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武岡 由樹大学院医学研究科 医科学専攻助教
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■ 論文- OBJECTIVE: To elucidate the patient characteristics and outcomes of emergency surgery for spinal metastases and identify risk factors for emergency surgery. METHODS: We prospectively analyzed 216 patients with spinal metastases who underwent palliative surgery from 2015 to 2020. The Eastern Cooperative Oncology Group performance status, Barthel index, EuroQol-5 dimension (EQ5D), and neurological function were assessed at surgery and at 1, 3, and 6 months postoperatively. Multivariate analysis was performed to identify risk factors for emergency surgery. RESULTS: In total, 146 patients underwent nonemergency surgery and 70 patients underwent emergency surgery within 48 hours of diagnosis of a surgical indication. After propensity score matching, we compared 61 patients each who underwent nonemergency and emergency surgery. Regardless of matching, the median performance status and the mean Barthel index and EQ5D score showed a tendency toward worse outcomes in the emergency than nonemergency group both preoperatively and 1 month postoperatively, although the surgery greatly improved these values in both groups. The median survival time tended to be shorter in the emergency than nonemergency group. The multivariate analysis showed that lesions located at T3-10 (p = 0.002; odds ratio [OR], 2.92; 95% confidence interval [CI], 1.48-5.75) and Frankel grades A-C (p < 0.001; OR, 4.91; 95% CI, 2.45-9.86) were independent risk factors for emergency surgery. CONCLUSION: Among patients with spinal metastases, preoperative and postoperative subjective health values and postoperative survival are poorer in emergency than nonemergency surgery. Close attention to patients with T3-10 metastases is required to avoid poor outcomes after emergency surgery.2024年03月, Neurospine, 21(1) (1), 314 - 327, 英語, 国際誌研究論文（学術雑誌）
- Background and Objectives: Bone metastasis cancer boards (BMCBs) focusing on the management of bone metastases have been gathering much attention. However, the association of BMCBs with spinal surgery in patients with spinal metastases remains unclear. In this retrospective single-center observational study, we aimed to clarify the effect of a BMCB on spinal metastasis treatment. Materials and Methods: We reviewed consecutive cases of posterior decompression and/or instrumentation surgery for metastatic spinal tumors from 2008 to 2019. The BMCB involved a team of specialists in orthopedics, rehabilitation medicine, radiation oncology, radiology, palliative supportive care, oncology, and hematology. We compared demographics, eastern cooperative oncology group performance status (ECOGPS), Barthel index (BI), number of overall versus emergency surgeries, and primary tumors between patients before (2008-2012) and after (2013-2019) BMCB establishment. Results: A total of 226 patients including 33 patients before BMCB started were enrolled; lung cancer was the most common primary tumor. After BMCB establishment, the mean patient age was 5 years older (p = 0.028), the mean operating time was 34 min shorter (p = 0.025), the mean hospital stay was 34.5 days shorter (p < 0.001), and the mean BI before surgery was 12 points higher (p = 0.049) than before. Moreover, the mean number of surgeries per year increased more than fourfold to 27.6 per year (p < 0.01) and emergency surgery rates decreased from 48.5% to 29.0% (p = 0.041). Patients with an unknown primary tumor before surgery decreased from 24.2% to 9.3% (p = 0.033). Postoperative deterioration rates from 1 to 6 months after surgery of ECOGPS and BI after BMCB started were lower than before (p = 0.045 and p = 0.027, respectively). Conclusion: The BMCB decreased the emergency surgery and unknown primary tumor rate despite an increase in the overall number of spinal surgeries. The BMCB also contributed to shorter operation times, shorter hospital stays, and lower postoperative deterioration rates of ECOGPS and BI.2023年11月, Medicina (Kaunas, Lithuania), 59(12) (12), 英語, 国際誌研究論文（学術雑誌）
- (公社)日本リハビリテーション医学会, 2023年10月, The Japanese Journal of Rehabilitation Medicine, 60(秋季特別号) (秋季特別号), S355 - S355, 日本語骨転移患者に対するリハビリテーション治療効果 傾向スコアマッチングを用いた検討
- (一社)日本臨床スポーツ医学会, 2023年10月, 日本臨床スポーツ医学会誌, 31(4) (4), S232 - S232, 日本語
- The number of advanced-age patients with spinal metastases is rising. This study was performed to clarify the characteristics and surgical outcomes of spinal metastases in advanced-age patients. We prospectively analyzed 216 patients with spinal metastases from 2015 to 2020 and divided them into three age groups: <70 years (n = 119), 70-79 years (n = 73), and ≥80 years (n = 24). Although there were no significant intergroup differences in preoperative characteristics and surgery-related factors except for age, patients aged ≥80 years tended to have a worse performance status (PS), Barthel index, and EuroQol-5 dimension (EQ-5D) before and after surgery than the other two groups. Although the median PS, mean Barthel index and mean EQ-5D greatly improved postoperatively in each group, the median PS and mean Barthel index at 6 months and the mean EQ-5D at 1 month postoperatively were significantly poorer in the ≥80-year group than the 70-79-year group. The rates of postoperative complications and re-deterioration of the EQ-5D were significantly higher in the oldest group than in the other two groups. Although surgery for spinal metastases improved the PS, Barthel index, and EQ-5D regardless of age, clinicians should be aware of the poorer outcomes and higher complication rates in advanced-age patients.2023年07月, Journal of clinical medicine, 12(14) (14), 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Degenerative disc disease, a major cause of low back pain and associated neurological symptoms, is a global health problem with the high morbidity, workforce loss, and socioeconomic burden. The present surgical strategy of disc resection and/or spinal fusion results in the functional loss of load, shock absorption, and movement; therefore, the development of new biological therapies is demanded. This achievement requires the understanding of intervertebral disc cell fate during aging