Involvement of DJ-1 in the pathogenesis of intervertebral disc degeneration via hexokinase 2-mediated mitophagy.

Intervertebral disc degeneration (IDD) is an important pathological basis for degenerative spinal diseases and is involved in mitophagy dysfunction. However, the molecular mechanisms underlying mitophagy regulation in IDD remain unclear. This study aimed to clarify the role of DJ-1 in regulating mitophagy during IDD pathogenesis. Here, we showed that the mitochondrial localization of DJ-1 in nucleus pulposus cells (NPCs) first increased and then decreased in response to oxidative stress. Subsequently, loss- and gain-of-function experiments revealed that overexpression of DJ-1 in NPCs inhibited oxidative stress-induced mitochondrial dysfunction and mitochondria-dependent apoptosis, whereas knockdown of DJ-1 had the opposite effect. Mechanistically, mitochondrial translocation of DJ-1 promoted the recruitment of hexokinase 2 (HK2) to damaged mitochondria by activating Akt and subsequently Parkin-dependent mitophagy to inhibit oxidative stress-induced apoptosis in NPCs. However, silencing Parkin, reducing mitochondrial recruitment of HK2, or inhibiting Akt activation suppressed DJ-1-mediated mitophagy. Furthermore, overexpression of DJ-1 ameliorated IDD in rats through HK2-mediated mitophagy. Taken together, these findings indicate that DJ-1 promotes HK2-mediated mitophagy under oxidative stress conditions to inhibit mitochondria-dependent apoptosis in NPCs and could be a therapeutic target for IDD.

Interleukin-17A Promotes Proliferation and Osteogenic Differentiation of Human Ligamentum Flavum Cells Through Regulation of ß-Catenin Signaling.

STUDY DESIGN: A basic experimental study. OBJECTIVE: To elucidate the role and mechanism of interleukin (IL)-17A in thoracic ossification of the ligamentum flavum (TOLF). SUMMARY OF BACKGROUND DATA: TOLF is characterized by the replacement of the thoracic ligamentum flavum with ossified tissue and is one of the leading causes of thoracic spinal stenosis. IL-17A is an important member of the IL-17 family that has received widespread attention for its key contributions to the regulation of bone metabolism and heterotopic ossification. However, it is unclear whether IL-17A is involved in TOLF. MATERIALS AND METHODS: Cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine staining were performed to assess the proliferation of ligamentum flavum cells (LFCs). Alkaline phosphatase activity assay, Alizarin red staining, and protein level expression of osteogenic-related genes were used to evaluate the osteogenic differentiation potential of LFCs. The effect of IL-17A on the proliferation and osteogenic differentiation of LFCs was further assessed after silencing ß-catenin by transfection with small interfering RNA. In addition, the possible source of IL-17A was further demonstrated by coculture assays of T helper 17 (Th17) cells with LFCs. Student t test was used for comparisons between groups, and the one-way analysis of variance, followed by the Tukey post hoc test, was used for comparison of more than two groups. RESULTS: IL-17A was elevated in TOLF tissue compared with normal ligamentum flavum. IL-17A stimulation promoted the proliferation and osteogenic differentiation of LFCs derived from patients with TOLF. We found that IL-17A promoted the proliferation and osteogenic differentiation of LFCs by regulating the ß-catenin signaling. Coculture of Th17 cells with LFCs enhanced ß-catenin signaling-mediated proliferation and osteogenic differentiation of LFCs. However, these effects were markedly attenuated after the neutralization of IL-17A. CONCLUSIONS: This is the first work we are aware of to highlight the importance of IL-17A in TOLF. IL-17A secreted by Th17 cells in the ligamentum flavum may be involved in the ossification of the microenvironment by regulating ß-catenin signaling to promote the proliferation and osteogenic differentiation of LFCs.

DJ-1-mediated p62 degradation delays intervertebral disc degeneration by inhibiting apoptosis of nucleus pulposus cells.

