Clinical Characteristics, Surgical Outcomes, and Risk Factors for Emergency Surgery in Patients With Spinal Metastases: A Prospective Cohort Study.

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.

Effect of Bone Metastasis Cancer Board on Spinal Surgery Outcomes: A Retrospective Study.

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.

Clinical Characteristics and Surgical Outcomes of Metastatic Spine Tumors in the Very Elderly: A Prospective Cohort Study in a Super-Aged Society.

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.

Preoperative Base Excess as a Predictor of Perioperative Complications in Patients with Nonidiopathic Scoliosis who Have High Risk Associated with General Anesthesia.

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.

The Combination of Separation Surgery and Intensity Modulated Radiation Therapy (IMRT) for a Primary Osteosarcoma of the Spine: A Case Report and Literature Review.

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.

Anti-Inflammatory Effects of Adiponectin Receptor Agonist AdipoRon against Intervertebral Disc Degeneration.

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)-1ß (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-1ß 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.

Intervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy.

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.

Regenerative Capability of Human Nucleus Pulposus Cells in Degenerated Disc Under Hydrostatic Pressure Mimicking Physiologically Relevant Intradiscal Pressure In Vitro.

STUDY DESIGN: Isolated human nucleus pulposus (hNP) cells from the degenerated intervertebral disc (IVD) were incubated under hydrostatic pressure (HP) and evaluated for regenerative potential. OBJECTIVES: To characterize metabolic turnover in hNP cells isolated from degenerated IVDs classified by Pfirrmann grade under physiologically relevant HP at high osmolality in vitro. SUMMARY OF BACKGROUND DATA: We demonstrated that bovine caudal nucleus pulposus cells isolated from healthy cows produced more extracellular matrix under cyclic HP followed by constant pressure (mimicking physiological intradiscal pressure in humans) than under no pressure in vitro. We assessed the effects of pressure on human degenerated cells isolated under the same regimen of pressure used for bovine cells. MATERIALS AND METHODS: hNP cells isolated from discarded tissue classified as Pfirrmann grade 2 to 3 (n = 13: age, 46.7 ± 14.0) and grade 4 (n = 13: age, 53.0 ± 11.5) were incubated under cyclic HP at 0.2 to 0.7 MPa, 0.5 Hz for 2 days followed by constant pressure at 0.3 MPa for 1 day, repeated twice over 6 days. The gene expression and immunohistology of matrix molecules and catabolic and anticatabolic proteins were evaluated. RESULTS: Aggrecan and collagen type II expression were significantly more upregulated under HP in grades 2 to 3 than in grade 4 tissues (both, P < 0.01). Linear regression analysis showed a positive correlation between matrix metalloproteinase 13 and tissue inhibitor for metalloproteinase 2 expression in grades 2 to 3, whereas a negative correlation was found in grade 4 ( P < 0.05). Immunohistological staining revealed the activation of a mechanoreceptor, transient receptor potential vanilloid 4, under HP. CONCLUSIONS: Resident cells in mild-moderate degenerated discs classified as Pfirrmann grade 2 to 3 have the potential to promote extracellular matrix production and maintain adequate cell viability under physiological spinal loading. RELEVANCE: This study explored the potential of degenerated remnant nucleus pulposus cells under a physiological environment, possibly leading to establishing strategies for IVD regeneration.

Separation Surgery and Postoperative Intensity-Modulated Radiation Therapy for a High-Grade Myxofibrosarcoma Involving the Spine: A Case Report.

BACKGROUND Myxofibrosarcoma involving the spine is a rare and intractable disease. Although wide surgical resection is the mainstay of treatment, it is often difficult to complete marginal en-bloc resection due to adjacent neurovascular components in the spine. Separation surgery, a partial resection to achieve circumferential separation and high-dose irradiation such as postoperative intensity-modulated radiation therapy, has received much attention as a new therapy for spinal tumors. However, little evidence regarding separation surgery with intensity-modulated radiation therapy for a spinal myxofibrosarcoma exists. CASE REPORT We present a case of a 75-year-old man with progressive myelopathy. Radiological examination revealed severe spinal cord compression due to an unknown widespread multiple tumor in the cervical and thoracic spine. Computed tomography-guided biopsy showed high-grade sarcoma. Positron emission tomography detected no other tumors in the body. Separation surgery was therefore performed with posterior stabilization. Hematoxylin and eosin staining showed storiform cellular infiltrates and pleomorphic cell nuclei. Histopathology identified high-grade myxofibrosarcoma. Postoperative intensity-modulated radiation therapy of 60 Gy in 25 fractions was completed without any adverse effects. The patient had greatly improved neurological function, was capable of walking with a cane, and had no recurrence for at least 1 year after surgery. CONCLUSIONS We reported a case of an unresectable high-grade myxofibrosarcoma of the spine successfully treated with the combination of separation surgery and postoperative intensity-modulated radiation therapy. This combination therapy is a relatively safe and effective treatment option in patients with impending neurological damage by unresectable sarcomas when total en-bloc resection is challenging due to the size, location, or adhesion.

