Development of a novel animal model of lumbar vertebral endplate lesion by intervertebral disk injection of monosodium iodoacetate in rats.

PURPOSE: Vertebral endplate lesions (EPLs) caused by severe disk degeneration are associated with low back pain. However, its pathophysiology remains unclear. In this study, we aimed to develop a vertebral EPL rat model mimicking severe intervertebral disk (IVD) degeneration by injecting monosodium iodoacetate (MIA) into the IVDs and evaluating it by assessing pain-related behavior, micro-computed tomography (CT) findings, and histological changes. METHODS: MIA was injected into the L4-5 and L5-6 IVDs of Sprague-Dawley rats. Their behavior was examined by measuring the total distance traveled and the total number of rearing in an open square arena. Bone alterations and volume around the vertebral endplate were assessed using micro-CT. Safranin-O staining, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining were performed for histological assessment. RESULTS: The total distance and number of rearing times in the open field were significantly reduced in a time-dependent manner. Micro-CT revealed intervertebral osteophytes and irregularities in the endplates at 12 weeks. The bone volume/tissue volume (BV/TV) around the endplates significantly increased from 6 weeks onward. Safranin-O staining revealed severe degeneration of IVDs and endplate disorders in a dose- and time-dependent manner. Calcitonin gene-related peptide-positive nerve fibers significantly increased from 6 weeks onward. However, the number of osteoclasts decreased over time. CONCLUSION: Our rat EPL model showed progressive morphological vertebral endplate changes in a time- and concentration-dependent manner, similar to the degenerative changes in human IVDs. This model can be used as an animal model of severe IVD degeneration to better understand the pathophysiology of EPL.

Impact of surgical treatment on patient reported outcome in patients with spinal metastases from prostate cancer.

OBJECTIVE: This study aimed to elucidate postoperative outcomes in patients with spinal metastases of prostate cancer, with a focus on patient-oriented assessments. METHODS: This was a prospective multicenter registry study involving 35 centers. A total of 413 patients enrolled in the Japanese Association for Spine Surgery and Oncology Multicenter Prospective Study of Surgery for Metastatic Spinal Tumors were evaluated for inclusion. The eligible patients were followed for at least 1 year after surgery. The Frankel Classification, Eastern Cooperative Oncology Group Performance Status, visual analog scale for pain, face scale, Barthel Index, vitality index, indications for oral pain medication, and the EQ-5D-5L questionnaire were used for evaluating functional status, activities of daily living, and patient motivation. RESULTS: Of the 413 eligible patients, 41 with primary prostate cancer were included in the study. The patient-oriented assessments indicated that the patients experienced postoperative improvements in quality of life and motivation in most items, with the improvements extending for up to 6 months. More than half of the patients with Frankel classifications B or C showed improved neurological function at 1 month after surgery, and most patients presented maintained or improved their classification at 6 months. CONCLUSION: Surgical intervention for spinal metastases of prostate cancer significantly improved neurological function, quality of life, and motivation of the patients. Consequently, our results support the validity of surgical intervention for improving the neurological function and overall well-being of patients with spinal metastases of prostate cancer.

Evaluation of Epiconus and Conus Medullaris Disorders due to Thoracolumbar Vertebral Fracture using Motor Evoked Potentials.

STUDY DESIGN: A retrospective case-control study. OBJECTIVE: To characterize the motor evoked potential (MEP) when the epiconus or conus medullaris is compressed by a fracture of the T12 or L1 vertebra. SUMMARY OF BACKGROUND DATA: Although the characteristics of compressive cervical and thoracic myelopathy with transcranial magnetic stimulation MEP have been reported, the MEP parameters in compressive disorders of the epiconus and conus medullaris have not yet been characterized. METHODS: Twenty patients with T12 or L1 vertebral fractures who had lower extremity symptoms due to compression of the epiconus or conus medullaris were included. These patients were compared with 28 healthy controls and 32 patients with cervical spondylotic radiculopathy (CSR) without spinal cord compression. MEPs of abductor hallucis muscles were recorded using transcranial magnetic stimulation and electrical stimulation of the tibial nerve. MEP latency, central motor conduction time (CMCT), and peripheral conduction time (PCT) were evaluated. RESULTS: MEP latency, CMCT, and PCT were significantly longer in patients with fractures than in healthy controls and patients with CSR. MEP latency was most accurate for differentiating patients with fracture from healthy controls (cutoff value, 40.0 ms, sensitivity, 95.0%; specificity, 100%), and CMCT was most accurate for comparing patients with fracture and CSR (cutoff value, 15.5 ms, sensitivity, 80.0%; specificity, 93.8%). In the distinction between patients with fracture and CSR, 16 of the 20 patients with fracture exceeded the cutoff values for any of the parameters, and 12 of them exceeded the cutoff values for all parameters. There was no significant correlation between the linear distance from the most inferior end of the spinal cord to the site of compression and any of the MEP parameters. CONCLUSION: Both CMCT and PCT are often prolonged in compressive lesions of the epiconus and conus medullaris, and MEP latency and CMCT are useful in the diagnosis.

Differentiation of the Intradural Extramedullary Spinal Tumors, Schwannomas, and Meningiomas Utilizing the Contrast Ratio as a Quantitative Magnetic Resonance Imaging Method.