Intervertebral disc degeneration (IDD) is the most important pathological basis of degenerative spinal diseases, for which effective interventions are still lacking. Oxidative stress is considered to be one of the leading pathological mechanisms contributing to IDD. However, the exact role of DJ-1 as an essential member of the antioxidant defense system in IDD is still unclear. Therefore, the aim of this study was to investigate the role played by DJ-1 in IDD and to reveal its potential molecular mechanisms. Western blot and immunohistochemical staining assays were performed to detect the expression of DJ-1 in degenerative nucleus pulposus cells (NPCs). After overexpression of DJ-1 in NPCs by lentiviral transfection, DCFH-DA and MitoSOX fluorescent probes were used to evaluate the levels of reactive oxygen species (ROS); while western blot, TUNEL staining, and Caspase-3 activity were used to assess apoptosis. Immunofluorescence staining was used to demonstrate the relationship between DJ-1 and p62. After inhibition of lysosomal degradation function with chloroquine, p62 degradation and apoptosis in DJ-1 overexpressing NPCs were further examined. In vivo, we assessed the therapeutic effect of upregulated DJ-1 on IDD by X-ray, MRI and Safranin O-Fast green staining. The protein expression of DJ-1 was significantly decreased in degenerated NPCs, accompanied by increased apoptosis. However, overexpression of DJ-1 significantly inhibited the elevated ROS levels and apoptosis in NPCs under oxidative stress. Mechanistically, our results showed that upregulation of DJ-1 promoted p62 degradation via the autophagic lysosomal pathway and that the protective effect of DJ-1 on NPCs under oxidative stress was partially mediated by promoting lysosomal pathway degradation of p62. Moreover, intradiscal injection of adeno-associated virus for overexpression of DJ-1 mitigated the progression of IDD in rats. This study reveals that DJ-1 maintains the homeostasis of NPCs by promoting the degradation of p62 through the autophagic lysosomal pathway, suggesting that DJ-1 is a promising new target for IDD intervention.

Prevalence, diagnosis, and impact on clinical outcomes of dural ossification in the thoracic ossification of the ligamentum flavum: a systematic review.

STUDY DESIGN: Systematic review. BACKGROUND CONTEXT: Thoracic ossification of the ligamentum flavum (TOLF) has become the principal cause of thoracic spinal stenosis. Dural ossification (DO) was a common clinical feature accompanying with TOLF. However, on account of the rarity, we know little about the DO in TOLF so far. PURPOSE: This study was conducted to elucidate the prevalence, diagnostic measures, and impact on the clinical outcomes of DO in TOLF by integrating the existing evidence. METHODS: PubMed, Embase, and Cochrane Database were comprehensively searched for studies relevant to the prevalence, diagnostic measures, or impact on the clinical outcomes of DO in TOLF. All retrieved studies meeting the inclusion and criterion were included into this systematic review. RESULTS: The prevalence of DO in TOLF treated surgically was 27% (281/1046), ranging from 11 to 67%. Eight diagnostic measures have been put forward to predict the DO in TOLF using the CT or MRI modalities, including "tram track sign", "comma sign", "bridge sign", "banner cloud sign", "T2 ring sign", TOLF-DO grading system, CSAOR grading system, and CCAR grading system. DO did not affect the neurological recovery of TOLF patients treated with the laminectomy. The rate of dural tear or CSF leakage in TOLF patients with DO was approximately 83% (149/180). CONCLUSION: The prevalence of DO in TOLF treated surgically was 27%. Eight diagnostic measures have been put forward to predict the DO in TOLF. DO did not affect the neurological recovery of TOLF treated with laminectomy but was associated with high risk of complications.

Identification and validation of ferroptosis-related gene signature in intervertebral disc degeneration.