The Identification of Risk Factors for Symptomatic Spinal Metastasis Onset: A Prospective Cohort Study of 128 Asymptomatic Spinal Metastasis Patients.

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.

Survival Rate after Palliative Surgery Alone for Symptomatic Spinal Metastases: A Prospective Cohort Study.

The effect of spine surgery for symptomatic spinal metastases (SSM) on patient prognosis remains unclear. This study aimed to reveal the prognosis of patients with SSM after spine surgery. One hundred twenty-two patients with SSM were enrolled in this prospective cohort study. The patients who received chemotherapy after enrollment were excluded. The decision of surgery depended on patient's willingness; the final cohort comprised 31 and 24 patients in the surgery and non-surgery groups, respectively. The patients were evaluated by their performance status (PS), activities of daily living (ADL) and ambulatory status. Survival was evaluated by the Kaplan-Meier method. The PS, ADL and ambulation were significantly improved in the surgery group compared to non-surgery group. The median survival was significantly longer in the surgery group (5.17 months, 95% confidence interval (CI) 3.27 to 7.07) than in the non-surgery group (2.23 months, 95% CI 2.03 to 2.43; p = 0.003). Furthermore, the patients with a better PS, ADL and ambulatory status had a significantly longer survival. Surgery improved the PS, ADL, ambulation and survival of patients with SSM. In the management of SSM, spine surgery is not only palliative but may also prolong survival.

Protective Effects of Growth Differentiation Factor-6 on the Intervertebral Disc: An In Vitro and In Vivo Study.

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-1ß (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-1ß 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.

Improved Accuracy and Safety of Pedicle Screw Placement by Using a Probe with an Electrical Conductivity-Measuring Device during Severe Syndromic and Neuromuscular Scoliosis Spine Surgery.

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.

Surgical outcomes and risk factors for poor outcomes in patients with cervical spine metastasis: a prospective study.

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.

Inhibition of Autophagy at Different Stages by ATG5 Knockdown and Chloroquine Supplementation Enhances Consistent Human Disc Cellular Apoptosis and Senescence Induction rather than Extracellular Matrix Catabolism.

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-1ß (IL-1ß) 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-1ß (69.9%, p = 0.0008). Moreover, ATG5 RNAi accelerated IL-1ß-induced changes in apoptosis and senescence. Meanwhile, ATG5 RNAi unaffected IL-1ß-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.

Delayed notochordal cell disappearance through integrin α5ß1 mechanotransduction during ex-vivo dynamic loading-induced intervertebral disc degeneration.

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 α5ß1 is important in the process of disc degeneration, the relationship between integrin α5ß1 and notochordal cell disappearance remains unclear. The purpose of this study was to elucidate the role of integrin α5ß1 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 α5ß1 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 α5ß1. 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 α5ß1 pathway, and future potential treatment of integrin regulation for intervertebral disc disease.

A novel topical treatment for bone metastases using a gelatin hydrogel incorporating cisplatin as a sustained release system.

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.

Prospective cohort study of surgical outcome for spinal metastases in patients aged 70 years or older.

AIMS: With recent progress in cancer treatment, the number of advanced-age patients with spinal metastases has been increasing. It is important to clarify the influence of advanced age on outcomes following surgery for spinal metastases, especially with a focus on subjective health state values. METHODS: We prospectively analyzed 101 patients with spinal metastases who underwent palliative surgery from 2013 to 2016. These patients were divided into two groups based on age (< 70 years and ≥ 70 years). The Eastern Cooperative Oncology Group (ECOG) performance status (PS), Barthel index (BI), and EuroQol-5 dimension (EQ-5D) score were assessed at study enrolment and at one, three, and six months after surgery. The survival times and complications were also collected. RESULTS: In total, 65 patients were aged < 70 years (mean 59.6 years; 32 to 69) and 36 patients were aged ≥ 70 years (mean 75.9 years; 70 to 90). In both groups, the PS improved from PS3 to PS1 by spine surgery, the mean BI improved from < 60 to > 80 points, and the mean EQ-5D score improved from 0.0 to > 0.7 points. However, no significant differences were found in the improvement rates and values of the PS, BI, and EQ-5D score at any time points between the two groups. The PS, BI, and EQ-5D score improved throughout the follow-up period in approximately 90% of patients in each group. However, the improved PS, BI, and EQ-5D scores subsequently deteriorated in some patients, and the redeterioration rate of the EQ-5D was significantly higher in patients aged ≥ 70 than < 70 years (p = 0.027). CONCLUSION: Palliative surgery for spinal metastases improved the PS, activities of daily living, and quality of life, regardless of age. However, clinicians should be aware of the higher risk of redeterioration of the quality of life in advanced-age patients. Cite this article: Bone Joint J 2020;102-B(12):1709-1716.

Improved bone bonding of hydroxyapatite spacers with a high porosity in a quantitative computed tomography-image pixel analysis: A prospective 1-year comparative study of the consecutive cohort undergoing double-door cervical laminoplasty.

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.

Reduced nucleotomy-induced intervertebral disc disruption through spontaneous spheroid formation by the Low Adhesive Scaffold Collagen (LASCol).

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.