and degeneration. METHODS: Literature review was performed to clarify the current concepts and future perspectives of disc cell fate, focused on apoptosis, senescence, and autophagy. RESULTS: The intervertebral disc has a complex structure with the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplates. While the AF arises from the mesenchyme, the NP originates from the notochord. Human disc NP notochordal phenotype disappears in adolescence, accompanied with cell death induction and chondrocyte proliferation. Discs morphologically and biochemically degenerate from early childhood as well, thereby suggesting a possible involvement of cell fate including age-related phenotypic changes in the disease process. As the disc is the largest avascular organ in the body, nutrient deprivation is a suspected contributor to degeneration. During aging and degeneration, disc cells undergo senescence, irreversible growth arrest, producing proinflammatory cytokines and matrix-degradative enzymes. Excessive stress ultimately leads to programmed cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis. Autophagy, the intracellular degradation and recycling system, plays a role in maintaining cell homeostasis. While the incidence of apoptosis and senescence increases with age and degeneration severity, autophagy can be activated earlier, in response to limited nutrition and inflammation, but impaired in aged, degenerated discs. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is a signal integrator to determine disc cell fate. CONCLUSIONS: Cell fate and microenvironmental regulation by modulating PI3K/Akt/mTOR signaling is a potential biological treatment for degenerative disc disease.2023年06月, North American Spine Society journal, 14, 100210 - 100210, 英語, 国際誌研究論文（学術雑誌）
- INTRODUCTION: Patients with nonidiopathic scoliosis often have a high risk associated with general anesthesia because of cardiac or pulmonary dysfunction secondary to underlying diseases. Base excess has been reported as a predictor in the management of trauma and cancer, although not yet in scoliosis. This study was performed to clarify the surgical outcomes and the association of perioperative complications with base excess in patients with nonidiopathic scoliosis who have a high risk associated with general anesthesia. METHODS: Patients with nonidiopathic scoliosis who were referred to our institution from 2009 to 2020 because of their high risk associated with general anesthesia were retrospectively enrolled. High-risk factors for anesthesia were determined by a senior anesthesiologist and categorized into circulatory or pulmonary dysfunction. Perioperative complications were analyzed using the Clavien-Dindo classification; severe complications were defined as grade ≥III. We investigated high-risk factors for anesthesia, underlying diseases, preoperative and postoperative Cobb angle, surgery-related factors, base excess, and postoperative management. These variables were statistically compared between patients with and without complications. RESULTS: Thirty-six patients (mean age, 17.9 years old; range, 11-40 years old) were enrolled (two patients declined surgery). High-risk factors were circulatory dysfunction in 16 patients and pulmonary dysfunction in 20 patients. The mean Cobb angle improved from 85.1° (36°-128°) preoperatively to 43.6° (9°-83°) postoperatively. Three intraoperative complications and 23 postoperative complications occurred in 20 (55.6%) patients. Severe complications occurred in 10 (27.8%) patients. All patients underwent postoperative intensive care unit management after posterior all-screw construction. A large preoperative Cobb angle (p=0.021) and base excess outliers (>3 or <-3 mEq/L) (p=0.005) were significant risk factors for complications. CONCLUSIONS: Patients with nonidiopathic scoliosis who have a high risk associated with general anesthesia have a higher complication rate. Preoperative large deformity and base excess (>3 or <-3 mEq/L) could be predictors of complications.2023年05月, Spine surgery and related research, 7(3) (3), 268 - 275, 英語, 国内誌研究論文（学術雑誌）
- Adiponectin, a hormone secreted by adipocytes, has anti-inflammatory effects and is involved in various physiological and pathological processes such as obesity, inflammatory diseases, and cartilage diseases. However, the function of adiponectin in intervertebral disc (IVD) degeneration is not well understood. This study aimed to elucidate the effects of AdipoRon, an agonist of adiponectin receptor, on human IVD nucleus pulposus (NP) cells, using a three-dimensional in vitro culturing system. This study also aimed to elucidate the effects of AdipoRon on rat tail IVD tissues using an in vivo puncture-induced IVD degeneration model. Analysis using quantitative polymerase chain reaction demonstrated the downregulation of gene expression of proinflammatory and catabolic factors by interleukin (IL)-1β (10 ng/mL) in human IVD NP cells treated with AdipoRon (2 μM). Furthermore, western blotting showed AdipoRon-induced suppression of p65 phosphorylation (p < 0.01) under IL-1β stimulation in the adenosine monophosphate-activated protein kinase (AMPK) pathway. Intradiscal administration of AdipoRon was effective in alleviating the radiologic height loss induced by annular puncture of rat tail IVD, histomorphological degeneration, production of extracellular matrix catabolic factors, and expression of proinflammatory cytokines. Therefore, AdipoRon could be a new therapeutic candidate for alleviating the early stage of IVD degeneration.2023年05月, International journal of molecular sciences, 24(10) (10), 英語, 国際誌研究論文（学術雑誌）