Lower back pain (LBP) is a leading cause of disability in the elderly and intervertebral disc degeneration (IDD) is the major contributor to LBP. Ferroptosis is a newly discovered programmed cell death, characterized by iron-dependent lethal lipid peroxidation. Growing evidence has shown that ferroptosis plays important roles in various human diseases. However, the underlying mechanism of ferroptosis in IDD remains elusive. This study is aimed to uncover the key roles of ferroptosis in the pathogenesis and progression of IDD comprehensively. To investigate the ferroptosis related differentially expressed genes (FRDEGs) in IDD, we analyzed the microarray data from the Gene Expression Omnibus (GEO) database. Then we performed functional enrichment analysis and protein-protein interaction (PPI) network analysis, and screened out the hub FRDEGs. To further evaluate the predictive value of these hub FRDEGs, we performed ROC analysis based on the GSE124272 dataset. A total of 80 FRDEGs were identified, including 20 downregulated and 60 upregulated FRDEGs. The FRDEGs were primarily involved in the biological processes of response to chemical, and response to stress. KEGG pathway enrichment analysis showed that the FRDEGs were mainly involved in ferroptosis, TNF signaling pathway, HIF-1 signaling pathway, NOD-like receptor signaling pathway, and IL-17 signaling pathway. Ten hub OSRDEGs were obtained according to the PPI analysis, including HMOX1, KEAP1, MAPK1, HSPA5, TXNRD1, IL6, PPARA, JUN, HIF1A, DUSP1. The ROC analysis and RT-qPCR validation results suggested that most of the hub FRDEGs might be potential signature genes for IDD. This study reveals that ferroptosis might provide promising strategy for the diagnosis and treatment of IDD.

Incidence and risk factors of dural ossification in patients with thoracic ossification of the ligamentum flavum.

OBJECTIVE: Dural ossification (DO) is a common clinical feature in patients with thoracic ossification of the ligamentum flavum (OLF) and associated with the increased risk of perioperative complications. However, few studies have been conducted to determine the incidence and independent risk factors of DO in patients with thoracic OLF. The aim of this retrospective study was to determine the incidence and independent risk factors of DO in patients with thoracic OLF. METHODS: A total of 107 patients with thoracic OLF who were admitted to the authors' hospital from December 2020 to December 2021 were included in this study. The independent risk factors of DO in patients with thoracic OLF were determined through univariate analysis followed by multivariate logistic regression analysis with p < 0.05. The diagnostic efficacy of the DO in OLF (DO-OLF) risk classification model was determined on the basis of independent risk factors and evaluated on the basis of sensitivity, specificity, and agreement rate. RESULTS: The incidence of DO in patients with thoracic OLF was 35% (37/107 patients). The tuberous type according to the Sato classification (OR 9.75, p < 0.01) and larger (≥ 9°) supine local kyphosis angle (LKA) (OR 8.13, p < 0.01) were two independent risk factors of DO in thoracic OLF. The DO-OLF risk classification, a novel approach for the diagnosis of DO in patients with thoracic OLF, was established on the basis of the combination of the tuberous type according to the Sato classification and larger supine LKA. The sensitivity, specificity, and agreement rate of this approach for distinguishing between patients with thoracic OLF at high and low risk of DO were 87%, 93%, and 91%, respectively. CONCLUSIONS: The incidence of DO in patients with thoracic OLF was 35%. The tuberous type according to the Sato classification and larger supine LKA (≥ 9°) were independent risk factors of DO in patients with thoracic OLF. The novel DO-OLF risk classification approach could serve as an efficient method for predicting DO in patients with thoracic OLF.

Mesenchymal Stem Cells May Alleviate the Intervertebral Disc Degeneration by Reducing the Oxidative Stress in Nucleus Pulposus Cells.

Background: Stem cell therapy is a promising therapeutic modality for intervertebral disc degeneration (IDD). Oxidative stress is a vital contributor to the IDD; however, the definite role of oxidative stress in stem cell therapy for IDD remains obscure. The aim of this study was to determine the vital role of oxidative stress-related differentially expressed genes (OSRDEGs) in degenerative NPCs cocultured with mesenchymal stem cells (MSCs). Methods: A series of bioinformatic methods were used to calculate the oxidative stress score and autophagy score, identify the OSRDEGs, conduct the function enrichment analysis and protein-protein interaction (PPI) analysis, build the relevant competing endogenous RNA (ceRNA) regulatory networks, and explore the potential association between oxidative stress and autophagy in degenerative NPCs cocultured with MSCs. Results: There was a significantly different oxidative stress score between NPC/MSC samples and NPC samples (p < 0.05). Forty-one OSRDEGs were selected for the function enrichment and PPI analyses. Ten hub OSRDEGs were obtained according to the PPI score, including JUN, CAT, PTGS2, TLR4, FOS, APOE, EDN1, TXNRD1, LRRK2, and KLF2. The ceRNA regulatory network, which contained 17 DElncRNAs, 240 miRNAs, and 10 hub OSRDEGs, was constructed. Moreover, a significant relationship between the oxidative stress score and autophagy score was observed (p < 0.05), and 125 significantly related gene pairs were obtained (|r| > 0.90, p < 0.05). Conclusion: Stem cell therapy might repair the degenerative IVD via reducing the oxidative stress through the ceRNA regulatory work and restoration of autophagy in degenerative NPCs. This research could provide new insights into the mechanism research of stem cell therapy for IDD and potential therapeutic targets in the IDD treatment.

