Safety and feasibility of intravenous administration of a single dose of allogenic-Muse cells to treat human cervical traumatic spinal cord injury: a clinical trial.

INTRODUCTION: Spinal cord injury (SCI) is a devastating injury and remains one of the largest medical and social burdens because of its intractable nature. According to the recent advances in stem cell biology, the possibility of spinal cord regeneration and functional restoration has been suggested by introducing appropriate stem cells. Multilineage-differentiating stress enduring (Muse) cells are a type of nontumorigenic endogenous reparative stem cell. The positive results of Muse cell transplantation for SCI was shown previously. As a first step for clinical application in human SCI, we conducted a clinical trial aiming to confirm the safety and feasibility of intravenously injected donor-Muse cells. METHODS: The study design of the current trial was a prospective, multicenter, nonrandomized, nonblinded, single-arm study. The clinical trial registration number was JRCT1080224764. Patients with a cervical SCI with a neurological level of injury C4 to C7 with the severity of modified Frankel classification B1 and B2 were included. A primary endpoint was set for safety and feasibility. Our protocol was approved by the PMDA, and the trial was funded by the Life Science Institute, Tokyo, Japan. The present clinical trial recruited 10 participants (8 males and 2 females) with an average age of 49.3 ± 21.2 years old. All 10 participants received a single dose of allogenic CL2020 (a total of 15 × 106 cells, 2.1-2.7 × 105 cells/kg of body weight), which is a Muse cell-based product produced from human mesenchymal stem cells, by an intravenous drip. RESULTS: There were two reported severe adverse events, both of which were determined to have no causal relationship with Muse cell treatment. The change in the ISNCSCI motor score, the activity of daily living and quality of life scores showed statistically significant improvements compared to those data at the time of CL2020 administration. CONCLUSION: In the present trial, no safety concerns were identified, and Muse cell product transplantation demonstrated good tolerability. Future clinical trials with appropriate study designs incorporating a control arm will clarify the definitive efficacy of single-dose allogenic Muse cell treatment with intravenous administration to treat SCI. TRIAL REGISTRATION: jRCT, JRCT1080224764. Registered 03 July 2019, https://jrct.niph.go.jp/latest-detail/jRCT1080224764 .

The Validation of the Japanese Version of the Scoliosis Research Society-30 Questionnaire for Adolescent Idiopathic Scoliosis Patients.

Introduction: The Scoliosis Research Society-30 (SRS-30) is a questionnaire originally developed from the SRS-22r questionnaire and is used to evaluate adolescent idiopathic scoliosis (AIS). It comprised questions on five domains: function, pain, self-image, mental health, and satisfaction, with seven additional questions related to postoperative aspects. In addition to the original English version, translations in multiple languages have been effectively applied. Herein, we evaluated the internal consistency and external validity of the Japanese version of the SRS-30 for AIS patients. Methods: Among the 30 questions in SRS-30, the eight additional questions from SRS-22r were translated and back-translated to create a Japanese version of the SRS-30. This translated questionnaire was then used to survey patients with AIS who underwent corrective fusion surgery one year postoperatively. The internal consistency of the responses was evaluated using the Cronbach α coefficient. Additionally, the Spearman correlation analyses were conducted to assess the correlation between the scores obtained from the SRS-30 Japanese version and SRS-22r and the Oswestry Disability Index (ODI) for the overall scale and the five domains. Results: A total of 81 cases (eight males and 73 females; mean age at surgery 14.4 years) were enrolled. The mean preoperative Cobb angle was 51.0°. The Cronbach α coefficient for the overall SRS-30 was 0.861, indicating high internal consistency, while the coefficients for each domain were as follows: function/activity, 0.697; pain, 0.405; self-image/appearance, 0.776; mental health, 0.845; and satisfaction, 0.559. The SRS-30 total score significantly correlated with the SRS-22r total (r=0.945, P<0.001) and the ODI (r=-0.511, P<0.001). The SRS-30 domains highly correlated with the corresponding SRS-22r domains, with correlations ranging from r=0.826 to 0.901 (all P<0.001). Conclusions: The Japanese version of the SRS-30 demonstrated good internal and external validity. The SRS-30 can be used as an assessment tool for health-related quality of life in AIS patients.