BACKGROUND: Schwannomas and meningiomas are the most common intradural extramedullary spinal tumors; however, differentiating between them using magnetic resonance imaging (MRI) is a frequent challenge. In this study, we aimed to investigate the use of the contrast ratio (CR) as a quantitative MRI method in the differentiation of schwannomas and meningiomas. METHODS: We analyzed the data of patients with intradural extramedullary spinal tumors who underwent surgery and were diagnosed with either schwannomas or meningiomas by histopathological analysis. Regions of interest were set for the entire spinal tumor on T2-weighted sagittal MRI. To obtain the CR values of spinal tumors (CRtumor), we used the signal intensity (SI) values of the tumor (SItumor) and spinal cord (SIcord) according to the following formula: [CRtumor = (SItumor-SIcord)/(SItumor+SIcord)]. RESULTS: The study included 50 patients (23 males and 27 females) with a mean age of 61.5 years old (11-85 years old). Histopathological analysis revealed that 33 and 17 patients were diagnosed with schwannomas and meningiomas, respectively. The mean CR values of the schwannomas and meningiomas were 0.3040 ± 0.1386 and 0.0173 ± 0.1929, respectively. The CR value of the schwannomas was statistically significantly higher than that of meningiomas (P < 0.01). The cutoff CR value obtained from the receiver operating characteristic curve was 0.143, with a specificity and sensitivity of 90.9% and 88.2%, respectively. Furthermore, the value for the area under the receiver operating characteristic curve was 0.925 (95% confidence interval: 0.852-0.998). CONCLUSIONS: The evaluation of CRs by using MRI to distinguish between schwannomas and meningiomas is a beneficial quantitative tool.

Myelin-Specific microRNA-23a/b Cluster Deletion Inhibits Myelination in the Central Nervous System during Postnatal Growth and Aging.

Microribonucleic acids (miRNAs) comprising miR-23a/b clusters, specifically miR-23a and miR-27a, are recognized for their divergent roles in myelination within the central nervous system. However, cluster-specific miRNA functions remain controversial as miRNAs within the same cluster have been suggested to function complementarily. This study aims to clarify the role of miR-23a/b clusters in myelination using mice with a miR-23a/b cluster deletion (KO mice), specifically in myelin expressing proteolipid protein (PLP). Inducible conditional KO mice were generated by crossing miR-23a/b clusterflox/flox mice with PlpCre-ERT2 mice; the offspring were injected with tamoxifen at 10 days or 10 weeks of age to induce a myelin-specific miR-23a/b cluster deletion. Evaluation was performed at 10 weeks or 12 months of age and compared with control mice that were not treated with tamoxifen. KO mice exhibit impaired motor function and hypoplastic myelin sheaths in the brain and spinal cord at 10 weeks and 12 months of age. Simultaneously, significant decreases in myelin basic protein (MBP) and PLP expression occur in KO mice. The percentages of oligodendrocyte precursors and mature oligodendrocytes are consistent between the KO and control mice. However, the proportion of oligodendrocytes expressing MBP is significantly lower in KO mice. Moreover, changes in protein expression occur in KO mice, with increased leucine zipper-like transcriptional regulator 1 expression, decreased R-RAS expression, and decreased phosphorylation of extracellular signal-regulated kinases. These findings highlight the significant influence of miR-23a/b clusters on myelination during postnatal growth and aging.

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 .

Prospective Registration Study for Establishing Minimal Clinically Important Differences in Patients Undergoing Surgery for Spinal Metastases.

STUDY DESIGN: Multicenter, prospective registry study. OBJECTIVE: To clarify minimal clinically important differences (MCIDs) for surgical interventions for spinal metastases, thereby enhancing patient care by integrating quality of life (QoL) assessments with clinical outcomes. SUMMARY OF BACKGROUND DATA: Despite its proven usefulness in degenerative spinal diseases and deformities, the MCID remains unexplored regarding surgery for spinal metastases. METHODS: This study included 171 (out of 413) patients from the multicenter "Prospective Registration Study on Surgery for Metastatic Spinal Tumors" by the Japan Association of Spine Surgeons. These were evaluated preoperatively and at 6 months postoperatively using the Face scale, EuroQol-5 Dimensions-5 Levels (EQ-5D-5L), including the visual analog scale (VAS), and performance status. The MCIDs were calculated using an anchor-based method, classifying participants into the improved, unchanged, and deteriorated groups based on the Face scale scores. Focusing on the improved and unchanged groups, the change in the EQ-5D-5L values from before to after treatment was analyzed, and the cutoff value with the highest sensitivity and specificity was determined as the MCID through receiver operating characteristic curve analysis. The validity of the MCIDs was evaluated using a distribution-based calculation method for patient-reported outcomes. RESULTS: The improved, unchanged, and deteriorated groups comprised 121, 28, and 22 participants, respectively. The anchor-based MCIDs for the EQ-5D-5L index, EQ-VAS, and domains of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were 0.21, 15.50, 1.50, 0.50, 0.50, 0.50, and 0.50, respectively; the corresponding distribution-based MCIDs were 0.17, 15,99, 0.77, 0.80, 0.78, 0.60, and 0.70, respectively. CONCLUSION: We identified MCIDs for surgical treatment of spinal metastases, providing benchmarks for future clinical research. By retrospectively examining whether the MCIDs are achieved, factors favoring their achievement and risks affecting them can be explored. This could aid in decisions on surgical candidacy and patient counseling.