High Body Mass Index Is Associated with an Increased Risk of the Onset and Severity of Ossification of Spinal Ligaments.

Background: Ossification of the posterior longitudinal ligament (OPLL) and that of ligamentum flavum (OLF) are the main types of the ossification of spinal ligaments (OSL) that cause the thoracic myelopathy. Although several studies have investigated the relationship of body mass index (BMI) with the onset or severity of OSL, it remains unverified due to the contradictory results of existing evidence. A systematic review and meta-analysis were performed in this work to determine the relationship of BMI with the onset and severity of OSL. Methods: PubMed, EMBASE, Web of Science, and Cochrane Library were comprehensively searched online for relevant studies focusing on the relationship of BMI with the onset or severity of the OSL. The difference in BMI of OSL (or severe OSL group) and non-OSL (or nonsevere OSL group) groups was evaluated using the mean difference (MD) with a corresponding 95% confidence interval (CI). Results: Fifteen studies were included in this systematic review and meta-analysis. The BMI of the OSL group was significantly higher than that of the non-OSL group (MD = 1.70 kg/m2, 95% CI = 1.02-2.39 kg/m2, and P < 0.01). Similar results were observed in the subgroup analysis of female (P < 0.01), OPLL (P < 0.01), and OLF (P < 0.01) populations. Three studies reported a significant association of BMI with the ossification index of OSL and the standardized regression coefficient ranging from 0.11 to 0.43 (P < 0.05). Moreover, a significantly higher BMI was observed in the severe OSL group compared with that in the nonsevere OSL group (MD = 3.09, 95% CI, 0.22-5.97 kg/m2, and P = 0.04). Conclusion: The significant association of high BMI with the onset and severity of OSL may provide new evidence and insights into the mechanism research and management of OSL.

The Nrf2 antioxidant defense system in intervertebral disc degeneration: Molecular insights.

Intervertebral disc degeneration (IDD) is a common degenerative musculoskeletal disorder and is recognized as a major contributor to discogenic lower back pain. However, the molecular mechanisms underlying IDD remain unclear, and therapeutic strategies for IDD are currently limited. Oxidative stress plays pivotal roles in the pathogenesis and progression of many age-related diseases in humans, including IDD. Nuclear factor E2-related factor 2 (Nrf2) is a master antioxidant transcription factor that protects cells against oxidative stress damage. Nrf2 is negatively modulated by Kelch-like ECH-associated protein 1 (Keap1) and exerts important effects on IDD progression. Accumulating evidence has revealed that Nrf2 can facilitate the transcription of downstream antioxidant genes in disc cells by binding to antioxidant response elements (AREs) in promoter regions, including heme oxygenase-1 (HO-1), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and NADPH quinone dehydrogenase 1 (NQO1). The Nrf2 antioxidant defense system regulates cell apoptosis, senescence, extracellular matrix (ECM) metabolism, the inflammatory response of the nucleus pulposus (NP), and calcification of the cartilaginous endplates (EP) in IDD. In this review, we aim to discuss the current knowledge on the roles of Nrf2 in IDD systematically.

High Systemic Immune-Inflammation Index and Body Mass Index Are Independent Risk Factors of the Thoracic Ossification of the Ligamentum Flavum.