Decrease in pelvic incidence after adult spinal deformity surgery is a predictive factor for progression of hip joint osteoarthritis.

BACKGROUND: This study aimed to evaluate the association between spinopelvic alignment parameters and hip osteoarthritis progression after spinal alignment correction surgery for adult spinal deformity, focusing on the preoperative to postoperative change in spinopelvic alignment. METHODS: This retrospective study enrolled 100 adult spinal deformity patients (196 hip joints) who underwent spinal fusion surgery, after excluding four joints with previous total hip arthroplasty. Acetabular roof obliquity (ARO), center edge angle (CE) and Kellgren and Lawrence (KL) grade were measured in the hip joint. Spinopelvic alignment parameters were measured preoperatively and 1-month postoperatively and the changes (Δ) during this period were calculated. Patients were followed-up for ≥ 5 years and factors associated with KL grade progression at 5-years postoperatively were determined by logistic regression analysis. RESULTS: In the analysis with all cases, KL grade progressed in 23 joints. Logistic regression analysis revealed age (OR: 1.098, 95% CI: 1.007-1.198, p = 0.019), ARO (OR: 1.176, 95% CI: 1.01-1.37, p = 0.026), and Δ PI (OR: 0.791, 95% CI: 0.688-0.997, p < 0.001) as parameters significantly associated with KL grade progression. On the other hand, in the analysis limited to 185 cases with 1-month postoperative KL grade of 0, KL grade progressed in 13 joints. Logistic regression analysis revealed PI-LL (OR: 1.058, 95% CI: 1.001-1.117, p = 0.04), ΔPI (OR: 0.785, 95% CI: 0.649-0.951, p < 0.001), and ΔCobb (OR: 1.127, 95% CI: 1.012-1.253, p = 0.009) as parameters significantly associated with progression. CONCLUSIONS: Both the overall and limited analyzes of this study identified preoperative to postoperative change in PI as parameters affecting the hip osteoarthritis progression after spinal fusion surgery. Decrease in PI might represent preexisting sacroiliac joint laxity. Patients with this risk factor should be carefully followed for possible hip osteoarthritis progression.

Histology and chronological magnetic resonance images of congenital spinal deformity: An experimental study in mice model.

BACKGROUND: The natural history of the congenital spinal deformity and its clinical magnitude vary widely in human species. However, we previously reported that the spinal deformities of congenital scoliosis mice did not progress throughout our observational period according to soft X-ray and MRI data. In this study, congenital vertebral and intervertebral malformations in mice were assessed via magnetic resonance (MR) and histological images. METHODS: Congenital spinal anomalies were chronologically assessed via soft X-ray and 7 T MR imaging. MR images were compared to the histological images to validate the findings around the malformations. RESULTS: Soft X-ray images showed the gross alignment of the spine and the contour of the malformed vertebrae, with the growth plate and cortical bone visible as higher density lines, but could not be used to distinguish the existence of intervertebral structures. In contrast, MR images could be used to distinguish each structure, including the cortical bone, growth plate, cartilaginous end plate, and nucleus pulposus, by combining the signal changes on T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI). The intervertebral structure adjacent to the malformed vertebrae also exhibited various abnormalities, such as growth plate and cartilaginous end plate irregularities, nucleus pulposus defects, and bone marrow formation. In the chronological observation, the thickness and shape of the malformed structures on T1WI did not change. CONCLUSIONS: Spinal malformations in mice were chronologically observed via 7 T MRI and histology. MR images could be used to distinguish the histological structures of normal and malformed mouse spines. Malformed vertebrae were accompanied by adjacent intervertebral structures that corresponded to the fully segmented structures observed in human congenital scoliosis, but the intervertebral conditions varied. This study suggested the importance of MRI and histological examinations of human congenital scoliosis patients with patterns other than nonsegmenting patterns, which may be used to predict the prognosis of patients with spinal deformities associated with malformed vertebrae.

Anterior fusion surgery with overcorrection in the treatment of adolescent idiopathic scoliosis with Lenke 1 AR curve type: how to achieve overcorrection and its effect on postoperative spinal alignment.