- Background: Symptomatic spinal metastasis (SSM) decreases the activities of daily living (ADL) and quality of life of cancer patients. However, the risk factors for SSM onset remain unclear. This prospective cohort study aimed to statistically analyze the significant risk factors. Methods: From 2016 to 2018, 210 consecutive patients with spinal metastases were prospectively registered. Patients with SSM at the first consultation and those who were unable to be followed-up owing to poor general condition were excluded. The demographic factors (age, sex, primary cancer, performance status, and ADL), clinical factors (radiation therapy, chemotherapy, molecularly targeted drugs, and bone-modifying agents (BMAs)), and Spinal Neoplastic Instability Score (SINS) were evaluated. Multivariate analysis was performed to identify the risk factors for SSM onset. Furthermore, the threshold was calculated from the receiver operating characteristic curve using the Youden index. Results: Thirty-nine patients who presented with SSM at the first consultation and 43 patients who were unable to be followed-up owing to poor general condition were excluded. Finally, 128 asymptomatic patients were included. Thirty-seven patients (28.9%) developed SSM during the follow-up period. The total SINS (OR: 1.739; 95% CI: 1.345-2.250) was identified as the most significant factor. The cut-off value of the SINS was 9.5 (sensitivity: 67.6%; specificity: 83.5%). Twenty-five (62.5%) of the forty patients with a SINS ≥ 10 developed SSM within a mean of 5.5 months (95% CI: 1.17-9.83). Furthermore, all patients with a SINS ≥ 13 developed SSM (n = 5) within a mean of 1.37 months (95% CI: 0.0-3.01). Conclusions: This study identified the significant risk factors for SSM onset and the threshold of the SINS. If long-term survival is expected, patients with a SINS ≥ 10 should be considered for intervention to prevent SSM.2023年02月, Cancers, 15(4) (4), 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Primary spinal osteosarcoma is a rare and intractable disease. Although en bloc resection is favorable for longer survival, it is not always achievable. Separation surgery, a partial resection with circumferential separation to safely deliver high-dose irradiation including intensity-modulated radiation therapy (IMRT), has been recently indicated for patients with spinal cord compression secondary to solid tumor metastases. However, little evidence regarding this combination approach to spinal osteosarcoma exists. CASE PRESENTATION: We report a 55-year-old male patient with a T1 tumor who underwent urgent decompression surgery for epidural spinal cord compression. Pathological findings revealed primary osteosarcoma. Separation surgery, IMRT, and adjuvant chemotherapy were applied to reduce the symptoms of epidural spinal cord compression. The patient was alive without local recurrence at the 5-year follow-up. CONCLUSIONS: Separation surgery with IMRT can be a relatively safe and effective treatment option in patients with osteosarcoma adjacent to spinal cord when en-bloc resection is challenging.2023年, Clinical medicine insights. Case reports, 16, 11795476231171891 - 11795476231171891, 英語, 国際誌
- (一社)日本臨床スポーツ医学会, 2022年10月, 日本臨床スポーツ医学会誌, 30(4) (4), S225 - S225, 日本語
- Growth differentiation factors (GDFs) regulate homeostasis by amplifying extracellular matrix anabolism and inhibiting pro-inflammatory cytokine production in the intervertebral disc (IVD). The aim of this study was to elucidate the effects of GDF-6 on human IVD nucleus pulposus (NP) cells using a three-dimensional culturing system in vitro and on rat tail IVD tissues using a puncture model in vivo. In vitro, Western blotting showed decreased GDF-6 expression with age and degeneration severity in surgically collected human IVD tissues (n = 12). Then, in moderately degenerated human IVD NP cells treated with GDF-6 (100 ng/mL), immunofluorescence demonstrated an increased expression of matrix components including aggrecan and type II collagen. Quantitative polymerase chain reaction analysis also presented GDF-6-induced downregulation of pro-inflammatory tumor necrosis factor (TNF)-α (p = 0.014) and interleukin (IL)-6 (p = 0.016) gene expression stimulated by IL-1β (10 ng/mL). Furthermore, in the mitogen-activated protein kinase pathway, Western blotting displayed GDF-6-induced suppression of p38 phosphorylation (p = 0.041) under IL-1β stimulation. In vivo, intradiscal co-administration of GDF-6 and atelocollagen was effective in alleviating rat tail IVD annular puncture-induced radiologic height loss (p = 0.005), histomorphological degeneration (p < 0.001), matrix metabolism (aggrecan, p < 0.001; type II collagen, p = 0.001), and pro-inflammatory cytokine production (TNF-α, p < 0.001; IL-6, p < 0.001). Consequently, GDF-6 could be a therapeutic growth factor for degenerative IVD disease.2022年03月, Cells, 11(7) (7), 英語, 国際誌研究論文（学術雑誌）
- An electrical conductivity-measuring device (ECD) has recently been developed to support pedicle screw placement. However, no evidence exists regarding its efficacy for syndromic/neuromuscular scoliosis with extremely difficult screwing. We retrospectively reviewed 2010-2016 medical records of 21 consecutive syndromic/neuromuscular scoliosis patients undergoing free-hand segmental fixation surgery at our institution and compared the pedicle screw insertion accuracy and safety between 10 with a conventional non-ECD probe (2010-2013) and 11 with an ECD probe (2014-2016). We analyzed preoperative pedicle shape and postoperative screw placement in computed tomography. There were no significant differences between ECD and non-ECD groups in demographic, clinical, and treatment characteristics including scoliosis severity and pedicle diameter. The abandonment rate due to liquorrhea or perforation was lower in ECD (12.3%) than in non-ECD (26.7%) (p < 0.01). Acceptable insertion without perforation or <2-mm lateral/cranial position was more frequent in ECD (67.1%) than in non-ECD (56.9%) (p = 0.02). Critical ≥5-mm medial/caudal malposition was not seen in ECD (0.0%) but in non-ECD (2.4%) (p = 0.02). The perforation distance was shorter in ECD (2.2 ± 1.1 mm) than in non-ECD (2.6 ± 1.7 mm) (p = 0.01). Results involve small sample size, selection, performance, and learning curve biases; nevertheless, ECD could be useful for more accurate and safer pedicle screw placement in severe syndromic/neuromuscular scoliosis.2022年01月, Journal of clinical medicine, 11(2) (2), 英語, 国際誌研究論文（学術雑誌）
