of scoliotic curvature, and undersized fusion cages are possible risk factors for cage migration. One patient with postoperative cage migration following bilateral screw fixation underwent revision surgery, and the pedicle screw fixation was found to be disrupted. Other than in this patient, cage migration occurred only in those treated by unilateral fixation. The potential for postoperative cage migration and limitations of unilateral fixation should be considered by spine surgeons.

The optimal timing for surgical intervention in cases of lumbar disc herniation is debatable. This retrospective study sought to determine whether early surgical intervention resulted in greater improvement in clinical outcomes.A total of 46 patients with lumbar disc herniation treated by microendoscopic discectomy were reviewed. Surgery was performed when leg pain persisted despite adequate conservative treatment. The patients were divided into two groups according to the duration of symptoms before surgery, the early group being symptomatic foror=3 months and the late group for3 months. Surgical time, blood loss, severity of back pain, leg pain and numbness (visual analogue scale, or VAS), and a patient-oriented evaluation score (Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, or JOABPEQ) before and after surgery were compared. The JOABPEQ is a new evaluation method for lumbar spinal disorders based on Roland-Morris disability questionnaires and Short Form 36.There were 23 patients in each group. No significant differences were found between the groups in patients' demographics (age, sex, type of herniation), surgical time, blood loss, or pre- and postoperative VAS (lower-back pain, leg pain, numbness). There were no significant differences between the groups in the scores for the five subscales - pain-related disorders, gait disturbance, lumbar spine dysfunction, social life disturbance, psychological disorders - of the preoperative JOABPEQ. Postoperative scores for psychological disorders improved significantly (P0.05) in the late group (mean score 39.9) compared to the early group (mean score 22.1). Interestingly, no significant difference of improvement in the scores other than psychological disorder was found between the two groups.Early surgical intervention did not result in greater improvement of clinical outcomes for patients with lumbar disc herniation. Later surgical intervention resulted in significant improvement of psychological disorders.

Most studies have focused on the association between diabetes mellitus (DM) and impaired osseous healing, but there is also evidence that diabetes impairs cartilage formation during fracture healing. To investigate the molecular mechanisms by which diabetes affects endochondral ossification, experiments were performed in a model of rat closed fracture healing complicated with diabetes. Diabetic rats were created by a single intravenous injection of streptozotocin (STZ), while controls were treated with vehicle alone. Fractures were made 2 weeks after STZ injection. Animals were killed at 4, 7, 10, 14, 21, 28 and 42 days following fracture, and samples were subject to radiographic, histological and molecular analyses. In the DM group, a significantly smaller cartilaginous callus was formed compared with controls throughout healing, with the cartilage area being reduced rapidly after day 14. When the bone union rate was evaluated radiographically on day 28, DM calluses exhibited a lower rate than controls. However, when evaluated on day 42, both groups showed an equivalent union rate. Cellular proliferation of chondroprogenitor cells and proliferating chondrocytes in soft calluses of the DM group was significantly reduced during early stages of healing (days 4 and 7), but no longer reduced thereafter. Moreover, expression levels of collagen type II, type X and osteopontin (OPN) were constantly low in the DM group. These results show the molecular basis for diminished cartilage formation and delayed union in fracture healing of the STZ-induced diabetic rats.

Recently, bioactive agents to stimulate bone formation have been available in the orthopedic field. We have shown previously that a single, local injection of basic fibroblast growth factor (bFGF) contributes to the formation of a larger cartilage (soft callus) but does not promote replacement of the cartilage by osseous tissue during experimental closed femoral fracture healing. Aiming at a clinical application, the present study was undertaken to clarify the effects of locally injected bFGF on bone (hard callus) formation and the mechanical properties of the callus in closed fracture healing in rats. Immediately after fracture, a carrier (200 muL of fibrin gel) containing 100 mug of bFGF or carrier alone was applied to the fracture site. At days 42 and 56 postfracture, the bone union rate, bone mineral density (BMD), and mechanical properties (strength and stiffness) of the callus were evaluated. Unexpectedly, with the exception of reduced stiffness in the FGF-injected callus at day 56, none of these parameters showed a significant difference between the control and the FGF-injected groups. Furthermore, the temporal expression pattern of OPN mRNA during healing was very similar between groups. We conclude that, in the healing of closed fractures of long bones, administration of bFGF forms a larger callus but does not necessarily accelerate the healing process.

The multifunctional adhesion molecule CD44 is a major cell-surface receptor for hyaluronic acid (HUA). Recent data suggest that it may also bind the ubiquitous bone-matrix protein, osteopontin (OPN). Because OPN has been shown to be a potentially important protein in bone remodelling, we investigated the hypothesis that OPN interactions with the CD44 receptor on bone cells participate in the regulation of the healing of fractures. We examined the spatial and temporal patterns of expression of OPN and CD44 in healing fractures of rat femora by in situ hybridisation and immunohistochemistry. We also localised HUA in the fracture callus using biotinylated HUA-binding protein. OPN was expressed in remodelling areas of the hard callus and was found in osteocytes, osteoclasts and osteoprogenitor cells, but not in cuboidal osteoblasts which were otherwise shown to express osteocalcin. The OPN signal in osteocytes was not uniformly distributed, but was restricted to specific regions near sites where OPN mRNA-positive osteoclasts were attached to bone surfaces. In the remodelling callus, intense immunostaining for CD44 was detected in osteocyte lacunae, along canaliculi, and on the basolateral plasma membrane of osteoclasts, but not in the cuboidal osteoblasts. HUA staining was detected in fibrous tissues but little was observed in areas of hard callus where bone remodelling was progressing. Our findings suggest that OPN, rather than HUA, is the major ligand for CD44 on bone cells in the remodelling phase of healing of fractures. They also raise the possibility that such interactions may be involved in the communication of osteocytes with each other and with osteoclasts on bone surfaces. The interactions between CD44 and OPN may have important clinical implications in the repair of skeletal tissues.

Background Lumbar floating fusion occasionally causes postoperative adjacent segment disorder (ASD) at lumbosacral level, causing L5 spinal nerve disorder by L5-S1 foraminal stenosis. The disorder is considered to be one of the major outcomes of L5-S1 ASD, which has not been evaluated yet. The present study aimed to evaluate the incidence and risk factors of postoperative L5 spinal nerve disorder after lumbar interbody fusion extending to the L5 vertebra. Methods We evaluated 125 patients with a diagnosis of spondylolisthesis who underwent floating fusion surgery with transforaminal lumbar interbody fusion with average postoperative period of 25.2 months. The patients were regarded as symptomatic with postoperative L5 spinal nerve disorder such as radicular pain/numbness in the lower limbs and/or motor dysfunction. We estimated and compared the wedging angle (frontal view) and height (lateral view) of the lumbosacral junction in pre- and postoperative plain X-ray images and the foraminal ratio (ratio of the narrower foraminal diameter to the wider diameter in the craniocaudal direction) in the preoperative magnetic resonance image. Risk factors for the incidence of L5 spinal nerve disorder were explored using multivariate logistic regression. Results Eight of the 125 patients (6.4 %) were categorized as symptomatic, an average of 13.3 months after surgery. The wedging angle was significantly higher, and the foraminal ratio was significantly decreased in the symptomatic group (both P