BACKGROUND: The efficacy of anterior fusion with overcorrection in the instrumented vertebra for Lenke 1 AR type curves has been reported, but how to achieve overcorrection and how overcorrection affects spinal alignment are unclear. The purpose of this study was to identify the factors that cause overcorrection, and to investigate how overcorrection affects postoperative spinal alignment in the surgical treatment of Lenke 1 AR type curves. METHODS: Patients who had anterior surgery for a Lenke type 1 or 2 and lumbar modifier AR (L4 vertebral tilt to the right) type scoliosis and minimum 2-year follow-up were included. The radiographic data were measured at preoperative, postoperative 1 month, and final follow-up. The UIV-LIV Cobb angle was determined as the Cobb angle between the upper instrumented vertebra (UIV) and the lower instrumented vertebra (LIV), and a negative number for this angle was considered overcorrection. The screw angle was determined to be the sum of the angle formed by the screw axis and the lower and upper endplates in the LIV and UIV, respectively. The change (Δ) in the parameters from postoperative to final follow-up was calculated. The relationships between the UIV-LIV Cobb angle and other radiographic parameters were evaluated by linear regression analyses. RESULTS: Fourteen patients met the inclusion criteria. Their median age was 15.5 years, and the median follow-up period was 53.6 months. The median UIV-LIV Cobb angle was -1.4° at postoperative 1 month. The median screw angle was 4.7°, and overcorrection was achieved in 11 (79%) cases at postoperative 1 month. The screw angle (r2 = 0.42, p = 0.012) and Δ FDUV-CSVL (the deviation of the first distal uninstrumented vertebra from the central sacral vertical line, r2 = 0.53, p = 0.003) were significantly correlated with the UIV-LIV Cobb angle. CONCLUSIONS: Screw placement in the UIV and LIV not parallel to the endplate, but angled, was an effective method to facilitate overcorrection in the instrumented vertebrae. The results of the present study suggest that overcorrection could bring spontaneous improvement of coronal balance below the instrumented segment during the postoperative period.

Current status and future prospects of the Japanese orthopaedic association national registry (JOANR), Japan's first national registry of orthopaedic surgery.

The Japanese Orthopaedic Association National Registry (JOANR) is Japan's first national registry of orthopaedic surgery, which has been developed after having been selected for the Project for Developing a Database of Clinical Outcome approved by the Health Policy Bureau of the Ministry of Health, Labour and Welfare. Its architecture has two levels of registration, one being the basic items of surgical procedure, disease, information on surgeons, surgery-related information, and outcome, and the other being detailed items in the affiliated registries of partner medical associations. It has a number of features, including the facts that, because it handles medical data, which constitute special care-required personal information, data processing is conducted entirely in a cloud environment with the imposition of high-level data security measures; registration of the implant data required to assess implant performance has been automated via a bar code reader app; and the system structure enables flexible collaboration with the registries of partner associations. JOANR registration is a requirement for accreditation as a core institution or partner institution under the board certification system, and the total number of cases registered during the first year of operation (2020) was 899,421 registered by 2,247 institutions, providing real-world evidence concerning orthopaedic surgery.

Thoracic kyphosis in light of lumbosacral alignment in thoracic adolescent idiopathic scoliosis: recognition of thoracic hypokyphosis and therapeutic implications.

BACKGROUND: The uniqueness of spinal sagittal alignment in thoracic adolescent idiopathic scoliosis (AIS), for example, the drastically smaller thoracic kyphosis seen in some patients, has been recognized but not yet fully understood. The purpose of this study was to clarify the characteristics of sagittal alignment of thoracic AIS and to determine the contributing factors. METHODS: Whole spine radiographs of 83 thoracic AIS patients (73 females) were analyzed. The measured radiographic parameters were the Cobb angle of thoracic scoliosis, thoracic kyphosis (TK), lumbar lordosis (LL), C7 sagittal vertical axis (C7 SVA), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Additionally, max-LL, which was defined as the maximum lordosis angle from the S1 endplate, the inflection point between thoracic kyphosis and lumbar lordosis, and the SVA of the inflection point (IP SVA) were measured. The factors significantly related to a decrease in TK were assessed by stepwise logistic regression analysis. In addition, cluster analysis was performed to classify the global sagittal alignment. RESULTS: The significant factors for a decrease in TK were an increase in SS (p = 0.0003, [OR]: 1.16) and a decrease in max-LL (p = 0.0005, [OR]: 0.89). According to the cluster analysis, the global sagittal alignment was categorized into the following three types: Type 1 (low SS, low max-LL, n = 28); Type 2 (high SS, low max-LL, n = 22); and Type 3 (high SS, high max-LL, n = 33). CONCLUSIONS: In thoracic AIS, a decreased TK corresponded to an increased SS or a decreased max-LL. The sagittal alignment of thoracic AIS patients could be classified into three types based on SS and max-LL. One of these three types includes the unique sagittal profile of very small TK.