- Objective: To clarify the complications of posterior fusion for atlantoaxial instability (AAI) in children with Down syndrome and to discuss the significance of surgical intervention.Methods: Twenty pediatric patients with Down syndrome underwent posterior fusion for AAI between February 2000 and September 2018 (age, 6.1 ± 1.9 years). C1–2 or C1–3 fusion and occipitocervical fusion were performed in 14 and 6 patients, respectively. The past medical history, operation time, estimated blood loss (EBL), duration of Halo vest immobilization, postoperative follow-up period, and intra- and perioperative complications were examined.Results: The operation time was 257.9 ± 55.6 minutes, and the EBL was 101.6 ± 77.9 mL. Complications related to the operation occurred in 6 patients (30.0%). They included 1 major complication (5.0%): hydrocephalus at 3 months postoperatively, possibly related to an intraoperative dural tear. Other surgery-related complications included 3 cases of superficial infections, 1 case of bone graft donor site deep infection, 1 case of C2 pedicle fracture, 1 case of Halo ring dislocation, 1 case of pseudoarthrosis that required revision surgery, and 1 case of temporary neurological deficit after Halo removal at 2 months postoperatively. Complications unrelated to the operation included 2 cases of respiratory infections and 1 case of implant loosening due to a fall at 9 months postoperatively.Conclusion: The complication rate of upper cervical fusion in patients with Down syndrome remained high; however, major complications decreased substantially. Improved intra- and perioperative management facilitates successful surgical intervention for upper cervical instability in pediatric patients with Down syndrome.The Korean Spinal Neurosurgery Society, 2021年12月, Neurospine, 18(4) (4), 778 - 785研究論文（学術雑誌）
- 株式会社医学書院, 2021年10月, 臨床整形外科, 56(10) (10), 1231 - 1237
- 中部日本整形外科災害外科学会, 2021年09月, 中部日本整形外科災害外科学会雑誌, 64(5) (5), 615 - 616, 日本語
- The loss of nucleus pulposus (NP) notochordal cells is one of the key initial hallmarks of age-related intervertebral disc degeneration. Although the transmembrane mechanoreceptor integrin α5β1 is important in the process of disc degeneration, the relationship between integrin α5β1 and notochordal cell disappearance remains unclear. The purpose of this study was to elucidate the role of integrin α5β1 in the homeostasis of notochordal cells using an ex-vivo dynamic loading culture system that we developed. Rat tail functional spinal units (n = 80 from 40 rats) were cultured under unloading or 1.3-MPa, 1.0-Hz dynamic compressive loading for 48 or 144 h with or without an integrin α5β1 inhibitor. Disc histomorphology, cell viability, apoptosis, senescence, and phenotypic expression were investigated. Consequently, histological degenerative disc changes with decreased cell viability and increased cell apoptosis and senescence were observed with an extended loading duration. Immunofluorescence revealed that the expression of notochordal cell markers, CD24 and brachyury, and chondrocyte markers, collagen type II and SRY-box 9, declined with loading. In particular, reduction in notochordal cell marker expression was more dramatic than that in chondrocyte marker expression. Apoptotic terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity was also higher in brachyury-positive notochordal cells. Furthermore, all these changes were delayed by inhibiting integrin α5β1. Findings of our dynamic loading regimen with a relatively high pressure suggest reproducibility of the cellularity and phenotypic disappearance of NP notochordal cells during adolescence, the susceptibility of notochordal cells to mechanical stimuli partially through the integrin α5β1 pathway, and future potential treatment of integrin regulation for intervertebral disc disease.2021年09月, Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 39(9) (9), 1933 - 1944, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Few studies have addressed the impact of palliative surgery for cervical spine metastasis on patients' performance status (PS) and quality of life (QOL). We investigated the surgical outcomes of patients with cervical spine metastasis and the risk factors for a poor outcome with a focus on the PS and QOL. METHODS: We prospectively analyzed patients with cervical spine metastasis who underwent palliative surgery from 2013 to 2018. The Eastern Cooperative Oncology Group PS (ECOGPS) and EuroQol 5-Dimension (EQ5D) score were assessed at study enrollment and 1, 3, and 6 months postoperatively. Neurological function was evaluated with Frankel grading. Univariate and multivariate analyses were performed to identify the risk factors for a poor surgical outcome, defined as no improvement or deterioration after improvement of the ECOGPS or EQ5D score within 3 months. RESULTS: Forty-six patients (mean age, 67.5 ± 11.7 years) were enrolled. Twelve postoperative complications occurred in 11 (23.9%) patients. The median ECOGPS improved from PS3 at study enrolment to PS2 at 1 month and PS1 at 3 and 6 months postoperatively. The mean EQ5D score improved from 0.085 ± 0.487 at study enrolment to 0.658 ± 0.356 at 1 month and 0.753 ± 0.312 at 3 months. A poor outcome was observed in 18 (39.1%) patients. The univariate analysis showed that variables with a P value of < 0.10 were sex (male), the revised Tokuhashi score, the new Katagiri score, the level of the main lesion, and the Frankel grade at baseline. The multivariate analysis identified the level of the main lesion (cervicothoracic junction) as the significant risk factor (odds ratio, 5.00; P = 0.025). CONCLUSIONS: Palliative surgery for cervical spine metastasis improved the PS and QOL, but a cervicothoracic junction lesion could be a risk factor for a poor outcome.2021年07月, Journal of orthopaedic surgery and research, 16(1) (1), 423 - 423, 英語, 国際誌研究論文（学術雑誌）