Background: Inflammation has been considered to play an important role in the pathogenesis of the thoracic ossification of the ligamentum flavum (OLF). However, the inflammation-related risk factors of thoracic OLF have not been fully investigated to date. Methods: A total of 95 patients (48 in the OLF group and 47 in the control group) were included in this retrospective study to explore the independent risk factors of thoracic OLF. The following demographic and clinical variables were compared between the two groups: gender, age, body mass index (BMI), coexistence of hypertension or diabetes, and inflammation-related variables. Multivariate logistic regression analysis was utilized to determine the independent risk factors. Results: High systemic immune-inflammation index (SII) (≥621) (odds ratio [OR] = 12.16, 95% confidence interval [CI] = 2.95-50.17, p < 0.01) and BMI (≥25 kg/m2) (OR = 9.17, 95%CI = 3.22-26.08, p < 0.01) were independent risk factors of thoracic OLF. SII (R = 0.38, p < 0.01) and BMI (R = 0.46, p < 0.01) were positively associated with OLF score. Conclusion: High SII and BMI were the independent risk factors of thoracic OLF. Multicenter prospective studies with a large population should be conducted in the future to verify our findings.

Oxidative Stress in Intervertebral Disc Degeneration: New Insights from Bioinformatic Strategies.

Oxidative stress has been proved to play important roles in the development of intervertebral disc degeneration (IDD); however, the underlying mechanism remains obscure to date. The aim of this study was to elucidate the vital roles of oxidative stress-related genes in the development of IDD using strict bioinformatic algorithms. The microarray data relevant to the IDD was downloaded from Gene Expression Omnibus database for further analysis. A series of bioinformatic strategies were used to determine the oxidative stress-related and IDD-related genes (OSIDDRGs), perform the function enrichment analysis and protein-protein interaction analysis, construct the lncRNA-miRNA-mRNA regulatory network, and investigate the potential relationship of oxidative stress to immunity abnormality and autophagy in IDD. We observed a significantly different status of oxidative stress between normal intervertebral disc tissues and IDD tissues. A total of 72 OSIDDRGs were screened out for the further function enrichment analysis, and 10 hub OSIDDRGs were selected to construct the lncRNA-miRNA-mRNA regulatory network. There was a very close association of oxidative stress with immunity abnormality and autophagy in IDD. Taken together, our findings can provide new insights into the mechanism research of oxidative stress in the development of IDD and offer new potential targets for the treatment strategies.

Factors associated with spinal fixation mechanical failure after tumor resection: a systematic review and meta-analysis.

BACKGROUND: No available meta-analysis has been published that systematically assessed spinal fixation mechanical failure after tumor resection based on largely pooled data. This systematic review and meta-analysis aimed to investigate the spinal fixation failure rate and potential risk factors for hardware failure. METHODS: Electronic articles published between January 1, 1979, and January 30, 2021, were searched and critically evaluated. The authors independently reviewed the abstracts and extracted data on the spinal fixation failure rate and potential risk factors. RESULTS: Thirty-eight studies were finally included in the meta-analysis. The pooled spinal fixation mechanical failure rate was 10%. The significant risk factors for hardware failure included tumor level and cage subsidence. Radiotherapy was a potential risk factor. CONCLUSION: The spinal fixation mechanical failure rate was 10%. Spinal fixation failure is mainly associated with tumor level, cage subsidence and radiotherapy. Durable reconstruction is needed for patients with these risk factors.

Epigenetic modifications in spinal ligament aging.

Spinal stenosis is a common degenerative spine disorder in the aged population and the spinal ligament aging is a main contributor to this chronic disease. However, the underlying mechanisms of spinal ligament aging remain unclear. Epigenetics is the study of heritable and reversible changes in the function of a gene or genome that occur without any alteration in the primary DNA sequence. Epigenetic alterations have been demonstrated to play crucial roles in age-related diseases and conditions, and they are recently studied as biomarkers and therapeutic targets in the field of cancer research. The main epigenetic modifications, including DNA methylation alteration, histone modifications as well as dysregulated noncoding RNA modulation, have all been implicated in spinal ligament aging diseases. DNA methylation modulates the expression of critical genes including WNT5A, GDNF, ACSM5, miR-497 and miR-195 during spinal ligament degeneration. Histone modifications widely affect gene expression and obvious histone modification abnormalities have been found in spinal ligament aging. MicroRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) exert crucial regulating effects on spinal ligament aging conditions via targeting various osteogenic or fibrogenic differentiation related genes. To our knowledge, there is no systematic review yet to summarize the involvement of epigenetic mechanisms of spinal ligament aging in degenerative spinal diseases. In this study, we systematically discussed the different epigenetic modifications and their potential functions in spinal ligament aging process.