Anterior instrumentation surgery for the treatment of Lenke type 1AR curve patterns.

OBJECTIVE: Previous studies have demonstrated that Lenke lumbar modifier A contains 2 distinct types (AR and AL), and the AR curve pattern is likely to develop adding-on (i.e., a progressive increase in the number of vertebrae included within the primary curve distally after posterior surgery). However, the results of anterior surgery are unknown. The purpose of this study was to present the surgical results in a cohort of patients undergoing scoliosis treatment for type 1AR curves and to compare anterior and posterior surgeries to consider the ideal indications and advantages of anterior surgery for type 1AR curves. METHODS: Patients with a Lenke type 1 or 2 and lumbar modifier AR (L4 vertebral tilt to the right) and a minimum 2-year postoperative follow-up were included. The incidence of adding-on and radiographic data were compared between the anterior and posterior surgery groups. The numbers of levels between the end, stable, neutral, and last touching vertebra to the lower instrumented vertebra (LIV) were also evaluated. RESULTS: Forty-four patients with a mean follow-up of 57 months were included. There were 14 patients in the anterior group and 30 patients in the posterior group. The main thoracic Cobb angle was not significantly different between the groups preoperatively and at final follow-up. At final follow-up, the anterior group had significantly less tilting of the LIV than the posterior group (-0.8° ± 4.5° vs 3° ± 4°). Distal adding-on was observed in no patient in the anterior group and in 6 patients in the posterior group at final follow-up (p = 0.025). In the anterior group, no LIV was set below the end vertebra, and all LIVs were set above last touching vertebra. The LIV was significantly more proximal in the anterior group than in the posterior surgery patients without adding-on for all reference vertebrae (p < 0.001). CONCLUSIONS: This is the first study to investigate the surgical results of anterior surgery for Lenke type 1AR curve patterns, and it showed that anterior surgery for the curves could minimize the distal extent of the instrumented fusion without adding-on. This would leave more mobile disc space below the fusion.

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

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.

The Development of a Nationwide, Multicenter Electronic Database for Spinal Instrumentation Surgery in Japan: Japanese Spinal Instrumentation Society Database (JSIS-DB).

(1) Background: Despite the number of complicated and expensive spine surgery procedures maintained by the national health insurance system in Japan, until now there has been no large-scale multicenter clinical database for this field to understand and improve healthcare expenditure and treatment outcomes. The purpose of this report is to announce the establishment and methodology of a nationwide registry system for spinal instrumentation surgeries by the Japanese Spinal Instrumentation Society (JSIS), and to report the progress over the first 1.5 years of this database's operation. (2) Methods: The JSIS recently produced an online database with an electronic server. The collected information included patient background, surgery information, and early complications of primary and revision cases. Analysis included data from February 2018, when registration began, to August 2019. (3) Results: As of August 2019, 73 facilities have completed the required paperwork to start, and 55 facilities have registered cases. Of the total 5456 registered cases, 4852 were valid and 2511 were completed. (4) Conclusions: JSIS-DB, the nationwide web-based registry system for spinal instrumentation surgery in Japan, was launched for the purpose of research, healthcare policy regulation, and improved patient care, and its methodology and progress in the first 1.5 years are reported in this study.

Can we use shorter constructs while maintaining satisfactory sagittal plane alignment for adult spinal deformity?