- Nucleus pulposus (NP) cells are exposed to changes in hydrostatic pressure (HP) and osmotic pressure within the intervertebral disc. We focused on main disc matrix components, chondroitin sulfate proteoglycan (CSPG) and hyaluronan (HA) to elucidate the capability of augmented CSPG to enhance the anabolism of bovine NP (bNP) cells under repetitive changes in HP at high osmolality. Aggrecan expression with CSPG in the absence of HP was significantly upregulated compared to the no-material control (phosphate buffer saline) under no HP at 3 days, and aggrecan expression with CSPG under HP was significantly higher than the control with HA under HP at 12 days. Collagen type I expression under no HP was significantly lower with CSPG than in controls at 3 days. Although matrix metalloproteinase 13 expression under HP was downregulated compared to no HP, it was significantly greater with HA than the control and CSPG, even under HP. Immunohistology revealed the involvement of mechanoreceptor of transient receptor potential vanilloid-4 activation under HP, suggesting an HP transduction mechanism. Addition of CSPG had anabolic and anti-fibrotic effects on bNP cells during the early culture period under no HP; furthermore, it showed synergy with dynamic HP to increase bNP-cell anabolism at later time points.2021年06月, International journal of molecular sciences, 22(11) (11), 英語, 国際誌研究論文（学術雑誌）
- 2021年06月, Neurospine, 18(2) (2), 290 - 291, 英語, 国際誌
- Background: The rabbit lumbar spine is a commonly utilized model for studying intervertebral disc degeneration and for the pre-clinical evaluation of regenerative therapies. Histopathology is the foundation for which alterations to disc morphology and cellularity with degeneration, or following repair or treatment are assessed. Despite this, no standardized histology grading scale has yet been established for the spine field for any of the frequently utilized animal models. Aims: The purpose of this study was to establish a new standardized scoring system to assess disc degeneration and regeneration in the rabbit model. Materials and Methods: The scoring system was formulated following a review of the literature and a survey of spine researchers. Validation of the scoring system was carried out using images provided by 4 independent laboratories, which were graded by 12 independent graders of varying experience levels. Reliability testing was performed via the computation of intra-class correlation coefficients (ICC) for each category and the total score. The scoring system was then further refined based on the results of the ICC analysis and discussions amongst the authors. Results: The final general scoring system involves scoring 7 features (nucleus pulposus shape, area, cellularity and matrix condensation, annulus fibrosus/nucleus pulposus border appearance, annulus fibrosus morphology, and endplate sclerosis/thickening) on a 0 (healthy) to 2 (severe degeneration) scale. ICCs demonstrated overall moderate to good agreement across graders. An addendum to the main scoring system is also included for use in studies evaluating regenerative therapeutics, which involves scoring cell cloning and morphology within the nucleus pulposus and inner annulus fibrosus. Discussion: Overall, this new scoring system provides an avenue to improve standardization, allow a more accurate comparison between labs and more robust evaluation of pathophysiology and regenerative treatments across the field. Conclusion: This study developed a histopathology scoring system for degeneration and regeneration in the rabbit model based on reported practice in the literature, a survey of spine researchers, and validation testing.2021年06月, JOR spine, 4(2) (2), e1147, 英語, 国際誌研究論文（学術雑誌）
- Background: Rats are a widely accepted preclinical model for evaluating intervertebral disc (IVD) degeneration and regeneration. IVD morphology is commonly assessed using histology, which forms the foundation for quantifying the state of IVD degeneration. IVD degeneration severity is evaluated using different grading systems that focus on distinct degenerative features. A standard grading system would facilitate more accurate comparison across laboratories and more robust comparisons of different models and interventions. Aims: This study aimed to develop a histology grading system to quantify IVD degeneration for different rat models. Materials & Methods: This study involved a literature review, a survey of experts in the field, and a validation study using 25 slides that were scored by 15 graders from different international institutes to determine inter- and intra-rater reliability. Results: A new IVD degeneration grading system was established and it consists of eight significant degenerative features, including nucleus pulposus (NP) shape, NP area, NP cell number, NP cell morphology, annulus fibrosus (AF) lamellar organization, AF tears/fissures/disruptions, NP-AF border appearance, as well as endplate disruptions/microfractures and osteophyte/ossification. The validation study indicated this system was easily adopted, and able to discern different severities of degenerative changes from different rat IVD degeneration models with high reproducibility for both experienced and inexperienced graders. In addition, a widely-accepted protocol for histological preparation of rat IVD samples based on the survey findings include paraffin embedding, sagittal orientation, section thickness < 10 μm, and staining using H&E and/or SO/FG to facilitate comparison across laboratories. Conclusion: The proposed histological preparation protocol and grading system provide a platform for more precise comparisons and more robust evaluation of rat IVD degeneration models and interventions across laboratories.2021年06月, JOR spine, 4(2) (2), e1150, 英語, 国際誌研究論文（学術雑誌）
- The intervertebral disc is the largest avascular organ. Autophagy is an important cell survival mechanism by self-digestion and recycling damaged components under stress, primarily nutrient deprivation. Resident cells would utilize autophagy to cope with the harsh disc environment. Our objective was to elucidate the roles of human disc cellular autophagy. In human disc cells, serum deprivation and pro-inflammatory interleukin-1β (IL-1β) stimulation increased autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and decreased autophagy substrate p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. Then, RNA interference (RNAi) of autophagy-related gene 5 (ATG5), essential for autophagy, showed decreases in ATG5 protein (26.8%-27.4%, p < 0.0001), which suppressed early-stage autophagy with decreased LC3-II and increased p62/SQSTM1. Cell viability was maintained by ATG5 RNAi in serum-supplemented media (95.5%, p = 0.28) but reduced in serum-free media (80.4%, p = 0.0013) with IL-1β (69.9%, p = 0.0008). Moreover, ATG5 RNAi accelerated IL-1β-induced changes in apoptosis and senescence. Meanwhile, ATG5 RNAi unaffected IL-1β-induced catabolic matrix metalloproteinase release, down-regulated anabolic gene expression, and mitogen-activated protein kinase pathway activation. Lysosomotropic chloroquine supplementation presented late-stage autophagy inhibition with apoptosis and senescence induction, while catabolic enzyme production was modest. Disc-tissue analysis detected age-related changes in ATG5, LC3-II, and p62/SQSTM1. In summary, autophagy protects against human disc cellular apoptosis and senescence rather than extracellular matrix catabolism.2021年04月, International journal of molecular sciences, 22(8) (8), 英語, 国際誌研究論文（学術雑誌）
- Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM-CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM-CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA-MB-231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM-CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM-CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p < .05). The current study suggests that local administration of GM-CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP.2021年03月, Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 39(3) (3), 525 - 535, 英語, 国際誌研究論文（学術雑誌）
- Intervertebral discs (IVDs) are exposed to changes in physicochemical stresses including hydrostatic and osmotic pressure via diurnal spinal motion. Homeostasis, degeneration, and regeneration in IVDs have been studied using in vitro, ex vivo, and animal models. However, incubation of nucleus pulposus (NP) cells in medium has limited capability to reproduce anabolic turnover and regeneration under physicochemical stresses. We developed a novel pressure/perfusion cell culture system and a semipermeable membrane pouch device for enclosing isolated NP cells for in vitro incubation under physicochemical stresses. We assessed the performance of this system to identify an appropriate stress loading regimen to promote gene expression and consistent accumulation of extracellular matrices by bovine caudal NP cells. Cyclic hydrostatic pressure (HP) for 4 days followed by constant HP for 3 days in high osmolality (HO; 450 mOsm/kg H2O) showed a trend towards upregulated aggrecan expression and dense accumulation of keratan sulfate without gaps by the NP cells. Furthermore, a repetitive regimen of cyclic HP for 2 days followed by constant HP for 1 day in HO (repeated twice) significantly upregulated gene expression of aggrecan (P < .05) compared to no pressure and suppressed matrix metalloproteinase-13 expression (P < .05) at 6 days. Our culture system and pouches will be useful to reproduce physicochemical stresses in NP cells for simulating anabolic, catabolic, and homeostatic turnover under diurnal spinal motion.2020年09月, JOR spine, 3(3) (3), e1105, 英語, 国際誌研究論文（学術雑誌）
- Back pain is a global health problem with a high morbidity and socioeconomic burden. Intervertebral disc herniation and degeneration are its primary cause, further associated with neurological radiculopathy, myelopathy, and paralysis. The current surgical treatment is principally discectomy, resulting in the loss of spinal movement and shock absorption. Therefore, the development of disc regenerative therapies is essential. Here we show reduced disc damage by a new collagen type I-based scaffold through actinidain hydrolysis-Low Adhesive Scaffold Collagen (LASCol)-with a high 3D spheroid-forming capability, water-solubility, and biodegradability and low antigenicity. In human disc nucleus pulposus and annulus fibrosus cells surgically obtained, time-dependent spheroid formation with increased expression of phenotypic markers and matrix components was observed on LASCol but not atelocollagen (AC). In a rat tail nucleotomy model, LASCol-injected and AC-injected discs presented relatively similar radiographic and MRI damage control; however, LASCol, distinct from AC, decelerated histological disc disruption, showing collagen type I-comprising LASCol degradation, aggrecan-positive and collagen type II-positive endogenous cell migration, and M1-polarized and also M2-polarized macrophage infiltration. Reduced nucleotomy-induced disc disruption through spontaneous spheroid formation by LASCol warrants further investigations of whether it may be an effective treatment without stem cells and/or growth factors for intervertebral disc disease.2020年03月, Biomaterials, 235, 119781 - 119781, 英語, 国際誌研究論文（学術雑誌）
- Laminoplasty using hydroxyapatite (HA) spacers is widely performed in patients with cervical myelopathy. However, spacer dislocation is a critical complication caused by bone absorption and inadequate bone conductivity, and can result in dural damage and restenosis. We thus designed a prospective cohort study to clarify the feasibility of increased porosity HA spacers for double-door laminoplasty by analyzing computed tomography (CT) images. Forty-seven patients underwent cervical laminoplasty. Two different types of CERATITE HA spacer were used, either high porosity (50%) or low porosity (35%). These HA spacers were placed in an alternating manner into the laminae in each patient. In total, 85 high-porosity (50%) HA spacers and 84 low-porosity (35%) HA spacers were implanted. At postoperative 2 weeks, 3 months, 6 months, and 1 year, CT images were obtained. In both groups, the percentage of bone-bonding boundary area of the HA spacer in contact with laminae and bone volume of the spinous process relative to the 2-week value were calculated by a 3D and 2D CT-image pixel analysis. The bone-bonding ratio was significantly higher in high-porosity (50%) than low-porosity (35%) HA spacers at 3 months and thereafter (1 year, 69.3 ± 27.8% and 49.7 ± 32.9% respectively, P < .01). The bone volume in both groups significantly decreased with time (1 year, 73.2 ± 29.8% and 69.0 ± 30.4% respectively, P < .01), indicating bone absorption. This showed no significant difference between the HA spacers (P = .15) but was higher in high-porosity (50%) than low-porosity (35%) HA spacers throughout the study period. Meanwhile, spacer breakage was found in 4.7% of high-porosity (50%) HA spacers and 1.2% of low-porosity (35%) HA spacers (P = .37). In summary, high-porosity (50%) HA spacers have the advantages of accelerated bone bonding and relatively decelerated bone absorption compared to low-porosity (35%) HA spacers; however, possibly more frequent breakage of HA spacers with a high porosity (50%) requires careful, extended postoperative follow-up.2020年03月, JOR spine, 3(1) (1), e1080, 英語, 国際誌研究論文（学術雑誌）