Preoperative Denosumab may increase the Risk of Local Recurrence of Giant-cell Tumor of Bone Treated with Curettage: A Systematic Review and Meta-analysis.

Objective: This systematic review and meta-analysis aimed to determine the effect of preoperative denosumab on the local recurrence of giant-cell tumor of bone (GCTB) treated with curettage. Methods: PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched. The following data were analyzed using meta-analysis: local recurrence rate of patients receiving denosumab followed by curettage (denosumab group), local recurrence rate of patients receiving curettage only (control group), and a comparison of the local recurrence rates of the two groups. Results: Nine studies that contained 672 patients with GCTB were included in this review. Patients in the denosumab group (preoperative denosumab followed by curettage) had a higher risk of local recurrence compared with those in the control group (curettage only) (odds ratio = 3.04, 95% confidence interval = 1.48-6.22, P < 0.01). The association between preoperative denosumab and local recurrence remained significant in most of the subgroup analyses, except for those with sample sizes < 59 (P = 0.09), sacral GCTB (P = 0.42), and usage of postoperative denosumab (P = 0.38). Conclusions: Preoperative denosumab may increase the risk of local recurrence of GCTB treated with curettage and should be used with caution in the management of GCTB.

Risk factors for the local recurrence of giant cell tumours of the sacrum treated with nerve-sparing surgery.

AIMS: There is a lack of evidence about the risk factors for local recurrence of a giant cell tumour (GCT) of the sacrum treated with nerve-sparing surgery, probably because of the rarity of the disease. This study aimed to answer two questions: first, what is the rate of local recurrence of sacral GCT treated with nerve-sparing surgery and second, what are the risk factors for its local recurrence? METHODS: A total of 114 patients with a sacral GCT who underwent nerve-sparing surgery at our hospital between July 2005 and August 2017 were reviewed. The rate of local recurrence was determined, and Kaplan-Meier survival analysis carried out to evaluate the mean recurrence-free survival. Possible risks factors including demographics, tumour characteristics, adjuvant therapy, operation, and laboratory indices were analyzed using univariate analysis. Variables with p < 0.100 in the univariate analysis were further considered in a multivariate Cox regression analysis to identify the risk factors. RESULTS: The rate of local recurrence of sacral GCT treated with nerve-sparing surgery was 28.95% (33/114). Multivariate Cox regression analysis showed that large tumour size (> 8.80 cm) (hazard ratio (HR) 3.16; 95% confidence interval (CI) 1.27 to 7.87; p = 0.014), high neutrophil-to-lymphocyte ratio (NLR) (> 2.09) (HR 3.13; 95% CI 1.28 to 7.62; p = 0.012), involvement of a sacroiliac joint (HR 3.09; 95% CI 1.06 to 9.04; p = 0.039), and massive intraoperative blood loss (> 1,550 ml) (HR 2.47; 95% CI 1.14 to 5.36; p = 0.022) were independent risk factors for local recurrence. CONCLUSION: Patients with a sacral GCT who undergo nerve-sparing surgery have a local recurrence rate of 29%. Large tumour size, high NLR, involvement of a sacroiliac joint, and massive intraoperative blood loss are independent risk factors. Cite this article: Bone Joint J 2020;102-B(10):1392-1398.

Percutaneous Endoscopic Lumbar Discectomy (PELD) via a Transforaminal and Interlaminar Combined Approach for Very Highly Migrated Lumbar Disc Herniation (LDH) Between L4/5 and L5/S1 Level.