OBJECTIVE: Issues with spinopelvic fixation for adult spinal deformity (ASD) include loss of the physiological mobility of the entire lumbar spine, perioperative complications, and medical costs. Little is known about the factors associated with successful short fusion for ASD. The authors evaluated radiographic and clinical outcomes after shorter fusion for different subtypes of ASD at 2 years postoperatively and examined factors associated with successful short fusion. METHODS: This was a single-center study of 37 patients who underwent short fusion and a minimum 2 years of follow-up for ASD in which lumbar kyphosis was the main deformity. The exclusion criteria were 1) age < 40 years, 2) previous lumbar vertebral fracture, 3) severe osteoporosis, 4) T10-L2 kyphosis > 20°, 5) scoliotic deformity with an upper end vertebra (UEV) above T12, and 6) concomitant Parkinson's disease or neurological disease. The surgical procedures, radiographic course, and Oswestry Disability Index (ODI) were assessed, and correlations between radiographic parameters and postoperative ODI at 2 years were analyzed. RESULTS: A mean of 3.5 levels were fused. The mean radiographic parameters preoperatively, at 2 weeks, and at 2 years, respectively, were as follows: coronal Cobb angle: 22.9°, 11.5°, and 12.6°; lumbar lordosis (LL): 12.9°, 35.8°, and 32.2°; pelvic incidence (PI) minus LL: 35.5°, 14.7°, and 19.2°; pelvic tilt: 29.4°, 23.1°, and 25.0°; and sagittal vertical axis 85.3, 36.7, and 59.2 mm. Abnormal proximal junctional kyphosis occurred in 8 cases. Revision surgery was performed to extend the length of fusion from a lower thoracic vertebra to the pelvis in 2 cases. The mean ODI scores preoperatively and at 2 years were 50.7% and 24.1%, respectively. Patient age, number of fused intervertebral segments, and radiographic parameters were analyzed by the stepwise method to identify factors contributing to the ODI score at 2 years, preoperative PI, and sagittal vertical axis at 2 years. On receiver operating characteristic curve analysis of the minimal clinically important difference of ODI (15%) and preoperative PI, the cutoff value of the preoperative PI was 47° (area under the curve 0.75). CONCLUSIONS: In terms of subtypes of ASD in which lumbar kyphosis is the main deformity, if the PI is < 47°, then the use of short fusion preserving mobile intervertebral segments can produce adequate LL for the PI, improving both postoperative global spinal alignment and quality of life.

Growing rod technique with prior foundation surgery and sublaminar taping for early-onset scoliosis.

OBJECTIVE: The aim of this study was to show the surgical results of growing rod (GR) surgery with prior foundation surgery (PFS) and sublaminar taping at an apex vertebra. METHODS: Twenty-two early-onset scoliosis (EOS) patients underwent dual GR surgery with PFS and sublaminar taping. PFS was performed prior to rod placement, including exposure of distal and proximal anchor areas and anchor instrumentation filled with a local bone graft. After a period of 3-5 months for the anchors to become solid, dual rods were placed for distraction. The apex vertebra was exposed and fastened to the concave side of the rods using sublaminar tape. Preoperative, post-GR placement, and final follow-up radiographic parameters were measured. Complications during the treatment period were evaluated using the patients' clinical records. RESULTS: The median age at the initial surgery was 55.5 months (range 28-99 months), and the median follow-up duration was 69.5 months (range 25-98 months). The median scoliotic curves were 81.5° (range 39°-126°) preoperatively, 30.5° (range 11°-71°) after GR placement, and 33.5° (range 12°-87°) at the final follow-up. The median thoracic kyphotic curves were 45.5° (range 7°-136°) preoperatively, 32.5° (range 15°-99°) after GR placement, and 42° (range 11°-93°) at the final follow-up. The median T1-S1 lengths were 240.5 mm (range 188-305 mm) preoperatively, 286.5 mm (range 232-340 mm) after GR placement, and 337.5 mm (range 206-423 mm) at the final follow-up. Complications occurred in 6 patients (27%). Three patients had implant-related complications, 2 patients had alignment-related complications, and 1 patient had a wound-related complication. CONCLUSIONS: A dual GR technique with PFS and sublaminar taping showed effective correction of scoliotic curves and a lower complication rate than previous reports when a conventional dual GR technique was used.