- Intervertebral disc degeneration is the primary cause of back pain and associated with neurological disorders including radiculopathy, myelopathy, and paralysis. The currently available surgical treatments predominantly include the excision of pathological discs, resulting in the function loss, immobilization, and potential additional complications due to the altered biomechanics. Gene therapy approach involves gene transfer into cells, affects RNA and protein synthesis of the encoded genes in the recipient cells, and facilitates biological treatment. Relatively long-exerting therapeutic effects by gene therapy are potentially advantageous to treat slow progressive degenerative disc disease. In gene therapy, the delivery method and selection of target gene(s) are essential. Although gene therapy was first mediated by viral vectors, technological progress has enabled to apply nonviral vectors and polyplex micelles for the disc. While RNA interference successfully provides specific downregulation of multiple genes in the disc, clustered regularly interspaced short palindromic repeats (CRISPR) system has increased attention to alter the process of intervertebral disc degeneration. Then, more recent findings of our studies have suggested autophagy, the intracellular self-digestion, and recycling system under the negative regulation by the mammalian target of rapamycin (mTOR), as a gene therapy target in the disc. Here we briefly review backgrounds and applications of gene therapy for the disc, introducing strategies of autophagy and mTOR signaling modulation through selective RNA interference.2020年03月, Neurospine, 17(1) (1), 3 - 14, 英語, 国際誌研究論文（学術雑誌）
- (公社)日本整形外科学会, 2018年08月, 日本整形外科学会雑誌, 92(8) (8), S1999 - S1999, 日本語
- STUDY DESIGN: A retrospective analysis. OBJECTIVE: The aim of this study was to clarify the postoperative improvement of walking ability and prognostic factors in nonambulatory patients with cervical myelopathy. SUMMARY OF BACKGROUND DATA: Many researchers have reported the surgical outcome in compressive cervical myelopathy. However, regarding severe gait disturbance,, it has not been clarified yet how much improvement can be expected. METHODS: One hundred thirty-one nonambulatory patients with cervical myelopathy were treated surgically and followed for an average of 3 years. Walking ability was graded according to the lower-extremity function subscore (L/E subscore) in Japanese Orthopedic Association score. We divided patients based on preoperative L/E subscores: group A, L/E subscore of 1 point (71 patients); and group B, 0 or 0.5 point (60 patients). The postoperative walking ability was graded by L/E subscore: excellent, ≥2 points; good, 1.5 points; fair, 1 point; and poor, 0.5 or 0 points. We compared preoperative and postoperative scores. The cutoff value of disease duration providing excellent improvement was investigated. RESULTS: Overall, 50 patients were graded as excellent (38.2%), and 21 patients were graded as good (16.0%). In group B, 17 patients (28.3%) were graded as excellent. Seventeen patients who were graded as excellent had shorter durations of myelopathic symptoms and/or gait disturbance (7.9 and 3.8 months respectively) than the others (29.5 and 8.9 months, respectively) (P < 0.05). Receiver-operating characteristic curve showed that the optimal cutoff values of the duration of myelopathic symptoms and gait disturbance providing excellent improvement were 3 and 2 months, respectively. CONCLUSION: Even if the patients were nonambulatory, 28.3% of them became able to walk without support after operation. If a patient becomes nonambulatory within 3 months from the onset of myelopathy or 2 months from the onset of gait disturbance, surgical treatment should be performed immediately to raise the possibility to improve stable gait. LEVEL OF EVIDENCE: 3.2018年08月, Spine, 43(16) (16), E927-E934, 英語, 国際誌研究論文（学術雑誌）
- (公社)日本リハビリテーション医学会, 2018年05月, The Japanese Journal of Rehabilitation Medicine, 55(特別号) (特別号), 1 - 6, 日本語新規低接着性コラーゲン(LASCol)はラット大腿骨骨欠損モデルにおいて骨癒合を促進する
- BACKGROUND: During modified gap-balancing technique, there is no consensus on the best method for obtaining appropriate soft-tissue balance and determining the femoral component rotation. METHODS: Sixty-five varus osteoarthritic patients underwent primary posterior-stabilized total knee arthroplasty using modified gap-balancing technique. The influence of joint distraction force on the soft-tissue balance measurement during the modified gap-balancing technique was evaluated with Offset Repo-Tensor between the osteotomized surfaces at extension, and between femoral posterior condyles and tibial osteotomized surface at flexion of the knee before the resection of femoral posterior condyles. The joint center gap (millimeters) and varus ligament balance (°) were measured under 20, 40, and 60 pounds of joint distraction forces, and the differences in these values at extension and flexion (the value at flexion minus the value at extension) were also calculated. RESULTS: The differences in joint center gap (-6.7, -6.8, and -6.9 mm for 20, 40, and 60 pounds, respectively) and varus ligament balance (3.5°, 3.8°, and 3.8°) at extension and flexion were not significantly different among different joint distraction forces, although the joint center gap and varus ligament balance significantly increased stepwise at extension and flexion as the joint distraction force increased. CONCLUSION: The difference in joint center gap and varus ligament balance at extension and flexion were consistent even among the different joint distraction forces. This novel index would be useful for the determination of femoral component rotation during the modified gap-balancing technique.2017年10月, The Journal of arthroplasty, 32(10) (10), 2995 - 2999, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: Palliative surgery for patients with spinal metastasis provides good clinical outcomes. However, there have been few studies on quality of