BACKGROUND Percutaneous endoscopic lumbar discectomy (PELD) has become one of the most popular minimally invasive surgeries for lumbar disc herniation (LDH), however, very highly migrated LDH is still a tricky issue for PELD. This study reported a new endoscopic discectomy strategy for the treatment of very highly migrated LDH between the L4/5 and L5/S1 level. MATERIAL AND METHODS The current study retrospectively analyzed 12 patients who accepted PELD for very highly migrated LDH between the L4/5 and L5/S1 level. Under local anesthesia, the transforaminal approach was chosen for the L4/5 level and the interlaminar approach was chosen for the L5/S1 level. The 10-point visual analogue scale (VAS) was used to assess back pain (VAS-Back) and leg pain (VAS-Leg). Oswestry disability index (ODI) and Modified Mac Nab Criteria were adopted as the functional evaluation methods. All patients were followed in the outpatient department for at least 12 months after their operation. RESULTS Our study showed that very highly migrated disc between L4/5 and L5/S1 level could be removed completely by this strategy. Except for 1 case of postoperative dysesthesia and 1 case of dural tear, no severe complication occurred. At the last follow-up, the average VAS-Back score of the study patients was reduced from 5.17±2.12 to 2.08±1.08 (P<0.05) and the average VAS-Leg score was reduced from 7.25±1.48 to 1.33±0.89 (P<0.05). The average ODI scores improved from 48.50±10.59 to 13.00±2.76 (P<0.05). According to the Modified Mac Nab Criteria, 83.33% of patients (10 out of 12 patients) received an excellent or good recovery and no poor result was reported. No recurrence was observed during follow up. CONCLUSIONS PELD via a transforaminal and interlaminar combined approach provides an alternative option for select patients with very highly migrated LDH between the L4/5 and L5/S1 level.

Feasibility of Virtual Reality Combined with Isocentric Navigation in Transforaminal Percutaneous Endoscopic Discectomy: A Cadaver Study.

OBJECTIVES: Transforaminal percutaneous endoscopic discectomy (TPED) is one of the most commonly used minimally invasive spine surgeries around the world. However, conventional surgical planning and intraoperative procedures for TPED have relied on surgeons' experience, which limits its standardization and popularization. Virtual reality (VR) is a novel technology for pre-surgical planning in various fields of medicine, while isocentric navigation can guide intraoperative procedures for TPED. The present study aimed to explore the feasibility of applying VR combined with isocentric navigation in TPED on cadavers. METHODS: The surgical levels were L3 /L4 and L4 /L5 as well as L5 /S1 of both sides of each cadaver specimen. First, the surgeon manually conducted the above procedures on the left side of every specimen without preoperative simulation and isocentric navigation (Group A). Then the same surgeon conducted the VR simulation for surgical planning of the right side (Group B). After VR simulation, the same surgeon made the percutaneous punctures and placed the working channel on the right side of the specimen at all levels. RESULTS: At the L3 /L4 level, the puncture-channel time was 11.36 ± 2.13 min in Group A and 11.29 ± 2.23 min in Group B (t = 0.097, P = 0.938). The exposure time was 17.21 ± 2.91 s in Group A and 14.64 ± 1.60 s in Group B (t = 2.534, P = 0.025). At the L4 /L5 level, the puncture-channel time was 13.86 ± 3.90 min in Group A and 11.93 ± 2.95 min in Group B (t = 2.291, P = 0.039). Exposure time was 20.64 ± 3.84 s in Group A and 16.43 ± 2.47 s in Group B (t = 6.118, P < 0.01). There were 7 patients undergoing foraminotomy in Group A and 3 patients undergoing foraminotomy in Group B (t = 2.280, P = 0.236). At the L5 /S1 level, the puncture-channel time was 18.21 ± 1.85 min in Group A and 15.71 ± 3.20 min in Group B (t = 2.476, P = 0.028). Exposure time was 26.07 ± 3.17 s in Group A and 22.50 ± 2.68 s in Group B (t = 2.980, P = 0.011). There were 14 patients receiving foraminotomy in Group A and 13 patients receiving foraminotomy in Group B (t = 1.000, P = 1.000). CONCLUSIONS: Virtual reality combined with isocentric navigation is feasible in TPED. It enables precise surgical planning and improves intraoperative procedures, and has the potential for application in clinical practice.

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis.