Can we stop the long fusion at L5 for selected adult spinal deformity patients with less severe disability and less complex deformity?

OBJECTIVES: It is controversial whether to stop the fusion at L5 or S1 in adult spinal deformity (ASD) surgery. Our hypothesis is that we can stop long fusion at L5 for selected patients with less severe disability and less complex deformity. Aim was to compare minimum 5-year outcomes between ASD patients with fusion to L5 versus S1. PATIENTS AND METHODS: Consecutive 40 patients (≥50 years of age) with ASD underwent spinal fusion from lower thoracic spine to L5 or S1 between 2008 and 2011. 33 patients (82.5 %) had a minimum 5-year follow-up. Lower instrumented vertebra (LIV) was L5 in 12 patients (L5 group) and S1 in 21 (S1 group). Clinical and radiographical parameters were compared between L5 and S1 group. RESULTS: There were statistically significant differences between two groups (L5 vs S1) in %male (50 % vs 14 %), %type-N of SRS-Schwab classification (83 % vs 38 %), preop ODI (40.5 vs 56), correction loss of LL (11˚ vs 3˚), final TK (32˚ vs 50˚), correction loss of TK (-1˚ vs 17˚), final improvement of PT (3˚ vs 10˚), final improvement of PI-LL (26˚ vs 39˚), PJK (8% vs 48 %), and revision surgery rate (50 % vs 14 %). Causes of revision surgery in L5 group were distal junctional failure in 5 patients and foraminal stenosis at L5-S1 in 1. All of them underwent additional spinal fusion to the sacrum. Whereas, causes of revision surgery in S1 group were rod fracture in 2 patients and proximal junctional failure in 1. CONCLUSION: Although fusion to L5 was conducted for selected ASD patients with less severe disability (better ODI) and less complex deformity (type N), 50 % of the patients required additional fusion to the pelvis. Decision making to stop the long fusion at L5 for ASD patients ≥50 years of age should be made with careful considerations.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

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/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 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.

Postoperative Status of Global Sagittal Alignment With Compensation in Adult Spinal Deformity.

STUDY DESIGN: A retrospective study of consecutive patients undergoing surgery for adult spinal deformity (ASD). OBJECTIVE: The aim of this study was to classify postoperative ASD patients by sagittal compensation and characterize the features of each group. SUMMARY OF BACKGROUND DATA: Sagittal compensatory mechanisms to keep the erect position would function in not only nonoperative ASD patients but also in postoperative patients. However, details of sagittal compensatory mechanisms after surgery have been unclear, because the majority of previous studies examined the compensatory mechanisms in nonoperative patients. METHODS: A total of 73 postoperative ASD patients were recruited. Spinopelvic parameters and Oswestry Disability Index (ODI) were measured before surgery, at 1-month and 2-year follow-up. The changes in parameters (Δ) between postoperative 1-month and 2-year were also evaluated. Cluster analysis based on pelvic tilt (PT) and sagittal vertical axis (SVA) at 2-year follow-up was performed, and then the parameters were compared among clusters. RESULTS: Cluster analysis identified three clusters: the physiological group (n = 38, PT = 19.6°, SVA = 17.2 mm), the compensated group (n = 23, PT = 34.3°, SVA = 45.6 mm), and the decompensated group (n = 12, PT = 36.6°, SVA = 118.8 mm). Comparisons of the parameters among the groups showed that the physiological group had smaller pelvic incidence minus lumbar lordosis (PI-LL) and better ODI. The compensated group had significantly larger Δ thoracic kyphosis (TK), Δ proximal junctional angle (PJA), and ΔPT than the physiological group. The decompensated group had significantly higher PI and higher age. CONCLUSION: Three groups were defined in terms of postoperative compensatory mechanisms. Patients in the physiological group had little postoperative alignment change and good ODI value. The compensated group had pelvic retroversion to keep SVA in the physiological range, but the compensation in the thoracic spine was unlikely to work. High PI and advanced age were characteristics of the decompensated group. LEVEL OF EVIDENCE: 4.

Current Trends in the Use of Patient-Reported Outcome Instruments in Degenerative Cervical Spine Surgery.