life (QOL) and cost-utility of this surgery. We aimed to elucidate QOL and cost-utility of surgical treatment for spinal metastasis. METHODS: We prospectively analyzed 47 patients with spinal metastasis from 2010 to 2014 who had a surgical indication. Thirty-one patients who desired surgery underwent spinal surgery (surgery group). Sixteen patients who did not want to undergo spinal surgery (non-surgery group). The EuroQol 5D (EQ-5D) and relevant costs were measured at one, three, six, and 12 months after study enrollment. Health state values were obtained by Japanese EQ-5D scoring and quality-adjusted life years (QALY) gained were calculated for each group. Cost-utility was expressed as the incremental cost-utility ratio (ICUR). RESULTS: Health state values improved from 0.036 at study enrollment to 0.448 at 12 months in the surgery group, but deteriorated from 0.056 to 0.019 in the non-surgery group, with a significant difference between groups (P < 0.05). The mean QALY gained at 12 months were 0.433 in the surgery group and 0.024 in the non-surgery group. The mean total cost per patient in the surgery group was $25,770 compared with $8615 in the non-surgery group. The ICUR using oneyear follow-up data was $42,003/QALY gained. CONCLUSIONS: Surgical treatment for spinal metastases is associated with significant improvement in health state value. In orthopaedic surgery, an ICUR less than $50,000/QALY gained is considered acceptable cost-effectiveness. Our results indicate that surgical treatment could be cost-effective.2017年06月, International orthopaedics, 41(6) (6), 1265 - 1271, 英語, 国際誌研究論文（学術雑誌）
- Expression of adiponectin receptors in human and rat intervertebral disc cells and changes in receptor expression during disc degeneration using a rat tail temporary static compression model.BACKGROUND: Adipose tissue is a large endocrine organ known to secret adiponectin, which has anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Adiponectin is widely involved in systemic disease, diabetes mellitus, and cardiac infraction. This study aimed to investigate the involvement of adiponectin in intervertebral disc (IVD) degeneration. METHODS: Adipose and IVD tissues were obtained from human patients undergoing surgery (n = 4) and from skeletally mature Sprague-Dawley rats (n = 21). Tissues were stained immunohistochemically for adiponectin and adiponectin receptors AdipoR1 and AdipoR2. Changes in adiponectin receptor expression with IVD degeneration severity were then investigated using a rat tail temporary compression model. Rat IVD tissues were stained immunohistochemically with AdipoR1 or AdipoR2, and immunopositive cell percentages were calculated. Rat nucleus pulposus (NP) and annulus fibrosus (AF) tissues were isolated separately and treated with recombinant adiponectin (Ad 0.1 or 1.0 μg/ml) and/or interleukin-1 beta (IL-1β) (0.2 μg/ml) for 24 h. The four groups were as follows: control group (no treatment), IL-1β group (IL-1β-only treatment), IL-1β+Ad (0.1) group (IL-1β and adiponectin [0.1 μg/ml] treatment), and IL-1β+Ad (1.0) group (IL-1β and adiponectin [1.0 μg/ml]). Real-time reverse transcription-polymerase chain reaction was performed to evaluate messenger-RNA (mRNA) expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). RESULTS: Adiponectin was widely expressed in human subcutaneous and epidural adipose tissue. In rat IVD tissue, adiponectin was not observed in NP and AF. However, both AdipoR1 and AdipoR2 were widely expressed in both human and rat IVD tissues, with no significant differences in expression levels between receptors. Furthermore, expression levels of AdipoR1 and AdipoR2 were gradually decreased with increased IVD degeneration severity. Interestingly, mRNA expression levels of TNF-α and IL-6 were significantly upregulated by IL-1β stimulation. TNF-α expression in the IL-1β+Ad 1.0 group was significantly lower than that in the IL-1β group in both NP and AF cells (P < 0.05). Finally, IL-6 expression was not affected by adiponectin treatment in IVD cells. CONCLUSIONS: This study investigated for the first time the expression of adiponectin receptors in human and rat IVD cells. The findings indicate that adiponectin produced by the systemic or epidural adipose tissue may be involved in the pathomechanism of IVD degeneration.2016年11月, Journal of orthopaedic surgery and research, 11(1) (1), 147 - 147, 英語, 国際誌研究論文（学術雑誌）
- (公社)日本整形外科学会, 2016年08月, 日本整形外科学会雑誌, 90(8) (8), S1659 - S1659, 日本語椎間板変性の病態解明 椎間板変性モデルについて[査読有り]研究論文（その他学術会議資料等）
- The aim of this study was to find a new predictive indicator for acetabular growth of developmental dysplasia of the hip. Seventy-three hips that were diagnosed with developmental dysplasia of the hip and treated by conservative reduction were included in our study. In 30 hips with center-edge angle ≤ 10° at age 4, the center-edge of the acetabular limbus angle (CEALA) in the arthrogram was measured. On the basis of the results, CEALA was significantly smaller in the secondary acetabular dysplasia group than in the normal group at maturity. In conclusion, CEALA is a more reliable and accurate predictive indicator for acetabular development than center-edge angle or acetabular index.2016年05月, Journal of pediatric orthopedics. Part B, 25(3) (3), 207 - 11, 英語, 国際誌研究論文（学術雑誌）
- (公社)日本整形外科学会, 2023年06月, 日本整形外科学会雑誌, 97(6) (6), S1352 - S1352, 日本語
- (公社)日本リハビリテーション医学会, 2019年05月, The Japanese Journal of Rehabilitation Medicine, 56(特別号) (特別号), 3 - 3, 日本語「ロコトレ」理学療法プログラムによる「ロコモ」患者の脊柱アライメントと体幹バランス改善効果
- (公社)日本リハビリテーション医学会, 2019年05月, The Japanese Journal of Rehabilitation Medicine, 56(特別号) (特別号), 3 - 14, 日本語「ロコトレ」理学療法プログラムによる「ロコモ」患者の脊柱アライメントと体幹バランス改善効果
- (一社)日本脊椎脊髄病学会, 2019年03月, Journal of Spine Research, 10(3) (3), 210 - 210, 日本語症候性側彎症手術における電磁気センサー付き椎弓根プローブの有用性
- (公社)日本リハビリテーション医学会, 2018年10月, The Japanese Journal of Rehabilitation Medicine, 55(秋季特別号) (秋季特別号), S299 - S299, 日本語ロコトレリハビリプログラムによる脊柱アライメントと体幹バランスの改善効果
- 2018年, 日本整形外科学会雑誌, 92(8) (8)新規低接着性scaffold collagen(LASCol)はラット骨欠損モデルにおいて骨癒合を促進する
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2025年04月01日 - 2029年03月31日シルクエラスチンによる椎間板変性治療体系の確立 ー人工椎間板作成の試みー
- 日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2022年04月01日 - 2025年03月31日メカノレセプターTRPV4による椎間板変性に対する治療アプローチ