Molecular target anticancer drugs are commonly used in various forms of cancers. It is a concern that the risk of serious adverse events (SAEs) and fatal adverse events (FAEs) of molecular target drugs are increasing. An up-to-date meta-analysis of all Phase II/III/IV randomized trials of molecular target anticancer drugs was conducted to calculate the increased risk of SAEs and FAEs. A systematic search of PubMed, Web of Science, and Cochrane Library up to April 6, 2017, was conducted. The study enrolled Phase II/III/IV randomized trials of cancer that compared molecular target drugs alone versus placebo or performed single-arm analysis of molecular target drugs. Data on SAEs and FAEs were extracted from the included studies and pooled to compute risk ratio (RR), the overall incidence, and 95% confidence interval (CI). In this meta-analysis, a total of 19,965 and 26,642 patients in randomized 53 and 65 Phase II/II/IV trials were included in the analysis of SAEs and FAEs associated with molecular target anticancer drug, respectively. There were significant differences in the relationship of molecular target anticancer drugs with SAEs (RR = 1.57, 95% CI = 1.35-1.82, P < 0.01, I2 = 81%) and FAEs (RR = 1.51, 95% CI = 1.19-1.91, P < 0.01, I2 = 0%) compared to placebo. The overall incidence of SAEs and FAEs was 0.269 (95% CI = 0.262-0.276, P < 0.01) and 0.023 (95% CI = 0.020-0.025, P < 0.01), respectively. Molecular target anticancer drugs significantly increased the risk of SAEs and FAEs. For patients taking molecular target drugs, efforts are needed to prevent the occurrence of SAEs and FAEs.

Reduced Radiation Exposure and Puncture Time of Percutaneous Transpedicular Puncture with Real-Time Ultrasound Volume Navigation.

OBJECTIVES: The present study introduced ultrasound volume navigation (UVN) to reduce the radiation exposure and puncture time of percutaneous transpedicular puncture in percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP). METHODS: We retrospectively reviewed the medical records of patients with osteoporotic vertebral compression fracture who had undergone PVP or PKP guided by UVN or fluoroscopy from September 2017 to December 2017. RESULTS: We enrolled 10 patients (6 women, 4 men) with 24 pedicles involved in the present study. Significant reductions in fluoroscopy frequency (2.58 vs. 17.42; P < 0.01), exposure time (2.36 vs. 15.69 seconds; P < 0.01), and puncture time (4.13 vs. 19.21 minutes; P < 0.01) for each pedicle were observed in the UVN group compared with the fluoroscopy group. Obvious correlations among fluoroscopy frequency, exposure time, and puncture time for each pedicle were observed (P < 0.01). The visual analog scale scores and Oswestry Disability Index were both significantly improved after the procedures. All patients achieved excellent or good clinical outcomes. No complications were observed in any patient. CONCLUSIONS: UVN could obviously reduce the radiation exposure and puncture time of percutaneous transpedicular puncture in PVP and PKP.

Guided Punctures with Ultrasound Volume Navigation in Percutaneous Transforaminal Endoscopic Discectomy: A Technical Note.

OBJECTIVE: Ultrasound volume navigation (UVN) has been widely used for accurate guidance and decreased radiation exposure. However, few studies have focused on the clinical significance of UVN in guiding percutaneous puncture in percutaneous transforaminal endoscopic discectomy (PTED). We evaluated UVN to guide percutaneous puncture in PTED. METHODS: We retrospectively reviewed the medical records of 12 patients (8 men and 4 women), who had undergone PTED with the help of UVN or fluoroscopic guidance for lumbar disc herniation from November 2017 to December 2017. RESULTS: The age of these 12 patients range was 26-71 years, and the body mass index range was 18.19-26.91 kg/m2. Of the 12 patients, 6 were in UVN group and 6 were in fluoroscopy group. The mean number of punctures was 1.00 in UVN group and 3.83 in fluoroscopy group. The mean exposure time was 3.60 and 13.80 seconds in UVN and fluoroscopy groups, respectively. The mean operation time was 48.17 minutes and 61.33 minutes in UVN and fluoroscopy groups, respectively. A positive relationship was found between operation time and exposure time (P < 0.05). All patients achieved excellent or good clinical outcomes. The Oswestry Disability Index and visual analog scales for leg pain and back pain all showed significant improvement after the procedure (P < 0.05). None of patients experienced a complication. CONCLUSIONS: UVN decreased the number of puncture attempts, radiation exposure, and operation time compared with fluoroscopic guidance in PTED. Therefore, UVN is a feasible and efficient method for guiding percutaneous puncture in PTED.