Study Design Bibliometric analysis. Objective To determine trends, frequency, and distribution of patient-reported outcome instruments (PROIs) in degenerative cervical spine surgery literature over the past decade. Methods A search was conducted via PubMed from 2004 to 2013 on five journals (The Journal of Bone and Joint Surgery, The Bone and Joint Journal, The Spine Journal, European Spine Journal, and Spine), which were chosen based on their impact factors and authors' consensus. All abstracts were screened and articles addressing degenerative cervical spine surgery using PROIs were included. Articles were then analyzed for publication date, study design, journal, level of evidence, and PROI trends. Prevalence of PROIs and level of evidence of included articles were analyzed. Results From 19,736 articles published, 241 articles fulfilled our study criteria. Overall, 53 distinct PROIs appeared. The top seven most frequently used PROIs were: Japanese Orthopaedic Association score (104 studies), visual analog scale for pain (100), Neck Disability Index (72), Short Form-36 (38), Nurick score (25), Odom criteria (21), and Oswestry Disability Index (15). Only 11 PROIs were used in 5 or more articles. Thirty-three of the PROIs were appeared in only 1 article. Among the included articles, 16% were of level 1 evidence and 32% were of level 4 evidence. Conclusion Numerous PROIs are currently used in degenerative cervical spine surgery. A consensus on which instruments to use for a given diagnosis or procedure is lacking and may be necessary for better communication and comparison, as well as for the accumulation and analysis of vast clinical data across multiple studies.

Iatrogenic contributions to cervical adjacent segment pathology: review article.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is widely accepted as a predictably excellent procedure. On the other hand, adjacent level pathology following ACDF is a well-known phenomenon which undercuts surgical outcome. However, the extent to which ACDF accelerates this phenomenon in the naturally degenerating cervical spine is still to be understood. QUESTIONS/PURPOSES: To summarize the current evidence concerning adjacent segment pathology in the light of biomechanics, natural history, postoperative course, and comparison between ACDF and total disc replacement (TDR). METHODS: This is a study of published articles. Articles were searched by the topic of adjacent disc pathology in cervical spine through Google Scholar and Pubmed. After review, 37 published articles were deemed suitable for the subject of this study. RESULTS: Biomechanical and clinical data strongly suggest that ASP is a presentation of the iatrogenically accelerated natural aging process of cervical spine. However, power study analysis with assumption showed that current RCTs are unlikely to prove this suggestion. CONCLUSION: Available data suggests that iatrogenic factors play a significant role in adjacent segment pathology following ACDF.

Vertebral body Hounsfield units as a predictor of incidental durotomy in primary lumbar spinal surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To assess the association between vertebral body Hounsfield unit (HU) measurements on quantitative computed tomography and the risk for incidental durotomy (ID). SUMMARY OF BACKGROUND DATA: ID during spine surgery has been associated with adverse postoperative sequelae that may require prolonged hospital stay and reoperation. Previously identified independent risk factors include age, revision surgery, and lumbar surgery. METHODS: ID was prospectively documented in spine surgery patients at a single institution during a 2-year period (incidence: 4%, 191/4,822). Patients with ID were matched 1:1 to a control cohort without ID based on age and sex. Inclusion criteria for both cohorts were primary lumbar surgery and quantitative computed tomographic scans within 1 year of date of surgery. Demographic, radiographical, and intraoperative data, along with dual x-ray absorptiometry t scores, were collected and analyzed. RESULTS: A total of 71 patients with ID met the inclusion criteria (38 male, 33 female). Average age of patients with ID was 63.8 ± 12.9 years (range: 34-85 yr). Computed tomographic scans were acquired 1.5 ± 2.2 months away from date of surgery (range: 0-12 mo). Inter-rater reliability for HU measurements between a fellowship-trained spine surgeon and a research fellow was strong (r = 0.901, P < 0.001). HU values were significantly lower in patients with ID than controls (149.2 ± 60.7 [range: 44.5-301.5] versus 177.0 ± 81.4, [range: 62.0-524.0], respectively; P = 0.023). The area under the receiver operating characteristic curve was 0.603 (P = 0.034). A threshold of 169 HU optimized sensitivity (0.718) and specificity (0.451), and patients with HU value 169 or less were found to be at increased risk for ID (odds ratio: 2.092, 95% confidence interval: 1.042-4.201, P = 0.037). CONCLUSION: Lower HU value is an accessible clinical marker for increased risk of ID. A threshold value of HU was defined (≤169) that may be used clinically to identify patients at elevated risk for ID, which may improve the informed decision making process prior to spinal surgery. LEVEL OF EVIDENCE: 3.

Multicenter prospective nonrandomized controlled clinical trial to prove neurotherapeutic effects of granulocyte colony-stimulating factor for acute spinal cord injury: analyses of follow-up cases after at least 1 year.

STUDY DESIGN: An open-labeled multicenter prospective nonrandomized controlled clinical trial. OBJECTIVE: To confirm the feasibility of using granulocyte colony-stimulating factor (G-CSF) for treatment of acute spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: We previously reported that G-CSF promotes functional recovery after compression-induced SCI in mice. On the basis of these findings, we conducted a multicenter prospective controlled clinical trial to assess the feasibility of G-CSF therapy for patients with acute SCI. METHODS: The trial ran from August 2009 to March 2011, and included 41 patients with SCI treated within 48 hours of onset. Informed consent was obtained from all patients. After providing consent, patients were divided into 2 groups. In the G-CSF group (17 patients), G-CSF (10 µg/kg/d) was intravenously administered for 5 consecutive days, and in the control group (24 patients), patients were similarly treated except for the G-CSF administration. We evaluated motor and sensory functions using the American Spinal Cord Injury Association score and American Spinal Cord Injury Association impairment scale at 1 week, 3 months, 6 months, and 1 year after onset. RESULTS: Only 2 patients did not experience American Spinal Cord Injury Association impairment scale improvement in the G-CSF group. In contrast, 15 patients in the control group did not experience American Spinal Cord Injury Association impairment scale improvement. In the analysis of increased American Spinal Cord Injury Association motor score, a significant increase in G-CSF group was detected from 1 week after the administration compared with the control group. After that, some spontaneous increase of motor score was detected in control group, but the significant increase in G-CSF group was maintained until 1 year of follow-up. CONCLUSION: Despite the limitation that patient selection was not randomized, the present results suggest the possibility that G-CSF administration has beneficial effects on neurological recovery in patients with acute SCI. LEVEL OF EVIDENCE: 3.

Phase-II conjugation ability for PAH metabolism in amphibians: characteristics and inter-species differences.

The present study examines amphibian metabolic activity - particularly conjugation - by analysis of pyrene (a four ring, polycyclic aromatic hydrocarbon) metabolites using high-performance liquid chromatography (HPLC) with fluorescence detector (FD), a mass spectrometry detector (MS) system and kinetic analysis of conjugation enzymes. Six amphibian species were exposed to pyrene (dissolved in water): African claw frog (Xenopus laevis); Tago's brown frog (Rana tagoi); Montane brown frog (Rana ornativentris); Wrinkled frog (Rana rugosa); Japanese newt (Cynops pyrrhogaster); and Clouded salamander (Hynobius nebulosus); plus one fish species, medaka (Oryzias latipes); and a fresh water snail (Clithon retropictus), and the resultant metabolites were collected. Identification of pyrene metabolites by HPLC and ion-trap MS system indicated that medaka mainly excreted pyrene-1-glucuronide (PYOG), while pyrene-1-sulfate (PYOS) was the main metabolite in all amphibian species. Pyrene metabolites in amphibians were different from those in invertebrate fresh water snails. Inter-species differences were also observed in pyrene metabolism among amphibians. Metabolite analysis showed that frogs relied more strongly on sulfate conjugation than did Japanese newts and clouded salamanders. Furthermore, urodelan amphibians, newts and salamanders, excreted glucose conjugates of pyrene that were not detected in the anuran amphibians. Kinetic analysis of conjugation by hepatic microsomes and cytosols indicated that differences in excreted metabolites reflected differences in enzymatic activities. Furthermore, pyrenediol (PYDOH) glucoside sulfate was detected in the Japanese newt sample. This novel metabolite has not been reported previously to this report, in which we have identified unique characteristics of amphibians in phase II pyrene metabolism.